CFGparadigms - User contributions [en]

Galectin-9

2012-01-22T01:05:38Z

Anna Crie:

Galectin-9 is one of the best-studied of the tandem-repeat galectins with glycan binding in both the N- and C-terminal domains <ref name="Wada 1997">Wada J, Kanwar YS. Identification and characterization of galectin-9, a novel beta-galactoside-binding mammalian lectin. J Biol Chem. 1997;272(9):6078-86</ref>. The protein lacks a signal sequence, like most galectins, and is synthesized in the cytosol on free polyribosomes. Galectin-9 is found outside of cells and may be exported by non-classical pathways. Galectin-9 exhibits a variety of biological activities, the majority of which have focused on its immunomodulatory role toward lymphocytes, were it shows specific interactions with TIM-3, and can negatively regulate Th1 type immunity<ref name="Zhu 2005">Zhu C, Anderson AC, Schubart A, Xiong H, Imitola J, Khoury SJ, Zheng XX, Strom TB, Kuchroo VK. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol. 2005;6(12):1245-52.</ref>. Mammalian galectin-9 exhibits affinity toward select glycan ligands, including sulfated glycans, and blood group-related glycans, and also interacts with glycans containing poly-N-acetyllactosamine (LacNAc) repeats (-3Galβ1-4GlcNAcβ1-)n through recognition of internal LacNAc repeats <ref name="Nagae 2008">Nagae M, Nishi N, Nakamura-Tsuruta S, Hirabayashi J, Wakatsuki S, Kato R. Structural analysis of the human galectin-9 N-terminal carbohydrate recognition domain reveals unexpected properties that differ from the mouse orthologue. J Mol Biol. 2008;375(1):119-35</ref>.

The crystal structure of the N-terminal carbohydrate recognition domain (CRD) been defined
<ref name="Nagae 2008"/><ref name="Yoshida 2010">Yoshida H, Teraoka M, Nishi N, Nakakita S, Nakamura T, Hirashima M, Kamitori S. X-ray structures of human galectin-9 C-terminal domain in complexes with a biantennary oligosaccharide and sialyllactose. J Biol Chem. 2010;285(47):36969-76. </ref><ref name="Nagae 2006">Nagae M, Nishi N, Murata T, Usui T, Nakamura T, Wakatsuki S, Kato R. Crystal structure of the galectin-9 N-terminal carbohydrate recognition domain from Mus musculus reveals the basic mechanism of carbohydrate recognition. J Biol Chem. 2006;281(47):35884-93.</ref>. The GBP shows strong interactions in a metal-free manner with poly-N-acetyllactosamine sequences comprised of repeating (-3Galβ1-4GlcNAcβ1-)n by recognizing internal N-acetyllactosamine repeats<ref name="Nagae 2008"/>. Generally, it binds distinct glycan ligands from [[Galectin-1]]<ref name="Bi 2008">Bi S, Earl LA, Jacobs L, Baum LG. Structural features of galectin-9 and galectin-1 that determine distinct T cell death pathways. J Biol Chem. 2008;283(18):12248-58</ref>. There are has three well-characterized linker domains between the CRDs, generated by alternative splicing<ref name="Nishi 2006">Nishi N, Itoh A, Shoji H, Miyanaka H, Nakamura T. Galectin-8 and galectin-9 are novel substrates for thrombin. Glycobiology. 2006;16(11):15C-20C.</ref>, that may regulate cellular localization and function of the protein. Truncation of linker domain between CRDs in recombinant forms of galectin-9 stabilize the protein to proteolysis<ref name="Nishi 2005">Nishi N, Itoh A, Fujiyama A, Yoshida N, Araya S, Hirashima M, Shoji H, Nakamura T. Development of highly stable galectins: truncation of the linker peptide confers protease-resistance on tandem-repeat type galectins. FEBS Lett. 2005;579(10):2058-64</ref>.

== CFG Participating Investigators contributing to the understanding of this paradigm ==
CFG Participating Investigators (PIs) contributing to the understanding of Galectin-9 include: Linda Baum, Richard Cummings, Gabriel Rabinovich, Sachiko Sato

== Progress toward understanding this GBP paradigm ==
This section documents what is currently known about Galectin-9, its carbohydrate ligand(s), and how they interact to mediate cell communication. Further information can be found in the GBP Molecule Page for [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_hum_Stlect_00120&sideMenu=no human] and [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_1307&sideMenu=no mouse] Galectin-9 in the CFG database.
=== Carbohydrate ligands ===

Human galectin-9 binding to glycans has been studied by a variety of techniques including glycan microarray analysis and frontal affinity chromatography.

On the CFG glycan microarray, the individual N- and C-terminal domains of recombinant dog (Canis lupus) galectin-9, generated as GST (glutathione-S-transferase) chimeras, showed similarities in glycan recognition, but also distinct differences<ref name="Poland 2011">Poland PA, Rondanino C, Kinlough CL, Heimburg-Molinaro J, Arthur CM, Stowell SR, Smith DF, Hughey RP. Identification and characterization of endogenous galectins expressed in Madin Darby canine kidney cells. J Biol Chem. 2011;286(8):6780-90</ref>. While both domains bound well to short sulfated glycans, such as 3-O-sulfated galactose in short LacNAc structures, only the N-terminal domain bound well to many glycans expressing blood group A-related sequences and to the Forssman glycolipid-like glycans, whereas the C-terminal domain bound less well to the blood group related structures, but showed binding to a linear sialylated poly-N-acetyllactosamine pentasaccharide.

In frontal affinity chromatography, recombinant human galectin-9 was found to preferentially bind to both branched N-glycans (Kd = 0.16 μM toward tetraantennary N-glycans terminating in galactose) and glycans with poly-N-acetyllactosamine sequences (Kd = 0.09 μM toward octasaccharides with 4 repeating LacNAc groups, and this was found for both the N- and C-terminal domains. By contrast, the N-terminal, but not the C-terminal domain, showed significant binding in the low μM range to Forssman glycolipid-derived pentasaccharides and to blood group A hexasaccharide<ref name="Hirabayashi 2012">Hirabayashi J, Hashidate T, Arata Y, Nishi N, Nakamura T, Hirashima M, Urashima T, Oka T, Futai M, Muller WE, Yagi F, Kasai K. Oligosaccharide specificity of galectins: a search by frontal affinity chromatography. Biochim Biophys Acta. 2002;1572(2-3):232-54</ref>.

Glycan microarray analyses in microarrays with relatively short glycan species<ref name="Horlacher 2010">Horlacher T, Oberli MA, Werz DB, Krock L, Bufali S, Mishra R, Sobek J, Simons K, Hirashima M, Niki T, Seeberger PH. Determination of carbohydrate-binding preferences of human galectins with carbohydrate microarrays. Chembiochem. 2010;11(11):1563-73</ref>, showed that both the recombinant full-length human galectin-9 and the N-terminal domain displayed very similar binding patterns, and both bound to LacNAc sequences and even better to short fucosylated glycans with terminal blood group A and B trisaccharide sequences.

=== Cellular expression of GBP and ligands ===

Galectin-9 is widely expressed in various tissues (heart, lung, liver, kidney, spleen, muscle, intestine, and thymus), but weakly expressed in brain<ref name="Wada 1997">Wada J, Ota K, Kumar A, Wallner EI, Kanwar YS. Developmental regulation, expression, and apoptotic potential of galectin-9, a beta-galactoside binding lectin. J Clin Invest. 1997;99(10):2452-61</ref>. Interestingly, the rat urate transporter was reported to be 99% identical to the sequence reported for rat galectin-9 <ref name="Leal-Pinto 1997">Leal-Pinto E, Tao W, Rappaport J, Richardson M, Knorr BA, Abramson RG. Molecular cloning and functional reconstitution of a urate transporter/channel. J Biol Chem. 1997;272(1):617-25</ref>, suggesting that these two proteins are the same<ref name="Lipkowitz 2001">Lipkowitz MS, Leal-Pinto E, Rappoport JZ, Najfeld V, Abramson RG. Functional reconstitution, membrane targeting, genomic structure, and chromosomal localization of a human urate transporter. J Clin Invest. 2001;107(9):1103-15.</ref><ref name="Lipkowitz 2004">Lipkowitz MS, Leal-Pinto E, Cohen BE, Abramson RG. Galectin 9 is the sugar-regulated urate transporter/channel UAT. Glycoconj J. 2004;19(7-9):491-8</ref>, and suggest that galectin-9 may have multiple functions, occurring as a polytopic transmembrane protein to function as the urate transporter, and as a soluble protein in its signaling and cell-binding forms.

=== Biosynthesis of ligands ===

 
=== Structure ===
Galectin-9 (long isoform in humans) has 355 amino acids and behaves as an ~35 kDa protein; short isoforms differ in the linker peptide length and have lower apparent sizes compared to the full-length long isoform.
The crystal structure of the N-terminal carbohydrate recognition domain (CRD) been defined.<ref name="Nagae 2010">Nagae M, Nishi N, Nakamura-Tsuruta S, Hirabayashi J, Wakatsuki S, Kato R. Structural analysis of the human galectin-9 N-terminal carbohydrate recognition domain reveals unexpected properties that differ from the mouse orthologue. J Mol Biol. 2008;375(1):119-35.</ref><ref name="Yoshida 2008">Yoshida H, Teraoka M, Nishi N, Nakakita S, Nakamura T, Hirashima M, Kamitori S. X-ray structures of human galectin-9 C-terminal domain in complexes with a biantennary oligosaccharide and sialyllactose. J Biol Chem. 2010;285(47):36969-76. </ref><ref name="Nagae 2006">Nagae M, Nishi N, Murata T, Usui T, Nakamura T, Wakatsuki S, Kato R. Crystal structure of the galectin-9 N-terminal carbohydrate recognition domain from Mus musculus reveals the basic mechanism of carbohydrate recognition. J Biol Chem. 2006;281(47):35884-93.</ref>
The GBP shows strong interactions in a metal-free manner with poly-N-acetyllactosamine sequences comprised of repeating (-3Galβ1-4GlcNAcβ1-)n by recognizing internal N-acetyllactosamine repeats <ref name="Nagae 2010"/>. Generally, it binds distinct glycan ligands from Galectin-1 <ref name="Bi 2008">Bi S, Earl LA, Jacobs L, Baum LG. Structural features of galectin-9 and galectin-1 that determine distinct T cell death pathways. J Biol Chem. 2008;283(18):12248-58.</ref>). There are has three well-characterized linker domains between the CRDs, generated by alternative splicing <ref name="Nishi 2006">Nishi N, Itoh A, Shoji H, Miyanaka H, Nakamura T. Galectin-8 and galectin-9 are novel substrates for thrombin. Glycobiology. 2006;16(11):15C-20C</ref>, that may regulate cellular localization and function of the protein. Truncation of linker domain between CRDs in recombinant forms of galectin-9 stabilize the protein to proteolysis <ref name="Nishi 2005">Nishi N, Itoh A, Fujiyama A, Yoshida N, Araya S, Hirashima M, Shoji H, Nakamura T. Development of highly stable galectins: truncation of the linker peptide confers protease-resistance on tandem-repeat type galectins. FEBS Lett. 2005;579(10):2058-64</ref>.

=== Biological roles of GBP-ligand interaction ===
It has been shown that galectin-9 binds to a unique glycoprotein ligand Tim-3 expressed in Th1 and Th17 cells<ref name="Seki 2008">Seki M, Oomizu S, Sakata KM, Sakata A, Arikawa T, Watanabe K, Ito K, Takeshita K, Niki T, Saita N, Nishi N, Yamauchi A, Katoh S, Matsukawa A, Kuchroo V, Hirashima M. Galectin-9 suppresses the generation of Th17, promotes the induction of regulatory T cells, and regulates experimental autoimmune arthritis. Clin Immunol. 2008;127(1):78-88.</ref><ref name="Niwa 2009">Niwa H, Satoh T, Matsushima Y, Hosoya K, Saeki K, Niki T, Hirashima M, Yokozeki H. Stable form of galectin-9, a Tim-3 ligand, inhibits contact hypersensitivity and psoriatic reactions: a potent therapeutic tool for Th1- and/or Th17-mediated skin inflammation. Clin Immunol. 2009;132(2):184-94.</ref><ref name="Naka 2009">Naka EL, Ponciano VC, Cenedeze MA, Pacheco-Silva A, Camara NO. Detection of the Tim-3 ligand, galectin-9, inside the allograft during a rejection episode. Int Immunopharmacol. 2009;9(6):658-62.</ref><ref name="Anderson 2007">Anderson DE. TIM-3 as a therapeutic target in human inflammatory diseases. Expert Opin Ther Targets. 2007;11(8):1005-9.</ref>. In addition, galectin-9 can interact with protein disulfide isomerase (PDI) at the cell surface, increasing retention of PDI on the surface and altering surface redox potential<ref name="Bi 2011">Bi S, Hong PW, Lee B, Baum LG. Galectin-9 binding to cell surface protein disulfide isomerase regulates the redox environment to enhance T-cell migration and HIV entry. Proc Natl Acad Sci U S A. 2011;108(26):10650-5</ref>. Galectin-9 null-mice have interesting phenotypes related to immune regulation. Galectin-9 null-mice develop acute and memory responses to Herpes Simplex Virus (HSV) that are of greater magnitude and better quality than those that occur in wild-type infected animals<ref name="Sehrawat 2010">Sehrawat S, Reddy PB, Rajasagi N, Suryawanshi A, Hirashima M, Rouse BT. Galectin-9/TIM-3 interaction regulates virus-specific primary and memory CD8 T cell response. PLoS Pathog. 2010;6(5):e1000882.</ref>; they exhibit increased resistance to influenza A virus compared to wild-type mice <ref name="Sharma 2011">Sharma S, Sundararajan A, Suryawanshi A, Kumar N, Veiga-Parga T, Kuchroo VK, Thomas PG, Sangster MY, Rouse BT. T cell immunoglobulin and mucin protein-3 (Tim-3)/Galectin-9 interaction regulates influenza A virus-specific humoral and CD8 T-cell responses. Proc Natl Acad Sci U S A. 2011;108(47):19001-6</ref>; and they exhibit susceptibility to experimentally-induced autoimmune disease <ref name="Seki 2008"/>. Galectin-9 expression is elevated in peripheral blood mononuclear cells (PBMCs) in patients with systemic lupus erythematosus<ref name="Wang 2008">Wang Y, Meng J, Wang X, Liu S, Shu Q, Gao L, Ju Y, Zhang L, Sun W, Ma C. Expression of human TIM-1 and TIM-3 on lymphocytes from systemic lupus erythematosus patients. Scand J Immunol. 2008;67(1):63-70</ref>. Galectin-9 is the only tandem-repeat galectin that has been administered in animal models of disease to assess therapeutic potential <ref name="Seki 2008"/><ref name="Tsuchiyama 2000">Tsuchiyama Y, Wada J, Zhang H, Morita Y, Hiragushi K, Hida K, Shikata K, Yamamura M, Kanwar YS, Makino H. Efficacy of galectins in the amelioration of nephrotoxic serum nephritis in Wistar Kyoto rats. Kidney Int. 2000;58(5):1941-52.</ref><ref name="Baba 2005">Baba M, Wada J, Eguchi J, Hashimoto I, Okada T, Yasuhara A, Shikata K, Kanwar YS, Makino H. Galectin-9 inhibits glomerular hypertrophy in db/db diabetic mice via cell-cycle-dependent mechanisms. J Am Soc Nephrol. 2005;16(11):3222-34.</ref>. Galectin-9 exhibits the ability induce apoptosis in some lymphocytes <ref name="Zhu 2005">Zhu C, Anderson AC, Schubart A, Xiong H, Imitola J, Khoury SJ, Zheng XX, Strom TB, Kuchroo VK. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol. 2005;6(12):1245-52.</ref><ref name="Bi 2011">Bi S, Hong PW, Lee B, Baum LG. Galectin-9 binding to cell surface protein disulfide isomerase regulates the redox environment to enhance T-cell migration and HIV entry. Proc Natl Acad Sci U S A. 2011;108(26):10650-5.</ref> and this can be inhibited by inclusion of lactose or inhibitors. Galectin-9 has eosinophil chemoattractant activity (26), and the term Ecalectin was given to a variant of T lymphocyte-derived galectin-9 that was found to be an eosinophil chemoattractant <ref name="Matsumoto 1998">Matsumoto R, Matsumoto H, Seki M, Hata M, Asano Y, Kanegasaki S, Stevens RL, Hirashima M. Human ecalectin, a variant of human galectin-9, is a novel eosinophil chemoattractant produced by T lymphocytes. J Biol Chem. 1998;273(27):16976-84</ref>.

== CFG resources used in investigations ==
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=galectin-9&maxresults=20 CFG database search results for Galectin-9].

=== Glycan profiling ===

 
=== Glycogene microarray ===
Probes for human galectin-9 have been included in all versions of the CFG glycogene chip, and probes for mouse galectin-9 are included on versions 2, 3, and 4.
 

=== Knockout mouse lines ===
CFG-generated [http://www.functionalglycomics.org/static/consortium/resources/DataCoreFGJb4.shtml Galectin-9 knockout mice] have been used to study the biological functions of this paradigm GBP. [http://www.functionalglycomics.org/glycomics/publicdata/investigator.jsp?investigator=judyteale (CFG PI data)]
 

=== Glycan array ===
Investigators have used CFG carbohydrate compounds and glycan array screening to study ligand binding specificity of Galectin-9 (for example, click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2735 here]). To see all glycan array results for Galectin-9, click [http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=galectin-9&cat=coreh here].

== Related GBPs ==
Galectin-4 [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=galectin-4&maxresults=20 (CFG data)], galectin-6, galectin-8 [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=galectin-8&maxresults=20 (CFG data)], and galectin-12 [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=galectin-12&maxresults=20 (CFG data)].

== References ==
<references/>

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: Linda Baum, Richard Cummings

Galectin-9

2012-01-22T01:05:05Z

Anna Crie:

Galectin-9 is one of the best-studied of the tandem-repeat galectins with glycan binding in both the N- and C-terminal domains <ref name="Wada 1997">Wada J, Kanwar YS. Identification and characterization of galectin-9, a novel beta-galactoside-binding mammalian lectin. J Biol Chem. 1997;272(9):6078-86</ref>. The protein lacks a signal sequence, like most galectins, and is synthesized in the cytosol on free polyribosomes. Galectin-9 is found outside of cells and may be exported by non-classical pathways. Galectin-9 exhibits a variety of biological activities, the majority of which have focused on its immunomodulatory role toward lymphocytes, were it shows specific interactions with TIM-3, and can negatively regulate Th1 type immunity<ref name="Zhu 2005">Zhu C, Anderson AC, Schubart A, Xiong H, Imitola J, Khoury SJ, Zheng XX, Strom TB, Kuchroo VK. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol. 2005;6(12):1245-52.</ref>. Mammalian galectin-9 exhibits affinity toward select glycan ligands, including sulfated glycans, and blood group-related glycans, and also interacts with glycans containing poly-N-acetyllactosamine (LacNAc) repeats (-3Galβ1-4GlcNAcβ1-)n through recognition of internal LacNAc repeats <ref name="Nagae 2008">Nagae M, Nishi N, Nakamura-Tsuruta S, Hirabayashi J, Wakatsuki S, Kato R. Structural analysis of the human galectin-9 N-terminal carbohydrate recognition domain reveals unexpected properties that differ from the mouse orthologue. J Mol Biol. 2008;375(1):119-35</ref>).

The crystal structure of the N-terminal carbohydrate recognition domain (CRD) been defined
<ref name="Nagae 2008"/><ref name="Yoshida 2010">Yoshida H, Teraoka M, Nishi N, Nakakita S, Nakamura T, Hirashima M, Kamitori S. X-ray structures of human galectin-9 C-terminal domain in complexes with a biantennary oligosaccharide and sialyllactose. J Biol Chem. 2010;285(47):36969-76. </ref><ref name="Nagae 2006">Nagae M, Nishi N, Murata T, Usui T, Nakamura T, Wakatsuki S, Kato R. Crystal structure of the galectin-9 N-terminal carbohydrate recognition domain from Mus musculus reveals the basic mechanism of carbohydrate recognition. J Biol Chem. 2006;281(47):35884-93.</ref>. The GBP shows strong interactions in a metal-free manner with poly-N-acetyllactosamine sequences comprised of repeating (-3Galβ1-4GlcNAcβ1-)n by recognizing internal N-acetyllactosamine repeats<ref name="Nagae 2008"/>. Generally, it binds distinct glycan ligands from [[Galectin-1]]<ref name="Bi 2008">Bi S, Earl LA, Jacobs L, Baum LG. Structural features of galectin-9 and galectin-1 that determine distinct T cell death pathways. J Biol Chem. 2008;283(18):12248-58</ref>. There are has three well-characterized linker domains between the CRDs, generated by alternative splicing<ref name="Nishi 2006">Nishi N, Itoh A, Shoji H, Miyanaka H, Nakamura T. Galectin-8 and galectin-9 are novel substrates for thrombin. Glycobiology. 2006;16(11):15C-20C.</ref>, that may regulate cellular localization and function of the protein. Truncation of linker domain between CRDs in recombinant forms of galectin-9 stabilize the protein to proteolysis<ref name="Nishi 2005">Nishi N, Itoh A, Fujiyama A, Yoshida N, Araya S, Hirashima M, Shoji H, Nakamura T. Development of highly stable galectins: truncation of the linker peptide confers protease-resistance on tandem-repeat type galectins. FEBS Lett. 2005;579(10):2058-64</ref>.

== CFG Participating Investigators contributing to the understanding of this paradigm ==
CFG Participating Investigators (PIs) contributing to the understanding of Galectin-9 include: Linda Baum, Richard Cummings, Gabriel Rabinovich, Sachiko Sato

== Progress toward understanding this GBP paradigm ==
This section documents what is currently known about Galectin-9, its carbohydrate ligand(s), and how they interact to mediate cell communication. Further information can be found in the GBP Molecule Page for [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_hum_Stlect_00120&sideMenu=no human] and [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_1307&sideMenu=no mouse] Galectin-9 in the CFG database.
=== Carbohydrate ligands ===

Human galectin-9 binding to glycans has been studied by a variety of techniques including glycan microarray analysis and frontal affinity chromatography.

On the CFG glycan microarray, the individual N- and C-terminal domains of recombinant dog (Canis lupus) galectin-9, generated as GST (glutathione-S-transferase) chimeras, showed similarities in glycan recognition, but also distinct differences<ref name="Poland 2011">Poland PA, Rondanino C, Kinlough CL, Heimburg-Molinaro J, Arthur CM, Stowell SR, Smith DF, Hughey RP. Identification and characterization of endogenous galectins expressed in Madin Darby canine kidney cells. J Biol Chem. 2011;286(8):6780-90</ref>. While both domains bound well to short sulfated glycans, such as 3-O-sulfated galactose in short LacNAc structures, only the N-terminal domain bound well to many glycans expressing blood group A-related sequences and to the Forssman glycolipid-like glycans, whereas the C-terminal domain bound less well to the blood group related structures, but showed binding to a linear sialylated poly-N-acetyllactosamine pentasaccharide.

In frontal affinity chromatography, recombinant human galectin-9 was found to preferentially bind to both branched N-glycans (Kd = 0.16 μM toward tetraantennary N-glycans terminating in galactose) and glycans with poly-N-acetyllactosamine sequences (Kd = 0.09 μM toward octasaccharides with 4 repeating LacNAc groups, and this was found for both the N- and C-terminal domains. By contrast, the N-terminal, but not the C-terminal domain, showed significant binding in the low μM range to Forssman glycolipid-derived pentasaccharides and to blood group A hexasaccharide<ref name="Hirabayashi 2012">Hirabayashi J, Hashidate T, Arata Y, Nishi N, Nakamura T, Hirashima M, Urashima T, Oka T, Futai M, Muller WE, Yagi F, Kasai K. Oligosaccharide specificity of galectins: a search by frontal affinity chromatography. Biochim Biophys Acta. 2002;1572(2-3):232-54</ref>.

Glycan microarray analyses in microarrays with relatively short glycan species<ref name="Horlacher 2010">Horlacher T, Oberli MA, Werz DB, Krock L, Bufali S, Mishra R, Sobek J, Simons K, Hirashima M, Niki T, Seeberger PH. Determination of carbohydrate-binding preferences of human galectins with carbohydrate microarrays. Chembiochem. 2010;11(11):1563-73</ref>, showed that both the recombinant full-length human galectin-9 and the N-terminal domain displayed very similar binding patterns, and both bound to LacNAc sequences and even better to short fucosylated glycans with terminal blood group A and B trisaccharide sequences.

=== Cellular expression of GBP and ligands ===

Galectin-9 is widely expressed in various tissues (heart, lung, liver, kidney, spleen, muscle, intestine, and thymus), but weakly expressed in brain<ref name="Wada 1997">Wada J, Ota K, Kumar A, Wallner EI, Kanwar YS. Developmental regulation, expression, and apoptotic potential of galectin-9, a beta-galactoside binding lectin. J Clin Invest. 1997;99(10):2452-61</ref>. Interestingly, the rat urate transporter was reported to be 99% identical to the sequence reported for rat galectin-9 <ref name="Leal-Pinto 1997">Leal-Pinto E, Tao W, Rappaport J, Richardson M, Knorr BA, Abramson RG. Molecular cloning and functional reconstitution of a urate transporter/channel. J Biol Chem. 1997;272(1):617-25</ref>, suggesting that these two proteins are the same<ref name="Lipkowitz 2001">Lipkowitz MS, Leal-Pinto E, Rappoport JZ, Najfeld V, Abramson RG. Functional reconstitution, membrane targeting, genomic structure, and chromosomal localization of a human urate transporter. J Clin Invest. 2001;107(9):1103-15.</ref><ref name="Lipkowitz 2004">Lipkowitz MS, Leal-Pinto E, Cohen BE, Abramson RG. Galectin 9 is the sugar-regulated urate transporter/channel UAT. Glycoconj J. 2004;19(7-9):491-8</ref>, and suggest that galectin-9 may have multiple functions, occurring as a polytopic transmembrane protein to function as the urate transporter, and as a soluble protein in its signaling and cell-binding forms.

=== Biosynthesis of ligands ===

 
=== Structure ===
Galectin-9 (long isoform in humans) has 355 amino acids and behaves as an ~35 kDa protein; short isoforms differ in the linker peptide length and have lower apparent sizes compared to the full-length long isoform.
The crystal structure of the N-terminal carbohydrate recognition domain (CRD) been defined.<ref name="Nagae 2010">Nagae M, Nishi N, Nakamura-Tsuruta S, Hirabayashi J, Wakatsuki S, Kato R. Structural analysis of the human galectin-9 N-terminal carbohydrate recognition domain reveals unexpected properties that differ from the mouse orthologue. J Mol Biol. 2008;375(1):119-35.</ref><ref name="Yoshida 2008">Yoshida H, Teraoka M, Nishi N, Nakakita S, Nakamura T, Hirashima M, Kamitori S. X-ray structures of human galectin-9 C-terminal domain in complexes with a biantennary oligosaccharide and sialyllactose. J Biol Chem. 2010;285(47):36969-76. </ref><ref name="Nagae 2006">Nagae M, Nishi N, Murata T, Usui T, Nakamura T, Wakatsuki S, Kato R. Crystal structure of the galectin-9 N-terminal carbohydrate recognition domain from Mus musculus reveals the basic mechanism of carbohydrate recognition. J Biol Chem. 2006;281(47):35884-93.</ref>
The GBP shows strong interactions in a metal-free manner with poly-N-acetyllactosamine sequences comprised of repeating (-3Galβ1-4GlcNAcβ1-)n by recognizing internal N-acetyllactosamine repeats <ref name="Nagae 2010"/>. Generally, it binds distinct glycan ligands from Galectin-1 <ref name="Bi 2008">Bi S, Earl LA, Jacobs L, Baum LG. Structural features of galectin-9 and galectin-1 that determine distinct T cell death pathways. J Biol Chem. 2008;283(18):12248-58.</ref>). There are has three well-characterized linker domains between the CRDs, generated by alternative splicing <ref name="Nishi 2006">Nishi N, Itoh A, Shoji H, Miyanaka H, Nakamura T. Galectin-8 and galectin-9 are novel substrates for thrombin. Glycobiology. 2006;16(11):15C-20C</ref>, that may regulate cellular localization and function of the protein. Truncation of linker domain between CRDs in recombinant forms of galectin-9 stabilize the protein to proteolysis <ref name="Nishi 2005">Nishi N, Itoh A, Fujiyama A, Yoshida N, Araya S, Hirashima M, Shoji H, Nakamura T. Development of highly stable galectins: truncation of the linker peptide confers protease-resistance on tandem-repeat type galectins. FEBS Lett. 2005;579(10):2058-64</ref>.

=== Biological roles of GBP-ligand interaction ===
It has been shown that galectin-9 binds to a unique glycoprotein ligand Tim-3 expressed in Th1 and Th17 cells<ref name="Seki 2008">Seki M, Oomizu S, Sakata KM, Sakata A, Arikawa T, Watanabe K, Ito K, Takeshita K, Niki T, Saita N, Nishi N, Yamauchi A, Katoh S, Matsukawa A, Kuchroo V, Hirashima M. Galectin-9 suppresses the generation of Th17, promotes the induction of regulatory T cells, and regulates experimental autoimmune arthritis. Clin Immunol. 2008;127(1):78-88.</ref><ref name="Niwa 2009">Niwa H, Satoh T, Matsushima Y, Hosoya K, Saeki K, Niki T, Hirashima M, Yokozeki H. Stable form of galectin-9, a Tim-3 ligand, inhibits contact hypersensitivity and psoriatic reactions: a potent therapeutic tool for Th1- and/or Th17-mediated skin inflammation. Clin Immunol. 2009;132(2):184-94.</ref><ref name="Naka 2009">Naka EL, Ponciano VC, Cenedeze MA, Pacheco-Silva A, Camara NO. Detection of the Tim-3 ligand, galectin-9, inside the allograft during a rejection episode. Int Immunopharmacol. 2009;9(6):658-62.</ref><ref name="Anderson 2007">Anderson DE. TIM-3 as a therapeutic target in human inflammatory diseases. Expert Opin Ther Targets. 2007;11(8):1005-9.</ref>. In addition, galectin-9 can interact with protein disulfide isomerase (PDI) at the cell surface, increasing retention of PDI on the surface and altering surface redox potential<ref name="Bi 2011">Bi S, Hong PW, Lee B, Baum LG. Galectin-9 binding to cell surface protein disulfide isomerase regulates the redox environment to enhance T-cell migration and HIV entry. Proc Natl Acad Sci U S A. 2011;108(26):10650-5</ref>. Galectin-9 null-mice have interesting phenotypes related to immune regulation. Galectin-9 null-mice develop acute and memory responses to Herpes Simplex Virus (HSV) that are of greater magnitude and better quality than those that occur in wild-type infected animals<ref name="Sehrawat 2010">Sehrawat S, Reddy PB, Rajasagi N, Suryawanshi A, Hirashima M, Rouse BT. Galectin-9/TIM-3 interaction regulates virus-specific primary and memory CD8 T cell response. PLoS Pathog. 2010;6(5):e1000882.</ref>; they exhibit increased resistance to influenza A virus compared to wild-type mice <ref name="Sharma 2011">Sharma S, Sundararajan A, Suryawanshi A, Kumar N, Veiga-Parga T, Kuchroo VK, Thomas PG, Sangster MY, Rouse BT. T cell immunoglobulin and mucin protein-3 (Tim-3)/Galectin-9 interaction regulates influenza A virus-specific humoral and CD8 T-cell responses. Proc Natl Acad Sci U S A. 2011;108(47):19001-6</ref>; and they exhibit susceptibility to experimentally-induced autoimmune disease <ref name="Seki 2008"/>. Galectin-9 expression is elevated in peripheral blood mononuclear cells (PBMCs) in patients with systemic lupus erythematosus<ref name="Wang 2008">Wang Y, Meng J, Wang X, Liu S, Shu Q, Gao L, Ju Y, Zhang L, Sun W, Ma C. Expression of human TIM-1 and TIM-3 on lymphocytes from systemic lupus erythematosus patients. Scand J Immunol. 2008;67(1):63-70</ref>. Galectin-9 is the only tandem-repeat galectin that has been administered in animal models of disease to assess therapeutic potential <ref name="Seki 2008"/><ref name="Tsuchiyama 2000">Tsuchiyama Y, Wada J, Zhang H, Morita Y, Hiragushi K, Hida K, Shikata K, Yamamura M, Kanwar YS, Makino H. Efficacy of galectins in the amelioration of nephrotoxic serum nephritis in Wistar Kyoto rats. Kidney Int. 2000;58(5):1941-52.</ref><ref name="Baba 2005">Baba M, Wada J, Eguchi J, Hashimoto I, Okada T, Yasuhara A, Shikata K, Kanwar YS, Makino H. Galectin-9 inhibits glomerular hypertrophy in db/db diabetic mice via cell-cycle-dependent mechanisms. J Am Soc Nephrol. 2005;16(11):3222-34.</ref>. Galectin-9 exhibits the ability induce apoptosis in some lymphocytes <ref name="Zhu 2005">Zhu C, Anderson AC, Schubart A, Xiong H, Imitola J, Khoury SJ, Zheng XX, Strom TB, Kuchroo VK. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol. 2005;6(12):1245-52.</ref><ref name="Bi 2011">Bi S, Hong PW, Lee B, Baum LG. Galectin-9 binding to cell surface protein disulfide isomerase regulates the redox environment to enhance T-cell migration and HIV entry. Proc Natl Acad Sci U S A. 2011;108(26):10650-5.</ref> and this can be inhibited by inclusion of lactose or inhibitors. Galectin-9 has eosinophil chemoattractant activity (26), and the term Ecalectin was given to a variant of T lymphocyte-derived galectin-9 that was found to be an eosinophil chemoattractant <ref name="Matsumoto 1998">Matsumoto R, Matsumoto H, Seki M, Hata M, Asano Y, Kanegasaki S, Stevens RL, Hirashima M. Human ecalectin, a variant of human galectin-9, is a novel eosinophil chemoattractant produced by T lymphocytes. J Biol Chem. 1998;273(27):16976-84</ref>.

== CFG resources used in investigations ==
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=galectin-9&maxresults=20 CFG database search results for Galectin-9].

=== Glycan profiling ===

 
=== Glycogene microarray ===
Probes for human galectin-9 have been included in all versions of the CFG glycogene chip, and probes for mouse galectin-9 are included on versions 2, 3, and 4.
 

=== Knockout mouse lines ===
CFG-generated [http://www.functionalglycomics.org/static/consortium/resources/DataCoreFGJb4.shtml Galectin-9 knockout mice] have been used to study the biological functions of this paradigm GBP. [http://www.functionalglycomics.org/glycomics/publicdata/investigator.jsp?investigator=judyteale (CFG PI data)]
 

=== Glycan array ===
Investigators have used CFG carbohydrate compounds and glycan array screening to study ligand binding specificity of Galectin-9 (for example, click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2735 here]). To see all glycan array results for Galectin-9, click [http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=galectin-9&cat=coreh here].

== Related GBPs ==
Galectin-4 [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=galectin-4&maxresults=20 (CFG data)], galectin-6, galectin-8 [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=galectin-8&maxresults=20 (CFG data)], and galectin-12 [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=galectin-12&maxresults=20 (CFG data)].

== References ==
<references/>

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: Linda Baum, Richard Cummings

Galectin-9

2012-01-22T01:02:49Z

Anna Crie:

Galectin-9 is one of the best-studied of the tandem-repeat galectins with glycan binding in both the N- and C-terminal domains <ref name="Wada 1997">Wada J, Kanwar YS. Identification and characterization of galectin-9, a novel beta-galactoside-binding mammalian lectin. J Biol Chem. 1997;272(9):6078-86</ref>. The protein lacks a signal sequence, like most galectins, and is synthesized in the cytosol on free polyribosomes. Galectin-9 is found outside of cells and may be exported by non-classical pathways. Galectin-9 exhibits a variety of biological activities, the majority of which have focused on its immunomodulatory role toward lymphocytes, were it shows specific interactions with TIM-3, and can negatively regulate Th1 type immunity <ref name="Zhu 2005">Zhu C, Anderson AC, Schubart A, Xiong H, Imitola J, Khoury SJ, Zheng XX, Strom TB, Kuchroo VK. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol. 2005;6(12):1245-52.</ref>. Mammalian galectin-9 exhibits affinity toward select glycan ligands, including sulfated glycans, and blood group-related glycans, and also interacts with glycans containing poly-N-acetyllactosamine (LacNAc) repeats (-3Galβ1-4GlcNAcβ1-)n through recognition of internal LacNAc repeats <ref name="Nagae 2008">Nagae M, Nishi N, Nakamura-Tsuruta S, Hirabayashi J, Wakatsuki S, Kato R. Structural analysis of the human galectin-9 N-terminal carbohydrate recognition domain reveals unexpected properties that differ from the mouse orthologue. J Mol Biol. 2008;375(1):119-35</ref>).

The crystal structure of the N-terminal carbohydrate recognition domain (CRD) been defined
<ref name="Nagae 2008"/><ref name="Yoshida 2010">Yoshida H, Teraoka M, Nishi N, Nakakita S, Nakamura T, Hirashima M, Kamitori S. X-ray structures of human galectin-9 C-terminal domain in complexes with a biantennary oligosaccharide and sialyllactose. J Biol Chem. 2010;285(47):36969-76. </ref>
<ref name="Nagae 2006">Nagae M, Nishi N, Murata T, Usui T, Nakamura T, Wakatsuki S, Kato R. Crystal structure of the galectin-9 N-terminal carbohydrate recognition domain from Mus musculus reveals the basic mechanism of carbohydrate recognition. J Biol Chem. 2006;281(47):35884-93.</ref>. The GBP shows strong interactions in a metal-free manner with poly-N-acetyllactosamine sequences comprised of repeating (-3Galβ1-4GlcNAcβ1-)n by recognizing internal N-acetyllactosamine repeats<ref name="Nagae 2008"/>. Generally, it binds distinct glycan ligands from [[Galectin-1]] <ref name="Bi 2008">Bi S, Earl LA, Jacobs L, Baum LG. Structural features of galectin-9 and galectin-1 that determine distinct T cell death pathways. J Biol Chem. 2008;283(18):12248-58</ref>. There are has three well-characterized linker domains between the CRDs, generated by alternative splicing<ref name="Nishi 2006">Nishi N, Itoh A, Shoji H, Miyanaka H, Nakamura T. Galectin-8 and galectin-9 are novel substrates for thrombin. Glycobiology. 2006;16(11):15C-20C.</ref>, that may regulate cellular localization and function of the protein. Truncation of linker domain between CRDs in recombinant forms of galectin-9 stabilize the protein to proteolysis<ref name="Nishi 2005">Nishi N, Itoh A, Fujiyama A, Yoshida N, Araya S, Hirashima M, Shoji H, Nakamura T. Development of highly stable galectins: truncation of the linker peptide confers protease-resistance on tandem-repeat type galectins. FEBS Lett. 2005;579(10):2058-64</ref>.

== CFG Participating Investigators contributing to the understanding of this paradigm ==
CFG Participating Investigators (PIs) contributing to the understanding of Galectin-9 include: Linda Baum, Richard Cummings, Gabriel Rabinovich, Sachiko Sato

== Progress toward understanding this GBP paradigm ==
This section documents what is currently known about Galectin-9, its carbohydrate ligand(s), and how they interact to mediate cell communication. Further information can be found in the GBP Molecule Page for [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_hum_Stlect_00120&sideMenu=no human] and [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_1307&sideMenu=no mouse] Galectin-9 in the CFG database.
=== Carbohydrate ligands ===

Human galectin-9 binding to glycans has been studied by a variety of techniques including glycan microarray analysis and frontal affinity chromatography.

On the CFG glycan microarray, the individual N- and C-terminal domains of recombinant dog (Canis lupus) galectin-9, generated as GST (glutathione-S-transferase) chimeras, showed similarities in glycan recognition, but also distinct differences<ref name="Poland 2011">Poland PA, Rondanino C, Kinlough CL, Heimburg-Molinaro J, Arthur CM, Stowell SR, Smith DF, Hughey RP. Identification and characterization of endogenous galectins expressed in Madin Darby canine kidney cells. J Biol Chem. 2011;286(8):6780-90</ref>. While both domains bound well to short sulfated glycans, such as 3-O-sulfated galactose in short LacNAc structures, only the N-terminal domain bound well to many glycans expressing blood group A-related sequences and to the Forssman glycolipid-like glycans, whereas the C-terminal domain bound less well to the blood group related structures, but showed binding to a linear sialylated poly-N-acetyllactosamine pentasaccharide.

In frontal affinity chromatography, recombinant human galectin-9 was found to preferentially bind to both branched N-glycans (Kd = 0.16 μM toward tetraantennary N-glycans terminating in galactose) and glycans with poly-N-acetyllactosamine sequences (Kd = 0.09 μM toward octasaccharides with 4 repeating LacNAc groups, and this was found for both the N- and C-terminal domains. By contrast, the N-terminal, but not the C-terminal domain, showed significant binding in the low μM range to Forssman glycolipid-derived pentasaccharides and to blood group A hexasaccharide<ref name="Hirabayashi 2012">Hirabayashi J, Hashidate T, Arata Y, Nishi N, Nakamura T, Hirashima M, Urashima T, Oka T, Futai M, Muller WE, Yagi F, Kasai K. Oligosaccharide specificity of galectins: a search by frontal affinity chromatography. Biochim Biophys Acta. 2002;1572(2-3):232-54</ref>.

Glycan microarray analyses in microarrays with relatively short glycan species<ref name="Horlacher 2010">Horlacher T, Oberli MA, Werz DB, Krock L, Bufali S, Mishra R, Sobek J, Simons K, Hirashima M, Niki T, Seeberger PH. Determination of carbohydrate-binding preferences of human galectins with carbohydrate microarrays. Chembiochem. 2010;11(11):1563-73</ref>, showed that both the recombinant full-length human galectin-9 and the N-terminal domain displayed very similar binding patterns, and both bound to LacNAc sequences and even better to short fucosylated glycans with terminal blood group A and B trisaccharide sequences.

=== Cellular expression of GBP and ligands ===

Galectin-9 is widely expressed in various tissues (heart, lung, liver, kidney, spleen, muscle, intestine, and thymus), but weakly expressed in brain<ref name="Wada 1997">Wada J, Ota K, Kumar A, Wallner EI, Kanwar YS. Developmental regulation, expression, and apoptotic potential of galectin-9, a beta-galactoside binding lectin. J Clin Invest. 1997;99(10):2452-61</ref>. Interestingly, the rat urate transporter was reported to be 99% identical to the sequence reported for rat galectin-9 <ref name="Leal-Pinto 1997">Leal-Pinto E, Tao W, Rappaport J, Richardson M, Knorr BA, Abramson RG. Molecular cloning and functional reconstitution of a urate transporter/channel. J Biol Chem. 1997;272(1):617-25</ref>, suggesting that these two proteins are the same<ref name="Lipkowitz 2001">Lipkowitz MS, Leal-Pinto E, Rappoport JZ, Najfeld V, Abramson RG. Functional reconstitution, membrane targeting, genomic structure, and chromosomal localization of a human urate transporter. J Clin Invest. 2001;107(9):1103-15.</ref><ref name="Lipkowitz 2004">Lipkowitz MS, Leal-Pinto E, Cohen BE, Abramson RG. Galectin 9 is the sugar-regulated urate transporter/channel UAT. Glycoconj J. 2004;19(7-9):491-8</ref>, and suggest that galectin-9 may have multiple functions, occurring as a polytopic transmembrane protein to function as the urate transporter, and as a soluble protein in its signaling and cell-binding forms.

=== Biosynthesis of ligands ===

 
=== Structure ===
Galectin-9 (long isoform in humans) has 355 amino acids and behaves as an ~35 kDa protein; short isoforms differ in the linker peptide length and have lower apparent sizes compared to the full-length long isoform.
The crystal structure of the N-terminal carbohydrate recognition domain (CRD) been defined.<ref name="Nagae 2010">Nagae M, Nishi N, Nakamura-Tsuruta S, Hirabayashi J, Wakatsuki S, Kato R. Structural analysis of the human galectin-9 N-terminal carbohydrate recognition domain reveals unexpected properties that differ from the mouse orthologue. J Mol Biol. 2008;375(1):119-35.</ref><ref name="Yoshida 2008">Yoshida H, Teraoka M, Nishi N, Nakakita S, Nakamura T, Hirashima M, Kamitori S. X-ray structures of human galectin-9 C-terminal domain in complexes with a biantennary oligosaccharide and sialyllactose. J Biol Chem. 2010;285(47):36969-76. </ref><ref name="Nagae 2006">Nagae M, Nishi N, Murata T, Usui T, Nakamura T, Wakatsuki S, Kato R. Crystal structure of the galectin-9 N-terminal carbohydrate recognition domain from Mus musculus reveals the basic mechanism of carbohydrate recognition. J Biol Chem. 2006;281(47):35884-93.</ref>
The GBP shows strong interactions in a metal-free manner with poly-N-acetyllactosamine sequences comprised of repeating (-3Galβ1-4GlcNAcβ1-)n by recognizing internal N-acetyllactosamine repeats <ref name="Nagae 2010"/>. Generally, it binds distinct glycan ligands from Galectin-1 <ref name="Bi 2008">Bi S, Earl LA, Jacobs L, Baum LG. Structural features of galectin-9 and galectin-1 that determine distinct T cell death pathways. J Biol Chem. 2008;283(18):12248-58.</ref>). There are has three well-characterized linker domains between the CRDs, generated by alternative splicing <ref name="Nishi 2006">Nishi N, Itoh A, Shoji H, Miyanaka H, Nakamura T. Galectin-8 and galectin-9 are novel substrates for thrombin. Glycobiology. 2006;16(11):15C-20C</ref>, that may regulate cellular localization and function of the protein. Truncation of linker domain between CRDs in recombinant forms of galectin-9 stabilize the protein to proteolysis <ref name="Nishi 2005">Nishi N, Itoh A, Fujiyama A, Yoshida N, Araya S, Hirashima M, Shoji H, Nakamura T. Development of highly stable galectins: truncation of the linker peptide confers protease-resistance on tandem-repeat type galectins. FEBS Lett. 2005;579(10):2058-64</ref>.

=== Biological roles of GBP-ligand interaction ===
It has been shown that galectin-9 binds to a unique glycoprotein ligand Tim-3 expressed in Th1 and Th17 cells<ref name="Seki 2008">Seki M, Oomizu S, Sakata KM, Sakata A, Arikawa T, Watanabe K, Ito K, Takeshita K, Niki T, Saita N, Nishi N, Yamauchi A, Katoh S, Matsukawa A, Kuchroo V, Hirashima M. Galectin-9 suppresses the generation of Th17, promotes the induction of regulatory T cells, and regulates experimental autoimmune arthritis. Clin Immunol. 2008;127(1):78-88.</ref><ref name="Niwa 2009">Niwa H, Satoh T, Matsushima Y, Hosoya K, Saeki K, Niki T, Hirashima M, Yokozeki H. Stable form of galectin-9, a Tim-3 ligand, inhibits contact hypersensitivity and psoriatic reactions: a potent therapeutic tool for Th1- and/or Th17-mediated skin inflammation. Clin Immunol. 2009;132(2):184-94.</ref><ref name="Naka 2009">Naka EL, Ponciano VC, Cenedeze MA, Pacheco-Silva A, Camara NO. Detection of the Tim-3 ligand, galectin-9, inside the allograft during a rejection episode. Int Immunopharmacol. 2009;9(6):658-62.</ref><ref name="Anderson 2007">Anderson DE. TIM-3 as a therapeutic target in human inflammatory diseases. Expert Opin Ther Targets. 2007;11(8):1005-9.</ref>. In addition, galectin-9 can interact with protein disulfide isomerase (PDI) at the cell surface, increasing retention of PDI on the surface and altering surface redox potential<ref name="Bi 2011">Bi S, Hong PW, Lee B, Baum LG. Galectin-9 binding to cell surface protein disulfide isomerase regulates the redox environment to enhance T-cell migration and HIV entry. Proc Natl Acad Sci U S A. 2011;108(26):10650-5</ref>. Galectin-9 null-mice have interesting phenotypes related to immune regulation. Galectin-9 null-mice develop acute and memory responses to Herpes Simplex Virus (HSV) that are of greater magnitude and better quality than those that occur in wild-type infected animals<ref name="Sehrawat 2010">Sehrawat S, Reddy PB, Rajasagi N, Suryawanshi A, Hirashima M, Rouse BT. Galectin-9/TIM-3 interaction regulates virus-specific primary and memory CD8 T cell response. PLoS Pathog. 2010;6(5):e1000882.</ref>; they exhibit increased resistance to influenza A virus compared to wild-type mice <ref name="Sharma 2011">Sharma S, Sundararajan A, Suryawanshi A, Kumar N, Veiga-Parga T, Kuchroo VK, Thomas PG, Sangster MY, Rouse BT. T cell immunoglobulin and mucin protein-3 (Tim-3)/Galectin-9 interaction regulates influenza A virus-specific humoral and CD8 T-cell responses. Proc Natl Acad Sci U S A. 2011;108(47):19001-6</ref>; and they exhibit susceptibility to experimentally-induced autoimmune disease <ref name="Seki 2008"/>. Galectin-9 expression is elevated in peripheral blood mononuclear cells (PBMCs) in patients with systemic lupus erythematosus<ref name="Wang 2008">Wang Y, Meng J, Wang X, Liu S, Shu Q, Gao L, Ju Y, Zhang L, Sun W, Ma C. Expression of human TIM-1 and TIM-3 on lymphocytes from systemic lupus erythematosus patients. Scand J Immunol. 2008;67(1):63-70</ref>. Galectin-9 is the only tandem-repeat galectin that has been administered in animal models of disease to assess therapeutic potential <ref name="Seki 2008"/><ref name="Tsuchiyama 2000">Tsuchiyama Y, Wada J, Zhang H, Morita Y, Hiragushi K, Hida K, Shikata K, Yamamura M, Kanwar YS, Makino H. Efficacy of galectins in the amelioration of nephrotoxic serum nephritis in Wistar Kyoto rats. Kidney Int. 2000;58(5):1941-52.</ref><ref name="Baba 2005">Baba M, Wada J, Eguchi J, Hashimoto I, Okada T, Yasuhara A, Shikata K, Kanwar YS, Makino H. Galectin-9 inhibits glomerular hypertrophy in db/db diabetic mice via cell-cycle-dependent mechanisms. J Am Soc Nephrol. 2005;16(11):3222-34.</ref>. Galectin-9 exhibits the ability induce apoptosis in some lymphocytes <ref name="Zhu 2005">Zhu C, Anderson AC, Schubart A, Xiong H, Imitola J, Khoury SJ, Zheng XX, Strom TB, Kuchroo VK. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol. 2005;6(12):1245-52.</ref><ref name="Bi 2011">Bi S, Hong PW, Lee B, Baum LG. Galectin-9 binding to cell surface protein disulfide isomerase regulates the redox environment to enhance T-cell migration and HIV entry. Proc Natl Acad Sci U S A. 2011;108(26):10650-5.</ref> and this can be inhibited by inclusion of lactose or inhibitors. Galectin-9 has eosinophil chemoattractant activity (26), and the term Ecalectin was given to a variant of T lymphocyte-derived galectin-9 that was found to be an eosinophil chemoattractant <ref name="Matsumoto 1998">Matsumoto R, Matsumoto H, Seki M, Hata M, Asano Y, Kanegasaki S, Stevens RL, Hirashima M. Human ecalectin, a variant of human galectin-9, is a novel eosinophil chemoattractant produced by T lymphocytes. J Biol Chem. 1998;273(27):16976-84</ref>.

== CFG resources used in investigations ==
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=galectin-9&maxresults=20 CFG database search results for Galectin-9].

=== Glycan profiling ===

 
=== Glycogene microarray ===
Probes for human galectin-9 have been included in all versions of the CFG glycogene chip, and probes for mouse galectin-9 are included on versions 2, 3, and 4.
 

=== Knockout mouse lines ===
CFG-generated [http://www.functionalglycomics.org/static/consortium/resources/DataCoreFGJb4.shtml Galectin-9 knockout mice] have been used to study the biological functions of this paradigm GBP. [http://www.functionalglycomics.org/glycomics/publicdata/investigator.jsp?investigator=judyteale (CFG PI data)]
 

=== Glycan array ===
Investigators have used CFG carbohydrate compounds and glycan array screening to study ligand binding specificity of Galectin-9 (for example, click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2735 here]). To see all glycan array results for Galectin-9, click [http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=galectin-9&cat=coreh here].

== Related GBPs ==
Galectin-4 [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=galectin-4&maxresults=20 (CFG data)], galectin-6, galectin-8 [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=galectin-8&maxresults=20 (CFG data)], and galectin-12 [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=galectin-12&maxresults=20 (CFG data)].

== References ==
<references/>

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: Linda Baum, Richard Cummings

Galectin-9

2012-01-22T00:46:44Z

Anna Crie: /* Biological roles of GBP-ligand interaction */

Galectin-9 is the best-studied of the tandem-repeat galectins and the crystal structure of the N-terminal carbohydrate recognition domain (CRD) is known. In addition, Galectin-9...
* uniquely binds poly-N-acetyllactosamine sequences by recognizing internal N-acetyllactosamine repeats<ref name="Nagae 2009">Nagae, M. et al. Structural analysis of the recognition mechanism of poly-N-acetyllactosamine by the human galectin-9 N-terminal carbohydrate recognition domain. Glycobiology 19, 112-117 (2009). </ref>
* binds distinct ligands from [[Galectin-1]]<ref name="Bi 2008">Bi, S., Earl, L.A., Jacobs, L. & Baum, L.G. Structural features of galectin-9 and galectin-1 that determine distinct T cell death pathways. J Biol Chem 283, 12248-12258 (2008).</ref>
* has three well-characterized linker domains between the CRDs, generated by alternative splicing, that regulate cellular localization and function of the protein
* is the only tandem-repeat galectin that has been administered in animal models of disease to assess therapeutic potential<ref name="Baba 2005">Baba, M. et al. Galectin-9 inhibits glomerular hypertrophy in db/db diabetic mice via cell-cycle-dependent mechanisms. J Am Soc Nephrol 16, 3222-3234 (2005). </ref><ref name="Seki 2008">Seki, M. et al. Galectin-9 suppresses the generation of Th17, promotes the induction of regulatory T cells, and regulates experimental autoimmune arthritis. Clin Immunol 127, 78-88 (2008).</ref><ref name="Tsuchiyama 2000">Tsuchiyama, Y. et al. Efficacy of galectins in the amelioration of nephrotoxic serum nephritis in Wistar Kyoto rats. Kidney Int 58, 1941-1952 (2000). </ref>
* null mice have increased susceptibility to autoimmune disease
* binds to a unique glycoprotein ligand Tim-3 expressed in Th1 and Th17 cells<ref name="Seki 2008" /><ref name="Naka 2009">Naka, E.L., Ponciano, V.C., Cenedeze, M.A., Pacheco-Silva, A. & Camara, N.O. Detection of the Tim-3 ligand, galectin-9, inside the allograft during a rejection episode. Int Immunopharmacol 9, 658-662 (2009).</ref><ref name="Niwa 2009">Niwa, H. et al. Stable form of galectin-9, a Tim-3 ligand, inhibits contact hypersensitivity and psoriatic reactions: a potent therapeutic tool for Th1- and/or Th17-mediated skin inflammation. Clin Immunol 132, 184-194 (2009).</ref><ref name="Anderson 2007">Anderson, D.E. TIM-3 as a therapeutic target in human inflammatory diseases. Expert Opin Ther Targets 11, 1005-1009 (2007). </ref>

== CFG Participating Investigators contributing to the understanding of this paradigm ==
CFG Participating Investigators (PIs) contributing to the understanding of Galectin-9 include: Linda Baum, Richard Cummings, Gabriel Rabinovich, Sachiko Sato

== Progress toward understanding this GBP paradigm ==
This section documents what is currently known about Galectin-9, its carbohydrate ligand(s), and how they interact to mediate cell communication. Further information can be found in the GBP Molecule Page for [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_hum_Stlect_00120&sideMenu=no human] and [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_1307&sideMenu=no mouse] Galectin-9 in the CFG database.
=== Carbohydrate ligands ===

Human galectin-9 binding to glycans has been studied by a variety of techniques including glycan microarray analysis and frontal affinity chromatography.

On the CFG glycan microarray, the individual N- and C-terminal domains of recombinant dog (Canis lupus) galectin-9, generated as GST (glutathione-S-transferase) chimeras, showed similarities in glycan recognition, but also distinct differences<ref name="Poland 2011">Poland PA, Rondanino C, Kinlough CL, Heimburg-Molinaro J, Arthur CM, Stowell SR, Smith DF, Hughey RP. Identification and characterization of endogenous galectins expressed in Madin Darby canine kidney cells. J Biol Chem. 2011;286(8):6780-90</ref>. While both domains bound well to short sulfated glycans, such as 3-O-sulfated galactose in short LacNAc structures, only the N-terminal domain bound well to many glycans expressing blood group A-related sequences and to the Forssman glycolipid-like glycans, whereas the C-terminal domain bound less well to the blood group related structures, but showed binding to a linear sialylated poly-N-acetyllactosamine pentasaccharide.

In frontal affinity chromatography, recombinant human galectin-9 was found to preferentially bind to both branched N-glycans (Kd = 0.16 μM toward tetraantennary N-glycans terminating in galactose) and glycans with poly-N-acetyllactosamine sequences (Kd = 0.09 μM toward octasaccharides with 4 repeating LacNAc groups, and this was found for both the N- and C-terminal domains. By contrast, the N-terminal, but not the C-terminal domain, showed significant binding in the low μM range to Forssman glycolipid-derived pentasaccharides and to blood group A hexasaccharide<ref name="Hirabayashi 2012">Hirabayashi J, Hashidate T, Arata Y, Nishi N, Nakamura T, Hirashima M, Urashima T, Oka T, Futai M, Muller WE, Yagi F, Kasai K. Oligosaccharide specificity of galectins: a search by frontal affinity chromatography. Biochim Biophys Acta. 2002;1572(2-3):232-54</ref>.

Glycan microarray analyses in microarrays with relatively short glycan species<ref name="Horlacher 2010">Horlacher T, Oberli MA, Werz DB, Krock L, Bufali S, Mishra R, Sobek J, Simons K, Hirashima M, Niki T, Seeberger PH. Determination of carbohydrate-binding preferences of human galectins with carbohydrate microarrays. Chembiochem. 2010;11(11):1563-73</ref>, showed that both the recombinant full-length human galectin-9 and the N-terminal domain displayed very similar binding patterns, and both bound to LacNAc sequences and even better to short fucosylated glycans with terminal blood group A and B trisaccharide sequences.

=== Cellular expression of GBP and ligands ===

Galectin-9 is widely expressed in various tissues (heart, lung, liver, kidney, spleen, muscle, intestine, and thymus), but weakly expressed in brain<ref name="Wada 1997">Wada J, Ota K, Kumar A, Wallner EI, Kanwar YS. Developmental regulation, expression, and apoptotic potential of galectin-9, a beta-galactoside binding lectin. J Clin Invest. 1997;99(10):2452-61</ref>. Interestingly, the rat urate transporter was reported to be 99% identical to the sequence reported for rat galectin-9 <ref name="Leal-Pinto 1997">Leal-Pinto E, Tao W, Rappaport J, Richardson M, Knorr BA, Abramson RG. Molecular cloning and functional reconstitution of a urate transporter/channel. J Biol Chem. 1997;272(1):617-25</ref>, suggesting that these two proteins are the same<ref name="Lipkowitz 2001">Lipkowitz MS, Leal-Pinto E, Rappoport JZ, Najfeld V, Abramson RG. Functional reconstitution, membrane targeting, genomic structure, and chromosomal localization of a human urate transporter. J Clin Invest. 2001;107(9):1103-15.</ref><ref name="Lipkowitz 2004">Lipkowitz MS, Leal-Pinto E, Cohen BE, Abramson RG. Galectin 9 is the sugar-regulated urate transporter/channel UAT. Glycoconj J. 2004;19(7-9):491-8</ref>, and suggest that galectin-9 may have multiple functions, occurring as a polytopic transmembrane protein to function as the urate transporter, and as a soluble protein in its signaling and cell-binding forms.

=== Biosynthesis of ligands ===

 
=== Structure ===
Galectin-9 (long isoform in humans) has 355 amino acids and behaves as an ~35 kDa protein; short isoforms differ in the linker peptide length and have lower apparent sizes compared to the full-length long isoform.
The crystal structure of the N-terminal carbohydrate recognition domain (CRD) been defined.<ref name="Nagae 2010">Nagae M, Nishi N, Nakamura-Tsuruta S, Hirabayashi J, Wakatsuki S, Kato R. Structural analysis of the human galectin-9 N-terminal carbohydrate recognition domain reveals unexpected properties that differ from the mouse orthologue. J Mol Biol. 2008;375(1):119-35.</ref><ref name="Yoshida 2008">Yoshida H, Teraoka M, Nishi N, Nakakita S, Nakamura T, Hirashima M, Kamitori S. X-ray structures of human galectin-9 C-terminal domain in complexes with a biantennary oligosaccharide and sialyllactose. J Biol Chem. 2010;285(47):36969-76. </ref><ref name="Nagae 2006">Nagae M, Nishi N, Murata T, Usui T, Nakamura T, Wakatsuki S, Kato R. Crystal structure of the galectin-9 N-terminal carbohydrate recognition domain from Mus musculus reveals the basic mechanism of carbohydrate recognition. J Biol Chem. 2006;281(47):35884-93.</ref>
The GBP shows strong interactions in a metal-free manner with poly-N-acetyllactosamine sequences comprised of repeating (-3Galβ1-4GlcNAcβ1-)n by recognizing internal N-acetyllactosamine repeats <ref name="Nagae 2010"/>. Generally, it binds distinct glycan ligands from Galectin-1 <ref name="Bi 2008">Bi S, Earl LA, Jacobs L, Baum LG. Structural features of galectin-9 and galectin-1 that determine distinct T cell death pathways. J Biol Chem. 2008;283(18):12248-58.</ref>). There are has three well-characterized linker domains between the CRDs, generated by alternative splicing <ref name="Nishi 2006">Nishi N, Itoh A, Shoji H, Miyanaka H, Nakamura T. Galectin-8 and galectin-9 are novel substrates for thrombin. Glycobiology. 2006;16(11):15C-20C</ref>, that may regulate cellular localization and function of the protein. Truncation of linker domain between CRDs in recombinant forms of galectin-9 stabilize the protein to proteolysis <ref name="Nishi 2005">Nishi N, Itoh A, Fujiyama A, Yoshida N, Araya S, Hirashima M, Shoji H, Nakamura T. Development of highly stable galectins: truncation of the linker peptide confers protease-resistance on tandem-repeat type galectins. FEBS Lett. 2005;579(10):2058-64</ref>.

=== Biological roles of GBP-ligand interaction ===
It has been shown that galectin-9 binds to a unique glycoprotein ligand Tim-3 expressed in Th1 and Th17 cells<ref name="Seki 2008">Seki M, Oomizu S, Sakata KM, Sakata A, Arikawa T, Watanabe K, Ito K, Takeshita K, Niki T, Saita N, Nishi N, Yamauchi A, Katoh S, Matsukawa A, Kuchroo V, Hirashima M. Galectin-9 suppresses the generation of Th17, promotes the induction of regulatory T cells, and regulates experimental autoimmune arthritis. Clin Immunol. 2008;127(1):78-88.</ref><ref name="Niwa 2009">Niwa H, Satoh T, Matsushima Y, Hosoya K, Saeki K, Niki T, Hirashima M, Yokozeki H. Stable form of galectin-9, a Tim-3 ligand, inhibits contact hypersensitivity and psoriatic reactions: a potent therapeutic tool for Th1- and/or Th17-mediated skin inflammation. Clin Immunol. 2009;132(2):184-94.</ref><ref name="Naka 2009">Naka EL, Ponciano VC, Cenedeze MA, Pacheco-Silva A, Camara NO. Detection of the Tim-3 ligand, galectin-9, inside the allograft during a rejection episode. Int Immunopharmacol. 2009;9(6):658-62.</ref><ref name="Anderson 2007">Anderson DE. TIM-3 as a therapeutic target in human inflammatory diseases. Expert Opin Ther Targets. 2007;11(8):1005-9.</ref>. In addition, galectin-9 can interact with protein disulfide isomerase (PDI) at the cell surface, increasing retention of PDI on the surface and altering surface redox potential<ref name="Bi 2011">Bi S, Hong PW, Lee B, Baum LG. Galectin-9 binding to cell surface protein disulfide isomerase regulates the redox environment to enhance T-cell migration and HIV entry. Proc Natl Acad Sci U S A. 2011;108(26):10650-5</ref>. Galectin-9 null-mice have interesting phenotypes related to immune regulation. Galectin-9 null-mice develop acute and memory responses to Herpes Simplex Virus (HSV) that are of greater magnitude and better quality than those that occur in wild-type infected animals<ref name="Sehrawat 2010">Sehrawat S, Reddy PB, Rajasagi N, Suryawanshi A, Hirashima M, Rouse BT. Galectin-9/TIM-3 interaction regulates virus-specific primary and memory CD8 T cell response. PLoS Pathog. 2010;6(5):e1000882.</ref>; they exhibit increased resistance to influenza A virus compared to wild-type mice <ref name="Sharma 2011">Sharma S, Sundararajan A, Suryawanshi A, Kumar N, Veiga-Parga T, Kuchroo VK, Thomas PG, Sangster MY, Rouse BT. T cell immunoglobulin and mucin protein-3 (Tim-3)/Galectin-9 interaction regulates influenza A virus-specific humoral and CD8 T-cell responses. Proc Natl Acad Sci U S A. 2011;108(47):19001-6</ref>; and they exhibit susceptibility to experimentally-induced autoimmune disease <ref name="Seki 2008"/>. Galectin-9 expression is elevated in peripheral blood mononuclear cells (PBMCs) in patients with systemic lupus erythematosus<ref name="Wang 2008">Wang Y, Meng J, Wang X, Liu S, Shu Q, Gao L, Ju Y, Zhang L, Sun W, Ma C. Expression of human TIM-1 and TIM-3 on lymphocytes from systemic lupus erythematosus patients. Scand J Immunol. 2008;67(1):63-70</ref>. Galectin-9 is the only tandem-repeat galectin that has been administered in animal models of disease to assess therapeutic potential <ref name="Seki 2008"/><ref name="Tsuchiyama 2000">Tsuchiyama Y, Wada J, Zhang H, Morita Y, Hiragushi K, Hida K, Shikata K, Yamamura M, Kanwar YS, Makino H. Efficacy of galectins in the amelioration of nephrotoxic serum nephritis in Wistar Kyoto rats. Kidney Int. 2000;58(5):1941-52.</ref><ref name="Baba 2005">Baba M, Wada J, Eguchi J, Hashimoto I, Okada T, Yasuhara A, Shikata K, Kanwar YS, Makino H. Galectin-9 inhibits glomerular hypertrophy in db/db diabetic mice via cell-cycle-dependent mechanisms. J Am Soc Nephrol. 2005;16(11):3222-34.</ref>. Galectin-9 exhibits the ability induce apoptosis in some lymphocytes <ref name="Zhu 2005">Zhu C, Anderson AC, Schubart A, Xiong H, Imitola J, Khoury SJ, Zheng XX, Strom TB, Kuchroo VK. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol. 2005;6(12):1245-52.</ref><ref name="Bi 2011">Bi S, Hong PW, Lee B, Baum LG. Galectin-9 binding to cell surface protein disulfide isomerase regulates the redox environment to enhance T-cell migration and HIV entry. Proc Natl Acad Sci U S A. 2011;108(26):10650-5.</ref> and this can be inhibited by inclusion of lactose or inhibitors. Galectin-9 has eosinophil chemoattractant activity (26), and the term Ecalectin was given to a variant of T lymphocyte-derived galectin-9 that was found to be an eosinophil chemoattractant <ref name="Matsumoto 1998">Matsumoto R, Matsumoto H, Seki M, Hata M, Asano Y, Kanegasaki S, Stevens RL, Hirashima M. Human ecalectin, a variant of human galectin-9, is a novel eosinophil chemoattractant produced by T lymphocytes. J Biol Chem. 1998;273(27):16976-84</ref>.

== CFG resources used in investigations ==
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=galectin-9&maxresults=20 CFG database search results for Galectin-9].

=== Glycan profiling ===

 
=== Glycogene microarray ===
Probes for human galectin-9 have been included in all versions of the CFG glycogene chip, and probes for mouse galectin-9 are included on versions 2, 3, and 4.
 

=== Knockout mouse lines ===
CFG-generated [http://www.functionalglycomics.org/static/consortium/resources/DataCoreFGJb4.shtml Galectin-9 knockout mice] have been used to study the biological functions of this paradigm GBP. [http://www.functionalglycomics.org/glycomics/publicdata/investigator.jsp?investigator=judyteale (CFG PI data)]
 

=== Glycan array ===
Investigators have used CFG carbohydrate compounds and glycan array screening to study ligand binding specificity of Galectin-9 (for example, click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2735 here]). To see all glycan array results for Galectin-9, click [http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=galectin-9&cat=coreh here].

== Related GBPs ==
Galectin-4 [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=galectin-4&maxresults=20 (CFG data)], galectin-6, galectin-8 [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=galectin-8&maxresults=20 (CFG data)], and galectin-12 [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=galectin-12&maxresults=20 (CFG data)].

== References ==
<references/>

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: Linda Baum, Richard Cummings

Galectin-9

2012-01-22T00:30:14Z

Anna Crie: /* Structure */

Galectin-9 is the best-studied of the tandem-repeat galectins and the crystal structure of the N-terminal carbohydrate recognition domain (CRD) is known. In addition, Galectin-9...
* uniquely binds poly-N-acetyllactosamine sequences by recognizing internal N-acetyllactosamine repeats<ref name="Nagae 2009">Nagae, M. et al. Structural analysis of the recognition mechanism of poly-N-acetyllactosamine by the human galectin-9 N-terminal carbohydrate recognition domain. Glycobiology 19, 112-117 (2009). </ref>
* binds distinct ligands from [[Galectin-1]]<ref name="Bi 2008">Bi, S., Earl, L.A., Jacobs, L. & Baum, L.G. Structural features of galectin-9 and galectin-1 that determine distinct T cell death pathways. J Biol Chem 283, 12248-12258 (2008).</ref>
* has three well-characterized linker domains between the CRDs, generated by alternative splicing, that regulate cellular localization and function of the protein
* is the only tandem-repeat galectin that has been administered in animal models of disease to assess therapeutic potential<ref name="Baba 2005">Baba, M. et al. Galectin-9 inhibits glomerular hypertrophy in db/db diabetic mice via cell-cycle-dependent mechanisms. J Am Soc Nephrol 16, 3222-3234 (2005). </ref><ref name="Seki 2008">Seki, M. et al. Galectin-9 suppresses the generation of Th17, promotes the induction of regulatory T cells, and regulates experimental autoimmune arthritis. Clin Immunol 127, 78-88 (2008).</ref><ref name="Tsuchiyama 2000">Tsuchiyama, Y. et al. Efficacy of galectins in the amelioration of nephrotoxic serum nephritis in Wistar Kyoto rats. Kidney Int 58, 1941-1952 (2000). </ref>
* null mice have increased susceptibility to autoimmune disease
* binds to a unique glycoprotein ligand Tim-3 expressed in Th1 and Th17 cells<ref name="Seki 2008" /><ref name="Naka 2009">Naka, E.L., Ponciano, V.C., Cenedeze, M.A., Pacheco-Silva, A. & Camara, N.O. Detection of the Tim-3 ligand, galectin-9, inside the allograft during a rejection episode. Int Immunopharmacol 9, 658-662 (2009).</ref><ref name="Niwa 2009">Niwa, H. et al. Stable form of galectin-9, a Tim-3 ligand, inhibits contact hypersensitivity and psoriatic reactions: a potent therapeutic tool for Th1- and/or Th17-mediated skin inflammation. Clin Immunol 132, 184-194 (2009).</ref><ref name="Anderson 2007">Anderson, D.E. TIM-3 as a therapeutic target in human inflammatory diseases. Expert Opin Ther Targets 11, 1005-1009 (2007). </ref>

== CFG Participating Investigators contributing to the understanding of this paradigm ==
CFG Participating Investigators (PIs) contributing to the understanding of Galectin-9 include: Linda Baum, Richard Cummings, Gabriel Rabinovich, Sachiko Sato

== Progress toward understanding this GBP paradigm ==
This section documents what is currently known about Galectin-9, its carbohydrate ligand(s), and how they interact to mediate cell communication. Further information can be found in the GBP Molecule Page for [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_hum_Stlect_00120&sideMenu=no human] and [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_1307&sideMenu=no mouse] Galectin-9 in the CFG database.
=== Carbohydrate ligands ===

Human galectin-9 binding to glycans has been studied by a variety of techniques including glycan microarray analysis and frontal affinity chromatography.

On the CFG glycan microarray, the individual N- and C-terminal domains of recombinant dog (Canis lupus) galectin-9, generated as GST (glutathione-S-transferase) chimeras, showed similarities in glycan recognition, but also distinct differences<ref name="Poland 2011">Poland PA, Rondanino C, Kinlough CL, Heimburg-Molinaro J, Arthur CM, Stowell SR, Smith DF, Hughey RP. Identification and characterization of endogenous galectins expressed in Madin Darby canine kidney cells. J Biol Chem. 2011;286(8):6780-90</ref>. While both domains bound well to short sulfated glycans, such as 3-O-sulfated galactose in short LacNAc structures, only the N-terminal domain bound well to many glycans expressing blood group A-related sequences and to the Forssman glycolipid-like glycans, whereas the C-terminal domain bound less well to the blood group related structures, but showed binding to a linear sialylated poly-N-acetyllactosamine pentasaccharide.

In frontal affinity chromatography, recombinant human galectin-9 was found to preferentially bind to both branched N-glycans (Kd = 0.16 μM toward tetraantennary N-glycans terminating in galactose) and glycans with poly-N-acetyllactosamine sequences (Kd = 0.09 μM toward octasaccharides with 4 repeating LacNAc groups, and this was found for both the N- and C-terminal domains. By contrast, the N-terminal, but not the C-terminal domain, showed significant binding in the low μM range to Forssman glycolipid-derived pentasaccharides and to blood group A hexasaccharide<ref name="Hirabayashi 2012">Hirabayashi J, Hashidate T, Arata Y, Nishi N, Nakamura T, Hirashima M, Urashima T, Oka T, Futai M, Muller WE, Yagi F, Kasai K. Oligosaccharide specificity of galectins: a search by frontal affinity chromatography. Biochim Biophys Acta. 2002;1572(2-3):232-54</ref>.

Glycan microarray analyses in microarrays with relatively short glycan species<ref name="Horlacher 2010">Horlacher T, Oberli MA, Werz DB, Krock L, Bufali S, Mishra R, Sobek J, Simons K, Hirashima M, Niki T, Seeberger PH. Determination of carbohydrate-binding preferences of human galectins with carbohydrate microarrays. Chembiochem. 2010;11(11):1563-73</ref>, showed that both the recombinant full-length human galectin-9 and the N-terminal domain displayed very similar binding patterns, and both bound to LacNAc sequences and even better to short fucosylated glycans with terminal blood group A and B trisaccharide sequences.

=== Cellular expression of GBP and ligands ===

Galectin-9 is widely expressed in various tissues (heart, lung, liver, kidney, spleen, muscle, intestine, and thymus), but weakly expressed in brain<ref name="Wada 1997">Wada J, Ota K, Kumar A, Wallner EI, Kanwar YS. Developmental regulation, expression, and apoptotic potential of galectin-9, a beta-galactoside binding lectin. J Clin Invest. 1997;99(10):2452-61</ref>. Interestingly, the rat urate transporter was reported to be 99% identical to the sequence reported for rat galectin-9 <ref name="Leal-Pinto 1997">Leal-Pinto E, Tao W, Rappaport J, Richardson M, Knorr BA, Abramson RG. Molecular cloning and functional reconstitution of a urate transporter/channel. J Biol Chem. 1997;272(1):617-25</ref>, suggesting that these two proteins are the same<ref name="Lipkowitz 2001">Lipkowitz MS, Leal-Pinto E, Rappoport JZ, Najfeld V, Abramson RG. Functional reconstitution, membrane targeting, genomic structure, and chromosomal localization of a human urate transporter. J Clin Invest. 2001;107(9):1103-15.</ref><ref name="Lipkowitz 2004">Lipkowitz MS, Leal-Pinto E, Cohen BE, Abramson RG. Galectin 9 is the sugar-regulated urate transporter/channel UAT. Glycoconj J. 2004;19(7-9):491-8</ref>, and suggest that galectin-9 may have multiple functions, occurring as a polytopic transmembrane protein to function as the urate transporter, and as a soluble protein in its signaling and cell-binding forms.

=== Biosynthesis of ligands ===

 
=== Structure ===
Galectin-9 (long isoform in humans) has 355 amino acids and behaves as an ~35 kDa protein; short isoforms differ in the linker peptide length and have lower apparent sizes compared to the full-length long isoform.
The crystal structure of the N-terminal carbohydrate recognition domain (CRD) been defined.<ref name="Nagae 2010">Nagae M, Nishi N, Nakamura-Tsuruta S, Hirabayashi J, Wakatsuki S, Kato R. Structural analysis of the human galectin-9 N-terminal carbohydrate recognition domain reveals unexpected properties that differ from the mouse orthologue. J Mol Biol. 2008;375(1):119-35.</ref><ref name="Yoshida 2008">Yoshida H, Teraoka M, Nishi N, Nakakita S, Nakamura T, Hirashima M, Kamitori S. X-ray structures of human galectin-9 C-terminal domain in complexes with a biantennary oligosaccharide and sialyllactose. J Biol Chem. 2010;285(47):36969-76. </ref><ref name="Nagae 2006">Nagae M, Nishi N, Murata T, Usui T, Nakamura T, Wakatsuki S, Kato R. Crystal structure of the galectin-9 N-terminal carbohydrate recognition domain from Mus musculus reveals the basic mechanism of carbohydrate recognition. J Biol Chem. 2006;281(47):35884-93.</ref>
The GBP shows strong interactions in a metal-free manner with poly-N-acetyllactosamine sequences comprised of repeating (-3Galβ1-4GlcNAcβ1-)n by recognizing internal N-acetyllactosamine repeats <ref name="Nagae 2010"/>. Generally, it binds distinct glycan ligands from Galectin-1 <ref name="Bi 2008">Bi S, Earl LA, Jacobs L, Baum LG. Structural features of galectin-9 and galectin-1 that determine distinct T cell death pathways. J Biol Chem. 2008;283(18):12248-58.</ref>). There are has three well-characterized linker domains between the CRDs, generated by alternative splicing <ref name="Nishi 2006">Nishi N, Itoh A, Shoji H, Miyanaka H, Nakamura T. Galectin-8 and galectin-9 are novel substrates for thrombin. Glycobiology. 2006;16(11):15C-20C</ref>, that may regulate cellular localization and function of the protein. Truncation of linker domain between CRDs in recombinant forms of galectin-9 stabilize the protein to proteolysis <ref name="Nishi 2005">Nishi N, Itoh A, Fujiyama A, Yoshida N, Araya S, Hirashima M, Shoji H, Nakamura T. Development of highly stable galectins: truncation of the linker peptide confers protease-resistance on tandem-repeat type galectins. FEBS Lett. 2005;579(10):2058-64</ref>.

=== Biological roles of GBP-ligand interaction ===

 

== CFG resources used in investigations ==
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=galectin-9&maxresults=20 CFG database search results for Galectin-9].

=== Glycan profiling ===

 
=== Glycogene microarray ===
Probes for human galectin-9 have been included in all versions of the CFG glycogene chip, and probes for mouse galectin-9 are included on versions 2, 3, and 4.
 

=== Knockout mouse lines ===
CFG-generated [http://www.functionalglycomics.org/static/consortium/resources/DataCoreFGJb4.shtml Galectin-9 knockout mice] have been used to study the biological functions of this paradigm GBP. [http://www.functionalglycomics.org/glycomics/publicdata/investigator.jsp?investigator=judyteale (CFG PI data)]
 

=== Glycan array ===
Investigators have used CFG carbohydrate compounds and glycan array screening to study ligand binding specificity of Galectin-9 (for example, click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2735 here]). To see all glycan array results for Galectin-9, click [http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=galectin-9&cat=coreh here].

== Related GBPs ==
Galectin-4 [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=galectin-4&maxresults=20 (CFG data)], galectin-6, galectin-8 [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=galectin-8&maxresults=20 (CFG data)], and galectin-12 [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=galectin-12&maxresults=20 (CFG data)].

== References ==
<references/>

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: Linda Baum, Richard Cummings

Galectin-9

2012-01-22T00:19:46Z

Anna Crie: /* Cellular expression of GBP and ligands */

Galectin-9

2012-01-22T00:15:42Z

Anna Crie: /* Carbohydrate ligands */

Galectin-9

2012-01-22T00:04:56Z

Anna Crie:

Galectin-9

2012-01-21T23:59:05Z

Anna Crie: /* Structure */

Galectin-9 is the best-studied of the tandem-repeat galectins and the crystal structure of the N-terminal carbohydrate recognition domain (CRD) is known. In addition, Galectin-9...
* uniquely binds poly-N-acetyllactosamine sequences by recognizing internal N-acetyllactosamine repeats<ref>Nagae, M. et al. Structural analysis of the recognition mechanism of poly-N-acetyllactosamine by the human galectin-9 N-terminal carbohydrate recognition domain. Glycobiology 19, 112-117 (2009). </ref>
* binds distinct ligands from [[Galectin-1]]<ref name="Bi 2008">Bi, S., Earl, L.A., Jacobs, L. & Baum, L.G. Structural features of galectin-9 and galectin-1 that determine distinct T cell death pathways. J Biol Chem 283, 12248-12258 (2008).</ref>
* has three well-characterized linker domains between the CRDs, generated by alternative splicing, that regulate cellular localization and function of the protein
* is the only tandem-repeat galectin that has been administered in animal models of disease to assess therapeutic potential<ref>Baba, M. et al. Galectin-9 inhibits glomerular hypertrophy in db/db diabetic mice via cell-cycle-dependent mechanisms. J Am Soc Nephrol 16, 3222-3234 (2005). </ref><ref name="Seki 2008">Seki, M. et al. Galectin-9 suppresses the generation of Th17, promotes the induction of regulatory T cells, and regulates experimental autoimmune arthritis. Clin Immunol 127, 78-88 (2008).</ref><ref name="Tsuchiyama 2000">Tsuchiyama, Y. et al. Efficacy of galectins in the amelioration of nephrotoxic serum nephritis in Wistar Kyoto rats. Kidney Int 58, 1941-1952 (2000). </ref>
* null mice have increased susceptibility to autoimmune disease
* binds to a unique glycoprotein ligand Tim-3 expressed in Th1 and Th17 cells<ref name="Seki 2008" /><ref>Naka, E.L., Ponciano, V.C., Cenedeze, M.A., Pacheco-Silva, A. & Camara, N.O. Detection of the Tim-3 ligand, galectin-9, inside the allograft during a rejection episode. Int Immunopharmacol 9, 658-662 (2009).
</ref><ref>Niwa, H. et al. Stable form of galectin-9, a Tim-3 ligand, inhibits contact hypersensitivity and psoriatic reactions: a potent therapeutic tool for Th1- and/or Th17-mediated skin inflammation. Clin Immunol 132, 184-194 (2009).</ref><ref>Anderson, D.E. TIM-3 as a therapeutic target in human inflammatory diseases. Expert Opin Ther Targets 11, 1005-1009 (2007). </ref>

== CFG Participating Investigators contributing to the understanding of this paradigm ==
CFG Participating Investigators (PIs) contributing to the understanding of Galectin-9 include: Linda Baum, Richard Cummings, Gabriel Rabinovich, Sachiko Sato

== Progress toward understanding this GBP paradigm ==
This section documents what is currently known about Galectin-9, its carbohydrate ligand(s), and how they interact to mediate cell communication. Further information can be found in the GBP Molecule Page for [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_hum_Stlect_00120&sideMenu=no human] and [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_1307&sideMenu=no mouse] Galectin-9 in the CFG database.
=== Carbohydrate ligands ===

Human galectin-9 binding to glycans has been studied by a variety of techniques including glycan microarray analysis and frontal affinity chromatography.

On the CFG glycan microarray, the individual N- and C-terminal domains of recombinant dog (Canis lupus) galectin-9, generated as GST (glutathione-S-transferase) chimeras, showed similarities in glycan recognition, but also distinct differences<ref>Poland PA, Rondanino C, Kinlough CL, Heimburg-Molinaro J, Arthur CM, Stowell SR, Smith DF, Hughey RP. Identification and characterization of endogenous galectins expressed in Madin Darby canine kidney cells. J Biol Chem. 2011;286(8):6780-90</ref>. While both domains bound well to short sulfated glycans, such as 3-O-sulfated galactose in short LacNAc structures, only the N-terminal domain bound well to many glycans expressing blood group A-related sequences and to the Forssman glycolipid-like glycans, whereas the C-terminal domain bound less well to the blood group related structures, but showed binding to a linear sialylated poly-N-acetyllactosamine pentasaccharide.

In frontal affinity chromatography, recombinant human galectin-9 was found to preferentially bind to both branched N-glycans (Kd = 0.16 μM toward tetraantennary N-glycans terminating in galactose) and glycans with poly-N-acetyllactosamine sequences (Kd = 0.09 μM toward octasaccharides with 4 repeating LacNAc groups, and this was found for both the N- and C-terminal domains. By contrast, the N-terminal, but not the C-terminal domain, showed significant binding in the low μM range to Forssman glycolipid-derived pentasaccharides and to blood group A hexasaccharide<ref>Hirabayashi J, Hashidate T, Arata Y, Nishi N, Nakamura T, Hirashima M, Urashima T, Oka T, Futai M, Muller WE, Yagi F, Kasai K. Oligosaccharide specificity of galectins: a search by frontal affinity chromatography. Biochim Biophys Acta. 2002;1572(2-3):232-54</ref>.

Glycan microarray analyses in microarrays with relatively short glycan species<ref>Horlacher T, Oberli MA, Werz DB, Krock L, Bufali S, Mishra R, Sobek J, Simons K, Hirashima M, Niki T, Seeberger PH. Determination of carbohydrate-binding preferences of human galectins with carbohydrate microarrays. Chembiochem. 2010;11(11):1563-73</ref>, showed that both the recombinant full-length human galectin-9 and the N-terminal domain displayed very similar binding patterns, and both bound to LacNAc sequences and even better to short fucosylated glycans with terminal blood group A and B trisaccharide sequences.

=== Cellular expression of GBP and ligands ===

Galectin-9 is widely expressed in various tissues (heart, lung, liver, kidney, spleen, muscle, intestine, and thymus), but weakly expressed in brain<ref>Wada J, Ota K, Kumar A, Wallner EI, Kanwar YS. Developmental regulation, expression, and apoptotic potential of galectin-9, a beta-galactoside binding lectin. J Clin Invest. 1997;99(10):2452-61</ref>. Interestingly, the rat urate transporter was reported to be 99% identical to the sequence reported for rat galectin-9 <ref>Leal-Pinto E, Tao W, Rappaport J, Richardson M, Knorr BA, Abramson RG. Molecular cloning and functional reconstitution of a urate transporter/channel. J Biol Chem. 1997;272(1):617-25</ref>, suggesting that these two proteins are the same<ref>Lipkowitz MS, Leal-Pinto E, Rappoport JZ, Najfeld V, Abramson RG. Functional reconstitution, membrane targeting, genomic structure, and chromosomal localization of a human urate transporter. J Clin Invest. 2001;107(9):1103-15.</ref><ref>Lipkowitz MS, Leal-Pinto E, Cohen BE, Abramson RG. Galectin 9 is the sugar-regulated urate transporter/channel UAT. Glycoconj J. 2004;19(7-9):491-8</ref>, and suggest that galectin-9 may have multiple functions, occurring as a polytopic transmembrane protein to function as the urate transporter, and as a soluble protein in its signaling and cell-binding forms.

=== Biosynthesis of ligands ===

 
=== Structure ===
Galectin-9 (long isoform in humans) has 355 amino acids and behaves as an ~35 kDa protein; short isoforms differ in the linker peptide length and have lower apparent sizes compared to the full-length long isoform.
The crystal structure of the N-terminal carbohydrate recognition domain (CRD) been defined<ref name="Nagae 2008">Nagae M, Nishi N, Nakamura-Tsuruta S, Hirabayashi J, Wakatsuki S, Kato R. Structural analysis of the human galectin-9 N-terminal carbohydrate recognition domain reveals unexpected properties that differ from the mouse orthologue. J Mol Biol. 2008;375(1):119-35</ref><ref name="Yoshida 2010">Yoshida H, Teraoka M, Nishi N, Nakakita S, Nakamura T, Hirashima M, Kamitori S. X-ray structures of human galectin-9 C-terminal domain in complexes with a biantennary oligosaccharide and sialyllactose. J Biol Chem. 2010;285(47):36969-76.</ref><ref name="Nagae 2006">Nagae M, Nishi N, Murata T, Usui T, Nakamura T, Wakatsuki S, Kato R. Crystal structure of the galectin-9 N-terminal carbohydrate recognition domain from Mus musculus reveals the basic mechanism of carbohydrate recognition. J Biol Chem. 2006;281(47):35884-93.</ref>. The GBP shows strong interactions in a metal-free manner with poly-N-acetyllactosamine sequences comprised of repeating (-3Galβ1-4GlcNAcβ1-)n by recognizing internal N-acetyllactosamine repeats <ref name="Nagae 2008"/>). Generally, it binds distinct glycan ligands from Galectin-1 <ref name="Bi 2008">Bi S, Earl LA, Jacobs L, Baum LG. Structural features of galectin-9 and galectin-1 that determine distinct T cell death pathways. J Biol Chem. 2008;283(18):12248-58. PMCID: 2431002</ref>. There are has three well-characterized linker domains between the CRDs, generated by alternative splicing<ref name="Nishi 2006">Nishi N, Itoh A, Shoji H, Miyanaka H, Nakamura T. Galectin-8 and galectin-9 are novel substrates for thrombin. Glycobiology. 2006;16(11):15C-20C</ref>, that may regulate cellular localization and function of the protein. Truncation of linker domain between CRDs in recombinant forms of galectin-9 stabilize the protein to proteolysis <ref name="Nishi 2005">Nishi N, Itoh A, Fujiyama A, Yoshida N, Araya S, Hirashima M, Shoji H, Nakamura T. Development of highly stable galectins: truncation of the linker peptide confers protease-resistance on tandem-repeat type galectins. FEBS Lett. 2005;579(10):2058-64</ref>.

=== Biological roles of GBP-ligand interaction ===

 

== CFG resources used in investigations ==
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=galectin-9&maxresults=20 CFG database search results for Galectin-9].

=== Glycan profiling ===

 
=== Glycogene microarray ===
Probes for human galectin-9 have been included in all versions of the CFG glycogene chip, and probes for mouse galectin-9 are included on versions 2, 3, and 4.
 

=== Knockout mouse lines ===
CFG-generated [http://www.functionalglycomics.org/static/consortium/resources/DataCoreFGJb4.shtml Galectin-9 knockout mice] have been used to study the biological functions of this paradigm GBP. [http://www.functionalglycomics.org/glycomics/publicdata/investigator.jsp?investigator=judyteale (CFG PI data)]
 

=== Glycan array ===
Investigators have used CFG carbohydrate compounds and glycan array screening to study ligand binding specificity of Galectin-9 (for example, click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2735 here]). To see all glycan array results for Galectin-9, click [http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=galectin-9&cat=coreh here].

== Related GBPs ==
Galectin-4 [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=galectin-4&maxresults=20 (CFG data)], galectin-6, galectin-8 [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=galectin-8&maxresults=20 (CFG data)], and galectin-12 [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=galectin-12&maxresults=20 (CFG data)].

== References ==
<references/>

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: Linda Baum, Richard Cummings

Galectin-9

2012-01-21T23:49:57Z

Anna Crie: /* Cellular expression of GBP and ligands */

Galectin-9

2012-01-21T23:46:02Z

Anna Crie: /* Carbohydrate ligands */

Galectin-9

2012-01-21T23:43:23Z

Anna Crie:

Sialoadhesin

2012-01-21T05:48:39Z

Anna Crie: /* Acknowledgements */

Sialoadhesin (Sn), also known as Siglec-1, is an atypical siglec, due to the presence of an unusually large number of Ig domains (17) and the absence of tyrosine-based intracellular signaling motifs. Sn is expressed uniquely by macrophage subsets in vivo and the 17 Ig domains are thought to be important for its ability to mediate sialic acid-dependent adhesive functions. This contrasts with most other siglecs which are much shorter and masked by cis binding to co-expressed sialic acids.

== CFG Participating Investigators contributing to the understanding of this paradigm ==
CFG Participating Investigators (PIs) contributing to the understanding of Sn include: Paul Crocker, Peter Delputte, Soerge Kelm, Ajit Varki

== Progress toward understanding this GBP paradigm ==
This section documents what is currently known about sialoadhesin, its carbohydrate ligand(s), and how they interact to mediate cell communication. Further information can be found in the GBP Molecule Page for [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_hum_Itlect_267&sideMenu=no human] and [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_mou_Itlect_193&sideMenu=no mouse] sialoadhesin (a.k.a. Siglec-1) in the CFG database.
=== Carbohydrate ligands ===

[[File:Sia3Gal_small.png]]

Sn is a fairly promiscuous receptor, with a preference for Siaα2-3Gal over Siaα2-6Gal terminated glycans. Sn prefers NeuNAc in α2,3-linkage over α2,6 and α2,8 linkages and does not recognize NeuGc or NeuAc9Ac. In pull-down experiments using Sn-Fc constructs, mucin-like proteins with multiple O-linked glycans seem to be preferred (eg CD43, Muc-1), but whether these represent preferred counterreceptors during cell-cell interactions between Sn+ macrophages and other cells is unknown
 

=== Cellular expression of GBP and ligands ===
Sn is expressed exclusively by cells of the mononuclear phagocyte lineage, including in some cases myeloid dendritic cells as well as classic macrophages. It is expressed constitutively by many tissue macrophages, particularly those in primary and secondary lymphoid organs and may play a role in antigen capture and tolerance. Sn can also be induced on macrophages by IFN-α or agents that induce expression of IFN-α such as LPS or poly-I:C. Ligands for Sn are regulated via expression of sialyltransferases and are found on many cells of the body. Surveys of haemopoietic targets have identified granulocytes as being rich in Sn ligands but the functional significance of this is unclear at present.
 

=== Biosynthesis of ligands ===

 
=== Structure ===
The crystal structure of the N-terminal carbohydrate-binding domain of sialoadhesin in complex with 3'-sialyllactose highlights the roles of three key conserved amino acids, tryptophan 2, arginine 97 and tryptophan 106, in the ligand-binding domains of the siglecs that are involved in interactions with the various characteristic groups that project from the pyranose ring of sialic acid. The structure provides a rationale for why sialoadhesin binds to N-acetyl- but not N-glycolyl neuraminic acid and the limited interactions with the lactose portion of the glycan are consistent with the ability of sialoadhesin to bind both 2-3 and 2-6 linked sialic acid.<ref name"Crocker1998">May, AP, Robinson, RC, Vinson, M, Crocker, PR and Jones, EY (1998) Crystal structure of the N-terminal domain of sialoadhesin in complex with 3 sialyllactose at 1.85 Å Resolution. Molecular Cell 1, 719-728</ref>
 

=== Biological roles of GBP-ligand interaction ===
Sn contributes to proinflammatory immune responses in a variety of autoimmune diseases<ref>Jiang, H. R. et al. Sialoadhesin promotes the inflammatory response in experimental autoimmune uveoretinitis. J Immunol 177, 2258-2264 (2006).</ref><ref>Ip, C. W., Kroner, A., Crocker, P. R., Nave, K. A. & Martini, R. Sialoadhesin deficiency ameliorates myelin degeneration and axonopathic changes in the CNS of PLP overexpressing mice. Neurobiol Dis 25, 105-111 (2007).</ref>, and this may be due to suppression of Treg expansion as demonstrated in experimental allergic encephalomyelitis, a model for multiple sclerosis<ref>Wu, C. et al. Sialoadhesin-positive macrophages bind regulatory T cells, negatively controlling their expansion and autoimmune disease progression. J Immunol 182, 6508-6516 (2009).</ref>. Sn has also been shown to function as a macrophage receptor for the porcine arterivirus<ref>Delputte, P. L. et al. Porcine arterivirus attachment to the macrophage-specific receptor sialoadhesin is
dependent on the sialic acid-binding activity of the N-terminal immunoglobulin domain of sialoadhesin. J Virol 81, 9546-9550 (2007).</ref> and can also promote macrophage uptake of sialylated bacteria such as ''Neisseria meningitidis''<ref>Jones, C., Virji, M. & Crocker, P. R. Recognition of sialylated meningococcal lipopolysaccharide by siglecs expressed on myeloid cells leads to enhanced bacterial uptake. Mol Microbiol 49, 1213-1225 (2003).</ref>.
 

== CFG resources used in investigations ==
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=Sialoadhesin&maxresults=20 CFG database search results for sialoadhesin].

=== Glycan profiling ===

 
=== Glycogene microarray ===
Probes for mouse and human sialoadhesin (under the name Siglec-1) have been included on all four versions of the CFG glycogene microarray.
 

=== Knockout mouse lines ===
The CFG did not undertake creation of knockout mice for sialoadhesin because generation of such mice was already underway. Studies of these mice indicate a role for sialoadhesin in regulation of the cellular and humoral immune response<ref name=”Oetke2006”>Oetke C, Vinson MC, Jones C, Crocker PR (2006) Sialoadhesin-deficient mice exhibit subtle changes in B- and T-cell populations and reduced immunoglobulin M levels. Mol. Cell. Biol. 26, 1549-57</ref>
 

=== Glycan array ===
The CFG glycan array has been probed with both murine and porcine Sn constructs, but no positive signals were obtained (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1383 here]), likely due to the low affinity of Sn for sialylated oligosaccharides.

== Related GBPs ==
None.

== References ==
<references/>

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: Paul Crocker, Sorge Kelm, James Paulson

Galectin-3

2012-01-21T05:47:19Z

Anna Crie: /* Acknowledgements */

Galectin-3...
* is the only member of the chimeric subfamily in mammals
* is a very well-studied glycan-binding protein (GBP)
* has a known crystal structure (C-terminal glycan-binding domain)
* has unique functions intra- and extra-cellularly, due to an unusual N-terminal domain that can participate in protein-protein interactions
* has a unique mode of multimerization
* is the only known anti-apoptotic galectin, and acts through intracellular action<ref>Saegusa J, Hsu DK, Liu W, Kuwabara I, Kuwabara Y, Yu L, Liu FT [http://www.ncbi.nlm.nih.gov/pubmed/18463681 Galectin-3 protects keratinocytes from UVB-induced apoptosis by enhancing AKT activation and suppressing ERK activation.] J Invest Dermatol. 2008 Oct;128(10):2403-11. PubMed PMID: 18463681; PubMed Central PMCID: PMC2768377.</ref>
* null mice have distinct phenotypes, including alterations in inflammatory and wound-healing responses, and cyst formation in disease<ref>Chiu MG, Johnson TM, Woolf AS, Dahm-Vicker EM, Long DA, Guay-Woodford L,
Hillman KA, Bawumia S, Venner K, Hughes RC, Poirier F, Winyard PJ. [http://www.ncbi.nlm.nih.gov/pubmed/17148658 Galectin-3 associates with the primary cilium and modulates cyst growth in congenital polycystic kidney disease.] Am J Pathol. 2006 Dec;169(6):1925-38.</ref>
* has unique functions in innate immune response to microbial pathogens
* has been administered in animal models of disease to assess therapeutic potential
* binds distinct cell surface glycoprotein ligands in lymphocytes compared to galectin-1
* expression is involved in growth modulation<ref>Baptiste TA, James A, Saria M, Ochieng J. [http://www.ncbi.nlm.nih.gov/pubmed/17184769 Mechano-transduction mediated secretion and uptake of galectin-3 in breast carcinoma cells: implications in the extracellular functions of the lectin.] Exp Cell Res. 2007 Feb 15;313(4):652-64. Epub 2006 Nov 16. PubMed PMID: 17184769; PubMed Central PMCID: PMC1885467.</ref>
 
Galectin-3 is the only member of the galectin family with an extended N-terminal region composed of tandem repeats of short amino-acid segments (a total of approximately 120 amino acids) connected to a C-terminal CRD. Like other galectins, galectin-3 lacks a signal sequence required for secretion through the classical secretory pathway, but the protein is released into the extracellular space. 
Galectin-3 can oligomerize in the presence of multivalent carbohydrate ligands and is capable of crosslinking glycans on the cell surface, thereby initiating transmembrane signaling events and affecting various cellular functions (reviewed in <ref name="Liu 2005">Liu FT, Rabinovich GA. [http://www.ncbi.nlm.nih.gov/pubmed/15630413 Galectins as modulators of tumour progression.] Nat Rev Cancer. 2005 Jan;5(1):29-41. Review. PubMed PMID: 15630413.</ref><ref>Almkvist J, Karlsson A. [http://www.ncbi.nlm.nih.gov/pubmed/14758082 Galectins as inflammatory mediators.] Glycoconj J.
2004;19(7-9):575-81. Review. PubMed PMID: 14758082.</ref><ref>Ochieng J, Furtak V, Lukyanov P. [http://www.ncbi.nlm.nih.gov/pubmed/14758076 Extracellular functions of galectin-3.] Glycoconj J. 2004;19(7-9):527-35. Review. PubMed PMID: 14758076.</ref>). This ability to self-associate is dependent on the N-terminal region of the protein.
 Compared to other galectins, intracellular functions of galectin-3 have been more extensively documented (reviewed in <ref>Liu FT, Patterson RJ, Wang JL. [http://www.ncbi.nlm.nih.gov/pubmed/12223274 Intracellular functions of galectins.] Biochim Biophys Acta. 2002 Sep 19;1572(2-3):263-73. Review. PubMed PMID: 12223274.</ref>). In some cases, intracellular proteins with which the protein interacts and which possibly mediate these functions have been identified. Galectin-3 can be phosphorylated at serines 6 & 12<ref>Huflejt ME, Turck CW, Lindstedt R, Barondes SH, Leffler H. [http://www.ncbi.nlm.nih.gov/pubmed/8253806 L-29, a soluble lactose-binding lectin, is phosphorylated on serine 6 and serine 12 in vivo and by casein kinase I.] J Biol Chem. 1993 Dec 15;268(35):26712-8. PubMed PMID:8253806.</ref>, and tyrosines 79,107 & 118 by c-Abl<ref>Balan V, Nangia-Makker P, Jang YS, Wang Y, Raz A. [http://www.ncbi.nlm.nih.gov/pubmed/20600357 Galectin-3: A novel substrate for c-Abl kinase.] Biochim Biophys Acta. 2010 Jun 30. PubMed PMID: 20600357</ref><ref>Li X, Ma Q, Wang J, Liu X, Yang Y, Zhao H, Wang Y, Jin Y, Zeng J, Li J, Song L, Li X, Li P, Qian X, Cao C. [http://www.ncbi.nlm.nih.gov/pubmed/20150913 c-Abl and Arg tyrosine kinases regulate lysosomal degradation of the oncoprotein Galectin-3.] Cell Death Differ. 2010 Aug;17(8):1277-87. Epub 2010 Feb 12. PubMed PMID: 20150913.</ref>.

== CFG Participating Investigators contributing to the understanding of this paradigm ==
CFG Participating Investigators (PIs) contributing to the understanding of Galectin-3 include: Pablo Argüeso, Linda Baum, Susan Bellis, Roger Chammas, Richard Cummings, James Dennis, Margaret, Huflejt, Fu-Tong Liu, Joshiah Ochieng, Noorjahan Panjawani, Mauro Perretti, Avraham Raz, James Rini, Maria Roque-Barreira, Sachiko Sato, Tariq Sethi, Irma van Die, Gerardo Vasta, John Wang, Paul Winyard, Vitaly Balan, Pratima Nangia-Makker

== Progress toward understanding this GBP paradigm ==
This section documents what is currently known about Galectin-3, its carbohydrate ligand(s), and how they interact to mediate cell communication. Further information can be found in the GBP Molecule Pages for [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_hum_Stlect_00118&sideMenu=no human] and [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_1306&sideMenu=no mouse] Galectin-3 in the CFG database.
=== Carbohydrate ligands ===

 
=== Cellular expression of GBP and ligands===
Galectin-3 is constitutively expressed in epithelial and myeloid cells, and regulated by processes that include cell proliferation, inflammation, and tumor initiation and progression[cite]. Gene expression in various cells and tissues have been performed with CFG [http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=galectin-3&cat=coree Core IgE].
 
=== Biosynthesis of ligands ===
The immunomodulatory activity of galectin 3 is mediated by binding to poly N-acetyllactosamine chains attached to the T cell receptor, resulting in a decrease in the lateral mobility of the receptor, which suppresses its activation. Attachment of the poly N-acetyllactosamine chains is dependent on the establishment of a 1-6 branch on the core oligosaccharide, through the action of GlcNAc transferase V (Mgat5) ([http://www.functionalglycomics.org/glycomics/molecule/jsp/glycoEnzyme/viewGlycoEnzyme.jsp?gbpId=gt_hum_553&sideMenu=true&pageType=general Human][http://www.functionalglycomics.org/glycomics/molecule/jsp/glycoEnzyme/viewGlycoEnzyme.jsp?gbpId=gt_mou_597&sideMenu=true&pageType=general Mouse]). Extension of the chain requires the action of UDP-GlcNAc:βGal β-1,3-N-acetylglucosaminyltransferase 1 ([http://www.functionalglycomics.org/glycomics/molecule/jsp/glycoEnzyme/viewGlycoEnzyme.jsp?gbpId=gt_hum_536&sideMenu=true&pageType=general Human][http://www.functionalglycomics.org/glycomics/molecule/jsp/glycoEnzyme/viewGlycoEnzyme.jsp?gbpId=gt_mou_571&sideMenu=true&pageType=general Mouse]) and galactosyltransferase and β1-4galatosyltransferase 1 ([http://www.functionalglycomics.org/glycomics/molecule/jsp/glycoEnzyme/viewGlycoEnzyme.jsp?gbpId=gt_hum_436&sideMenu=true&pageType=general Human][http://www.functionalglycomics.org/glycomics/molecule/jsp/glycoEnzyme/viewGlycoEnzyme.jsp?gbpId=gt_mou_460&sideMenu=true&pageType=general Mouse]).
 

=== Structure ===
The structures of the CRD of galectin-3 from X-ray crystallographic<ref>Seetharaman, J., Kanigsberg, A., Slaaby, R., Leffler, H., Barondes, S.H., and Rini, J.M. [http://www.ncbi.nlm.nih.gov/pubmed/9582341 X-ray crystal structure of the human galectin-3 carbohydrate recognition domain at 2.1 angstrom resolution.] J. Biol. Chem. 1998; 273: 13047–13052. PMID: 9582341.</ref> and NMR<ref>Umemoto K, Leffler H, Venot A, Valafar H, Prestegard JH. [http://www.ncbi.nlm.nih.gov/pubmed/12667058 Conformational differences in liganded and unliganded states of Galectin-3.] Biochem. 2003; 8;42(13):3688-3695. PMID: 12667058.</ref> analyses have been described. The proline-rich N-terminal domain is required for oligomerization of galectin-3<ref>Hsu DK, Zuberi RI, Liu FT. [http://www.ncbi.nlm.nih.gov/pubmed/1629216 Biochemical and biophysical characterization of human recombinant IgE-binding protein, an S-type animal lectin.] J Biol Chem. 1992; 267(20):14167-14174. PMID: 1629216.</ref> and demonstrates significant interaction with the CRD as initially suggested by observations that a monoclonal antibody recognizing an epitope in the N-terminus was capable of inhibiting glycan binding in the C-terminal CRD<ref>Liu FT, Hsu DK, Zuberi RI, Hill PN, Shenhav A, Kuwabara I, Chen SS. [http://www.ncbi.nlm.nih.gov/pubmed/8634249 Modulation of functional properties of galectin-3 by monoclonal antibodies binding to the non-lectin domains.] Biochemistry. 1996; 35(19):6073-6079. PMID: 8634249.</ref>, and revealed by NMR and EM studies<ref>Birdsall B, Feeney J, Burdett ID, Bawumia S, Barboni EA, Hughes RC. [http://www.ncbi.nlm.nih.gov/pubmed/11294654 NMR solution studies of hamster galectin-3 and electron microscopic visualization of surface-adsorbed complexes: evidence for interactions between the N- and C-terminal domains.] Biochem. 2001; 40:4859-4866. PMID: 11294654.</ref>.
 
=== Biological roles of GBP-ligand interaction ===

'''Regulation of cellular responses.''' 
Galectin-3 induces various kinds of biological responses in a variety cell types in vitro by engaging glycoproteins or glycolipids on the cell surfaces (reviewed in <ref>Rabinovich GA, Liu FT, Hirashima M, Anderson A. An emerging role for galectins in tuning the immune response: lessons from experimental models of inflammatory disease, autoimmunity and cancer. Scand J Immunol. 2007 Aug-Sep;66(2-3):143-58. Review. PubMed PMID:17635792 http://www.ncbi.nlm.nih.gov/pubmed/17635792</ref><ref>Liu FT. [http://www.ncbi.nlm.nih.gov/pubmed/15775687 Regulatory roles of galectins in the immune response.] Int Arch Allergy Immunol. 2005 Apr;136(4):385-400. Review. PubMed PMID: 15775687.</ref>). 

Galectin-3 can form lattices with selected cell surface glycans, in which galectin-3 oligomers bind to glycans on different glycoproteins displayed on the cell surface. Through this mechanism, galectin-3 modulates the properties and responses of the glycoproteins, such as their lateral mobility on the cell surface, rate of endocytosis, and transmission of signals at the cell surface (reviewed in <ref>Lajoie P, Goetz JG, Dennis JW, Nabi IR. [http://www.ncbi.nlm.nih.gov/pubmed/19398762 Lattices, rafts, and scaffolds: domainregulation of receptor signaling at the plasma membrane.] J Cell Biol. 2009 May 4;185(3):381-5. Epub 2009 Apr 27. Review. PubMed PMID: 19398762; PubMed Central PMCID: PMC2700393.</ref><ref>Grigorian A, Torossian S, Demetriou M. [http://www.ncbi.nlm.nih.gov/pubmed/19594640 T-cell growth, cell surface organization, and the galectin-glycoprotein lattice.] Immunol Rev. 2009 Jul;230(1):232-46. Review. PubMed PMID: 19594640.</ref><ref>Dennis JW, Nabi IR, Demetriou M. [http://www.ncbi.nlm.nih.gov/pubmed/20064370 Metabolism, cell surface organization, and disease.] Cell. 2009 Dec 24;139(7):1229-41. Review. PubMed PMID: 20064370.</ref>). 

Endogenous galectin-3 regulates cellular responses by functioning inside the cells, including pre-mRNA splicing, where galectin-3 functions as a component of spliceosomes<ref>Haudek KC, Spronk KJ, Voss PG, Patterson RJ, Wang JL, Arnoys EJ. [http://www.ncbi.nlm.nih.gov/pubmed/19616076 Dynamics of galectin-3 in the nucleus and cytoplasm.] Biochim Biophys Acta. 2010 Feb;1800(2):181-9. Epub 2009 Jul 16. Review. PubMed PMID: 19616076; PubMed Central PMCID: PMC2815258.</ref>, and regulation of expression of certain genes, including those for cyclin D1, thyroid-specific TTF-1 transcription factor, MUC2 mucin, and c-Jun N-terminal kinase (reviewed in <ref>Nakahara S, Raz A. [http://www.ncbi.nlm.nih.gov/pubmed/17726578 Regulation of cancer-related gene expression by galectin-3 and the molecular mechanism of its nuclear import pathway.] Cancer Metastasis Rev. 2007 Dec;26(3-4):605-10. Review. PubMed PMID: 17726578.</ref><ref>Yang RY, Rabinovich GA, Liu FT. [http://www.ncbi.nlm.nih.gov/pubmed/18549522 Galectins: structure, function and therapeutic potential.] Expert Rev Mol Med. 2008 Jun 13;10:e17. Review. PubMed PMID: 18549522.</ref>). 

Endogenous Galectin-3 inhibits apoptosis in various cell types by functioning inside the cells (reviewed in <ref>Hsu DK, Yang RY, Liu FT. [http://www.ncbi.nlm.nih.gov/pubmed/17132510 Galectins in apoptosis.] Methods Enzymol.2006;417:256-73. Review. PubMed PMID: 17132510.</ref><ref>Hsu DK, Liu FT. [http://www.ncbi.nlm.nih.gov/pubmed/14758074 Regulation of cellular homeostasis by galectins.] Glycoconj J. 2004;19(7-9):507-15. Review. PubMed PMID: 14758074.</ref>). 

Endogenous Galectin-3 controls intracellular trafficking of glycoproteins<ref>Delacour D, Koch A, Jacob R. [http://www.ncbi.nlm.nih.gov/pubmed/19650851 The role of galectins in protein trafficking.] Traffic. 2009 Oct;10(10):1405-13. Epub 2009 Jun 26. Review. PubMed PMID:19650851.</ref><ref>Stechly L, Morelle W, Dessein AF, André S, Grard G, Trinel D, Dejonghe MJ,Leteurtre E, Drobecq H, Trugnan G, Gabius HJ, Huet G. [http://www.ncbi.nlm.nih.gov/pubmed/19192249 Galectin-4-regulated delivery of glycoproteins to the brush border membrane of enterocyte-like cells.] Traffic. 2009 Apr;10(4):438-50. Epub 2009 Jan 24. PubMed PMID: 19192249.</ref>, which may be linked to its ability to translocate into the lumen of transport vesicles. Intracellular galectin-3 is associated with centrosomes in epithelial cells transiently during the process of epithelial polarization and may thus regulate epithelial polarization in enterocytes<ref>Delacour D, Koch A, Ackermann W, Eude-Le Parco I, Elsässer HP, Poirier F,Jacob R. [http://www.ncbi.nlm.nih.gov/pubmed/18211959 Loss of galectin-3 impairs membrane polarisation of mouse enterocytes in vivo.] J Cell Sci. 2008 Feb 15;121(Pt 4):458-65. Epub 2008 Jan 22. PubMed PMID:18211959.</ref><ref>Koch A, Poirier F, Jacob R, Delacour D. [http://www.ncbi.nlm.nih.gov/pubmed/19923323 Galectin-3, a novel centrosome-associated protein, required for epithelial morphogenesis.] Mol Biol Cell. 2010 Jan;21(2):219-31. Epub 2009 Nov 18. PubMed PMID: 19923323; PubMed Central PMCID: PMC2808235.</ref>. Galectin-3 contributes to maintenance of the barrier function of ocular surface epithelial cells<ref>Argüeso P, Guzman-Aranguez A, Mantelli F, Cao Z, Ricciuto J, Panjwani N. [http://www.ncbi.nlm.nih.gov/pubmed/19556244 Association of cell surface mucins with galectin-3 contributes to the ocular surface epithelial barrier.] J Biol Chem. 2009 Aug 21;284(34):23037-45. Epub 2009 Jun 25. PubMed PMID: 19556244; PubMed Central PMCID: PMC2755710.</ref>. 

'''Immunity and inflammation.''' 

''Functions demonstrated in vitro.'' 
T and B cells 
Endogenous galectin-3
:* regulates differentiation of B cells into plasma cells and memory B cells<ref>Acosta-Rodríguez EV, Montes CL, Motrán CC, Zuniga EI, Liu FT, Rabinovich GA, Gruppi A. [http://www.ncbi.nlm.nih.gov/pubmed/14688359 Galectin-3 mediates IL-4-induced survival and differentiation of B cells: functional cross-talk and implications during Trypanosoma cruzi infection.] J Immunol. 2004 Jan 1;172(1):493-502. PubMed PMID: 14688359.</ref>
:* is anti-apoptotic in B cell lines<ref>Hoyer KK, Pang M, Gui D, Shintaku IP, Kuwabara I, Liu FT, Said JW, Baum LG, Teitell MA. [http://www.ncbi.nlm.nih.gov/pubmed/14982843 An anti-apoptotic role for galectin-3 in diffuse large B-cell lymphomas.] Am J Pathol. 2004 Mar;164(3):893-902. PubMed PMID: 14982843; PubMed Central PMCID: PMC1614710.</ref> 

In T cells, purified galectin-3
:* induces IL-2 production<ref>Hsu DK, Hammes SR, Kuwabara I, Greene WC, Liu FT. [http://www.ncbi.nlm.nih.gov/pubmed/8623933 Human T lymphotropic virus-I infection of human T lymphocytes induces expression of the beta-galactoside-binding lectin, galectin-3.] Am J Pathol. 1996
May;148(5):1661-70. PubMed PMID: 8623933; PubMed Central PMCID: PMC1861566.</ref> and calcium influx<ref>Dong S, Hughes RC. [http://www.ncbi.nlm.nih.gov/pubmed/8898087 Galectin-3 stimulates uptake of extracellular Ca2+ in human Jurkat T-cells.] FEBS Lett. 1996 Oct 21;395(2-3):165-9. PubMed PMID: 8898087.</ref> in Jurkat T cells
:* induces apoptosis in human T leukemic cell lines, human peripheral blood mononuclear cells, and mouse activated T cells<ref>Fukumori T, Takenaka Y, Yoshii T, Kim HR, Hogan V, Inohara H, Kagawa S, Raz A. [http://www.ncbi.nlm.nih.gov/pubmed/14678989 CD29 and CD7 mediate galectin-3-induced type II T-cell apoptosis.] Cancer Res. 2003 Dec 1;63(23):8302-11. PubMed PMID: 14678989.</ref><ref name="Stillman 2006">Stillman BN, Hsu DK, Pang M, Brewer CF, Johnson P, Liu FT, Baum LG. [http://www.ncbi.nlm.nih.gov/pubmed/16393961 Galectin-3 and galectin-1 bind distinct cell surface glycoprotein receptors to induce T cell death.] J Immunol. 2006 Jan 15;176(2):778-89. PubMed PMID: 16393961.</ref>, normal human T cells<ref name="Stowell 2008">Stowell SR, Qian Y, Karmakar S, Koyama NS, Dias-Baruffi M, Leffler H, McEver RP, Cummings RD. [http://www.ncbi.nlm.nih.gov/pubmed/18292532 Differential roles of galectin-1 and galectin-3 in regulating leukocyte viability and cytokine secretion.] J Immunol. 2008 Mar 1;180(5):3091-102. PubMed PMID: 18292532.</ref>, and a human tumor infiltrating T cell line<ref>Peng W, Wang HY, Miyahara Y, Peng G, Wang RF. [http://www.ncbi.nlm.nih.gov/pubmed/18757439 Tumor-associated galectin-3 modulates the function of tumor-reactive T cells.] Cancer Res. 2008 Sep 1;68(17):7228-36. PubMed PMID: 18757439.</ref>. In some T cell lines, such as MOLT-4 cells, galectin-3 induces phosphatidylserine exposure, an early event in apoptosis, but not cell death<ref name="Stowell 2008"/>
:* induces apoptosis in both Th1 and Th2 cells<ref>Toscano MA, Bianco GA, Ilarregui JM, Croci DO, Correale J, Hernandez JD, Zwirner NW, Poirier F, Riley EM, Baum LG, Rabinovich GA. [http://www.ncbi.nlm.nih.gov/pubmed/17589510 Differential glycosylation of TH1, TH2 and TH-17 effector cells selectively regulates susceptibility to cell death.] Nat Immunol. 2007 Aug;8(8):825-34. Epub 2007 Jun 24. PubMed PMID: 17589510.</ref>
:* induces apoptosis in CD4-CD8- human thymocytes<ref name="Stillman 2006"/>
:* attenuates interaction of thymocytes with thymic nurse cells<ref>Silva-Monteiro E, Reis Lorenzato L, Kenji Nihei O, Junqueira M, Rabinovich GA, Hsu DK, Liu FT, Savino W, Chammas R, Villa-Verde DM. [http://www.ncbi.nlm.nih.gov/pubmed/17255323 Altered expression of galectin-3 induces cortical thymocyte depletion and premature exit of immature thymocytes during Trypanosoma cruzi infection.] Am J Pathol. 2007 Feb;170(2):546-56. PubMed PMID: 17255323; PubMed Central PMCID: PMC1851869.</ref> 

Endogenous Galectin-3 has anti-apoptotic activity in the human T cell line Jurkat<ref>Yang RY, Hsu DK, Liu FT. [http://www.ncbi.nlm.nih.gov/pubmed/8692888 Expression of galectin-3 modulates T-cell growth and
apoptosis.] Proc Natl Acad Sci U S A. 1996 Jun 25;93(13):6737-42. PubMed PMID:8692888; PubMed Central PMCID: PMC39096.</ref>. 

Galectin-3 has also been documented in the following T cell functions:
:* binds to Mgat5-modified T cell receptor (TCR) and suppresses T cell activation induced by TCR engagement; this is associated with a decrease in lateral mobility of TCR<ref>Demetriou M, Granovsky M, Quaggin S, Dennis JW. [http://www.ncbi.nlm.nih.gov/pubmed/11217864 Negative regulation of T-cell activation and autoimmunity by Mgat5 N-glycosylation.] Nature. 2001 Feb 8;409(6821):733-9. PubMed PMID: 11217864.</ref>
:* attenuates association of CD8 and TCR on CD8+ tumor-infiltrating lymphocytes, thus causing anergy<ref>Demotte N, Stroobant V, Courtoy PJ, Van Der Smissen P, Colau D, Luescher IF, Hivroz C, Nicaise J, Squifflet JL, Mourad M, Godelaine D, Boon T, van der Bruggen P. [http://www.ncbi.nlm.nih.gov/pubmed/18342010 Restoring the association of the T cell receptor with CD8 reverses anergy in human tumor-infiltrating lymphocytes.] Immunity. 2008 Mar;28(3):414-24. PubMed PMID: 18342010.</ref>
:* negatively regulates TCR-mediated CD4+ T cell activation at the immunological synapse, by intracellular action<ref>Chen HY, Fermin A, Vardhana S, Weng IC, Lo KF, Chang EY, Maverakis E, Yang RY, Hsu DK, Dustin ML, Liu FT. [http://www.ncbi.nlm.nih.gov/pubmed/19706535 Galectin-3 negatively regulates TCR-mediated CD4+ T-cell activation at the immunological synapse.] Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14496-501. Epub 2009 Aug 12. PubMed PMID: 19706535; PubMed Central PMCID: PMC2732795.</ref>

Dendritic cells 
Endogenous Galectin-3
:* suppresses the production of IL-12 by dendritic cells<ref name="Bernardes 2006">Bernardes ES, Silva NM, Ruas LP, Mineo JR, Loyola AM, Hsu DK, Liu FT, Chammas R, Roque-Barreira MC. [http://www.ncbi.nlm.nih.gov/pubmed/16723706 Toxoplasma gondii infection reveals a novel regulatory role for galectin-3 in the interface of innate and adaptive immunity.] Am J Pathol. 2006 Jun;168(6):1910-20. PubMed PMID: 16723706; PubMed Central PMCID: PMC1606628.</ref> and may suppress Th1 responses<ref name="Saegusa 2009">Saegusa J, Hsu DK, Chen HY, Yu L, Fermin A, Fung MA, Liu FT. [http://www.ncbi.nlm.nih.gov/pubmed/19179612 Galectin-3 is critical for the development of the allergic inflammatory response in a mouse model of atopic dermatitis.] Am J Pathol. 2009 Mar;174(3):922-31. Epub 2009 Jan 29. PubMed PMID: 19179612; PubMed Central PMCID: PMC2665752.</ref>
:* promotes Th2 polarization in the setting of antigen presentation to T cells by dendritic cells<ref name="Saegusa 2009"/>. Another study suggests that galectin-3 suppresses the antigen-presenting function of dendritic cells<ref name="Breuilh 2007">Breuilh L, Vanhoutte F, Fontaine J, van Stijn CM, Tillie-Leblond I, Capron M, Faveeuw C, Jouault T, van Die I, Gosset P, Trottein F. [http://www.ncbi.nlm.nih.gov/pubmed/17785480 Galectin-3 modulates immune and inflammatory responses during helminthic infection: impact of galectin-3 deficiency on the functions of dendritic cells.] Infect Immun. 2007 Nov;75(11):5148-57. Epub 2007 Sep 4. PubMed PMID: 17785480; PubMed Central PMCID: PMC2168304.</ref>)
:* promotes dendritic cell trafficking by functioning intracellularly<ref name="Hsu 2009">Hsu DK, Chernyavsky AI, Chen HY, Yu L, Grando SA, Liu FT. [http://www.ncbi.nlm.nih.gov/pubmed/18843294 Endogenous galectin-3 is localized in membrane lipid rafts and regulates migration of dendritic cells.] J Invest Dermatol. 2009 Mar;129(3):573-83. Epub 2008 Oct 9. PubMed PMID: 18843294; PubMed Central PMCID: PMC2645233.</ref>
Galectin-3 promotes adhesion of mouse dendritic cells<ref>[Vray B, Camby I, Vercruysse V, Mijatovic T, Bovin NV, Ricciardi-Castagnoli P,
Kaltner H, Salmon I, Gabius HJ, Kiss R. [http://www.ncbi.nlm.nih.gov/pubmed/15044384 Up-regulation of galectin-3 and its ligands by Trypanosoma cruzi infection with modulation of adhesion and migration of murine dendritic cells.] Glycobiology. 2004 Jul;14(7):647-57. Epub 2004 Mar 24.PubMed PMID: 15044384</ref>. 

Neutrophils 
Galectin-3 acts on these cells in the following manner:
:* induces oxidative burst<ref>Yamaoka A, Kuwabara I, Frigeri LG, Liu FT. [http://www.ncbi.nlm.nih.gov/pubmed/7897228 A human lectin, galectin-3 (epsilon bp/Mac-2), stimulates superoxide production by neutrophils.] J Immunol. 1995 Apr 1;154(7):3479-87. PubMed PMID: 7897228.</ref><ref>Karlsson A, Follin P, Leffler H, Dahlgren C. [http://www.ncbi.nlm.nih.gov/pubmed/9558402 Galectin-3 activates the NADPH-oxidase in exudated but not peripheral blood neutrophils.] Blood. 1998 May 1;91(9):3430-8. PubMed PMID: 9558402.</ref><ref>Almkvist J, Fäldt J, Dahlgren C, Leffler H, Karlsson A. [http://www.ncbi.nlm.nih.gov/pubmed/11159975 Lipopolysaccharide-induced gelatinase granule mobilization primes neutrophils for activation by galectin-3 and formylmethionyl-Leu-Phe.] Infect Immun. 2001 Feb;69(2):832-7. PubMed PMID: 11159975; PubMed Central PMCID: PMC97959.</ref> and L-selectin shedding as well as IL-8 production<ref name="Farnworth 2008">Farnworth SL, Henderson NC, Mackinnon AC, Atkinson KM, Wilkinson T, Dhaliwal K, Hayashi K, Simpson AJ, Rossi AG, Haslett C, Sethi T. [http://www.ncbi.nlm.nih.gov/pubmed/18202191 Galectin-3 reduces the severity of pneumococcal pneumonia by augmenting neutrophil function.] Am J Pathol. 2008 Feb;172(2):395-405. Epub 2008 Jan 17. PubMed PMID: 18202191; PubMed Central PMCID: PMC2312371.</ref>
:* promotes neutrophil adhesion to the extracellular protein laminin<ref>Kuwabara I, Liu FT. [http://www.ncbi.nlm.nih.gov/pubmed/8621934 Galectin-3 promotes adhesion of human neutrophils to laminin.] J Immunol. 1996 May 15;156(10):3939-44. PubMed PMID: 8621934.</ref> and endothelial cells<ref>Sato S, Ouellet N, Pelletier I, Simard M, Rancourt A, Bergeron MG. [http://www.ncbi.nlm.nih.gov/pubmed/11823514 Role of galectin-3 as an adhesion molecule for neutrophil extravasation during streptococcal pneumonia.] J Immunol. 2002 Feb 15;168(4):1813-22. PubMed PMID: 11823514.</ref>
:* induces phosphatidylserine exposure in the absence of cell death<ref name="Stowell 2008"/>, and induces apoptosis<ref>Fernández GC, Ilarregui JM, Rubel CJ, Toscano MA, Gómez SA, Beigier Bompadre M, Isturiz MA, Rabinovich GA, Palermo MS. [http://www.ncbi.nlm.nih.gov/pubmed/15604089 Galectin-3 and soluble fibrinogen act in concert to modulate neutrophil activation and survival: involvement of alternative MAPK pathways.] Glycobiology. 2005 May;15(5):519-27. Epub 2004 Dec 15. PubMed PMID: 15604089.</ref>
Endogenous galectin-3 protects neutrophils from apoptosis<ref name="Farnworth 2008"/>. 

Macrophages 
Endogenous galectin-3
:* is anti-apoptotic in macrophages treated with LPS and IFN-γ<ref name="Colnot 1998">Colnot C, Ripoche MA, Milon G, Montagutelli X, Crocker PR, Poirier F. [http://www.ncbi.nlm.nih.gov/pubmed/9767409 Maintenance of granulocyte numbers during acute peritonitis is defective in galectin-3-null mutant mice.] Immunology. 1998 Jul;94(3):290-6. PubMed PMID: 9767409; PubMed Central PMCID: PMC1364244.</ref>. It plays a critical role in the phagocytic function of macrophages in ingesting opsonized sheep red blood cells and apoptotic thymocytes. 
:* plays a critical role in alternative macrophage activation<ref>MacKinnon AC, Farnworth SL, Hodkinson PS, Henderson NC, Atkinson KM, Leffler H, Nilsson UJ, Haslett C, Forbes SJ, Sethi T. [http://www.ncbi.nlm.nih.gov/pubmed/18250477 Regulation of alternative macrophage activation by galectin-3.] J Immunol. 2008 Feb 15;180(4):2650-8. PubMed PMID: 18250477.</ref>

Recombinant galectin-3
:* triggers human peripheral blood monocytes to produce superoxide anion<ref>Liu FT, Hsu DK, Zuberi RI, Kuwabara I, Chi EY, Henderson WR Jr. [http://www.ncbi.nlm.nih.gov/pubmed/7573347 Expression and function of galectin-3, a beta-galactoside-binding lectin, in human monocytes and macrophages.] Am J Pathol. 1995 Oct;147(4):1016-28. PubMed PMID: 7573347; PubMed Central PMCID: PMC1871012.</ref> and potentiates LPS-induced IL-1 production<ref>Jeng KC, Frigeri LG, Liu FT. [http://www.ncbi.nlm.nih.gov/pubmed/7890309 An endogenous lectin, galectin-3 (epsilon BP/Mac-2), potentiates IL-1 production by human monocytes.] Immunol Lett. 1994 Oct;42(3):113-6. PubMed PMID: 7890309.</ref>
:* functions as a chemoattractant for monocytes and macrophages<ref>Sano H, Hsu DK, Yu L, Apgar JR, Kuwabara I, Yamanaka T, Hirashima M, Liu FT. [http://www.ncbi.nlm.nih.gov/pubmed/10925302 Human galectin-3 is a novel chemoattractant for monocytes and macrophages.] J Immunol. 2000 Aug 15;165(4):2156-64. PubMed PMID: 10925302.</ref>
:* is an opsonin and enhances the macrophage clearance of apoptotic neutrophils<ref>Karlsson A, Christenson K, Matlak M, Björstad A, Brown KL, Telemo E, Salomonsson E, Leffler H, Bylund J. [http://www.ncbi.nlm.nih.gov/pubmed/18849325 Galectin-3 functions as an opsonin and enhances the macrophage clearance of apoptotic neutrophils.] Glycobiology. 2009 Jan;19(1):16-20. Epub 2008 Oct 10. PubMed PMID: 18849325.</ref>
:* activates microglia (tissue macrophages of the central nervous system) to phagocytose degenerated myelin mediated by complement receptor-3 and scavenger receptor<ref>Rotshenker S. [http://www.ncbi.nlm.nih.gov/pubmed/19253007 The role of Galectin-3/MAC-2 in the activation of the innate-immune function of phagocytosis in microglia in injury and disease.] J Mol Neurosci. 2009 Sep;39(1-2):99-103. Epub 2009 Feb 28. Review. PubMed PMID:19253007.</ref> 
:* binds to a major xenoantigen, α-Gal [Galα(1,3)Galβ(1,4)GlcNAc], expressed on porcine endothelial cells<ref>Jin R, Greenwald A, Peterson MD, Waddell TK. [http://www.ncbi.nlm.nih.gov/pubmed/16818789 Human monocytes recognize porcine endothelium via the interaction of galectin 3 and alpha-GAL.] J Immunol. 2006 Jul 15;177(2):1289-95. PubMed PMID: 16818789.</ref> and mediates adhesion of human monocytes to porcine endothelial cells
:* suppresses LPS-induced production of inflammatory cytokines by macrophages, including IL-6, IL-12, and TNF-α<ref name="Li 2008">Li Y, Komai-Koma M, Gilchrist DS, Hsu DK, Liu FT, Springall T, Xu D. [http://www.ncbi.nlm.nih.gov/pubmed/18684969 Galectin-3 is a negative regulator of lipopolysaccharide-mediated inflammation.] J Immunol. 2008 Aug 15;181(4):2781-9. PubMed PMID: 18684969.</ref> 

Mast cells 
Galectin-3 induces mediator release from both IgE-sensitized and nonsensitized mast cells<ref>Frigeri LG, Zuberi RI, Liu FT. [http://www.ncbi.nlm.nih.gov/pubmed/8347574 Epsilon BP, a beta-galactoside-binding animal lectin, recognizes IgE receptor (Fc epsilon RI) and activates mast cells.] Biochemistry. 1993 Aug 3;32(30):7644-9. PubMed PMID: 8347574. </ref><ref>Zuberi RI, Frigeri LG, Liu FT. [http://www.ncbi.nlm.nih.gov/pubmed/8200029 Activation of rat basophilic leukemia cells by epsilon BP, an IgE-binding endogenous lectin.] Cell Immunol. 1994 Jun;156(1):1-12. PubMed PMID: 8200029.</ref>, but apoptosis following prolonged treatment (18-44 h)<ref>Suzuki Y, Inoue T, Yoshimaru T, Ra C. [http://www.ncbi.nlm.nih.gov/pubmed/18302939 Galectin-3 but not galectin-1 induces mast cell death by oxidative stress and mitochondrial permeability transition.] Biochim Biophys Acta. 2008 May;1783(5):924-34. Epub 2008 Feb 12. PubMed PMID: 18302939.</ref>. Endogenous Galectin-3 is a positive regulator of mast cell mediator release and cytokine production<ref>Chen HY, Sharma BB, Yu L, Zuberi R, Weng IC, Kawakami Y, Kawakami T, Hsu DK, Liu FT. [http://www.ncbi.nlm.nih.gov/pubmed/17015681 Role of galectin-3 in mast cell functions: galectin-3-deficient mast cells exhibit impaired mediator release and defective JNK expression.] J Immunol. 2006 Oct 15;177(8):4991-7. PubMed PMID: 17015681.</ref>. 

Eosinophils 
Recombinant galectin-3
:* suppresses IL-5 production by human eosinophils<ref>Cortegano I, del Pozo V, Cárdaba B, de Andrés B, Gallardo S, del Amo A, Arrieta I, Jurado A, Palomino P, Liu FT, Lahoz C. [http://www.ncbi.nlm.nih.gov/pubmed/9647247 Galectin-3 down-regulates IL-5 gene expression on different cell types.] J Immunol. 1998 Jul 1;161(1):385-9. PubMed PMID: 9647247.</ref>
:* mediates rolling and adhesion of eosinophils on immobilized VCAM-1 under conditions of flow<ref>Rao SP, Wang Z, Zuberi RI, Sikora L, Bahaie NS, Zuraw BL, Liu FT, Sriramarao P. [http://www.ncbi.nlm.nih.gov/pubmed/18025226 Galectin-3 functions as an adhesion molecule to support eosinophil rolling and adhesion under conditions of flow.] J Immunol. 2007 Dec 1;179(11):7800-7. PubMed PMID: 18025226.</ref>. 

''Functions demonstrated in vivo.'' 

A number of biological functions have been identified by using ''Lgals3-/-'' mice. With respect to acute inflammation and allergic inflammation galectin-3:
:# has a proinflammatory role in acute inflammation induced by intraperitoneal injection of thioglycollate broth, in terms of the neutrophil response,<ref name="Colnot 1998"/> and macrophage response<ref>Hsu DK, Yang RY, Pan Z, Yu L, Salomon DR, Fung-Leung WP, Liu FT. [http://www.ncbi.nlm.nih.gov/pubmed/10702423 Targeted disruption of the galectin-3 gene results in attenuated peritoneal inflammatory responses.] Am J Pathol. 2000 Mar;156(3):1073-83. PubMed PMID: 10702423; PubMed Central PMCID: PMC1876862.</ref>
:# promotes allergic airway inflammation, airway hyperresponsiveness, and a Th2 response in a mouse model of asthma in which mice are sensitized with ovalbumin systemically and challenged with the same antigen through the airways<ref>Zuberi RI, Hsu DK, Kalayci O, Chen HY, Sheldon HK, Yu L, Apgar JR, Kawakami T, Lilly CM, Liu FT. [http://www.ncbi.nlm.nih.gov/pubmed/15579447 Critical role for galectin-3 in airway inflammation and bronchial hyperresponsiveness in a murine model of asthma.] Am J Pathol. 2004 Dec;165(6):2045-53. PubMed PMID: 15579447; PubMed Central PMCID: PMC1618718.</ref>
:# promotes allergic skin inflammation and a systemic Th2 response in a model of atopic dermatitis, in which mice are repeatedly sensitized with ovalbumin epicutaneously<ref name="Saegusa 2009"/>
:# promotes allergic contact hypersensitivity, in which mice are sensitized with the hapten oxazalone, and then challenged with the same hapten at another skin site<ref name="Hsu 2009"/> (38)
However, rats and mice treated by intranasal delivery of cDNA encoding Galectin-3 showed reduced eosinophil infiltration following airway antigen challenge<ref>del Pozo V, Rojo M, Rubio ML, Cortegano I, Cárdaba B, Gallardo S, Ortega M, Civantos E, López E, Martín-Mosquero C, Peces-Barba G, Palomino P, González-Mangado N, Lahoz C. [http://www.ncbi.nlm.nih.gov/pubmed/12204873 Gene therapy with galectin-3 inhibits bronchial obstruction and inflammation in antigen challenged rats through interleukin-5 gene downregulation.] Am J Respir Crit Care Med. 2002 Sep 1;166(5):732-7. PubMed PMID: 12204873.</ref><ref>López E, del Pozo V, Miguel T, Sastre B, Seoane C, Civantos E, Llanes E, Baeza ML, Palomino P, Cárdaba B, Gallardo S, Manzarbeitia F, Zubeldia JM, Lahoz C. [http://www.ncbi.nlm.nih.gov/pubmed/16424226 Inhibition of chronic airway inflammation and remodeling by galectin-3 gene therapy in a murine model.] J Immunol. 2006 Feb 1;176(3):1943-50. PubMed PMID: 16424226.</ref>. 

With regard to autoimmunity, galectin-3
:* contributes to the disease severity in a mouse model of autoimmune encephalomyelitis (EAE) induced by immunization with a myelin oligodendrocyte glycoprotein peptide<ref>Jiang HR, Al Rasebi Z, Mensah-Brown E, Shahin A, Xu D, Goodyear CS, Fukada SY, Liu FT, Liew FY, Lukic ML. [http://www.ncbi.nlm.nih.gov/pubmed/19124760 Galectin-3 deficiency reduces the severity of experimental autoimmune encephalomyelitis.] J Immunol. 2009 Jan 15;182(2):1167-73. PubMed PMID: 19124760.</ref>
:* suppresses the development of glomerulopathy in mice rendered diabetic with streptozotocin, associated with lower accumulation of advanced glycation end products (AGE) in the kidneys<ref>Pugliese G, Pricci F, Iacobini C, Leto G, Amadio L, Barsotti P, Frigeri L, Hsu DK, Vlassara H, Liu FT, Di Mario U. [http://www.ncbi.nlm.nih.gov/pubmed/11689472 Accelerated diabetic glomerulopathy in galectin-3/AGE receptor 3 knockout mice.] FASEB J. 2001 Nov;15(13):2471-9. PubMed PMID: 11689472.</ref>
:* may serve as an AGE receptor and protects from AGE-induced tissue injury<ref>Iacobini C, Menini S, Oddi G, Ricci C, Amadio L, Pricci F, Olivieri A, Sorcini M, Di Mario U, Pesce C, Pugliese G. [http://www.ncbi.nlm.nih.gov/pubmed/15361471 Galectin-3/AGE receptor 3 knockout mice show accelerated AGE-induced glomerular injury: evidence for a protective role of galectin-3 as an AGE receptor.] FASEB J. 2004 Nov;18(14):1773-5. Epub 2004 Sep 10. PubMed PMID: 15361471</ref> and age-dependent changes<ref>Iacobini C, Oddi G, Menini S, Amadio L, Ricci C, Di Pippo C, Sorcini M, Pricci
F, Pugliese F, Pugliese G. [http://www.ncbi.nlm.nih.gov/pubmed/15870382 Development of age-dependent glomerular lesions in galectin-3/AGE-receptor-3 knockout mice.] Am J Physiol Renal Physiol. 2005 Sep;289(3):F611-21. Epub 2005 May 3. PubMed PMID: 15870382.</ref>
:* contributes to development of diabetes induced by multiple low doses of streptozotocin<ref>Mensah-Brown EP, Al Rabesi Z, Shahin A, Al Shamsi M, Arsenijevic N, Hsu DK, Liu FT, Lukic ML. [http://www.ncbi.nlm.nih.gov/pubmed/18845486 Targeted disruption of the galectin-3 gene results in decreased susceptibility to multiple low dose streptozotocin-induced diabetes in mice.] Clin Immunol. 2009 Jan;130(1):83-8. Epub 2008 Oct 8. PubMed PMID: 18845486.</ref>; this may be related to its upregulation of TNF-&alpha: and nitric oxide production by macrophages
:* contributes to ischemia and neovascularization in retina in a mouse model of oxygen-induced proliferative retinopathy after perfusion of preformed AGEs<ref>Stitt AW, McGoldrick C, Rice-McCaldin A, McCance DR, Glenn JV, Hsu DK, Liu FT, Thorpe SR, Gardiner TA. [http://www.ncbi.nlm.nih.gov/pubmed/15734857 Impaired retinal angiogenesis in diabetes: role of advanced glycation end products and galectin-3.] Diabetes. 2005 Mar;54(3):785-94. PubMed PMID: 15734857.</ref>
:* is expressed in foam cells and macrophages in atherosclerotic lesions<ref>Nachtigal M, Al-Assaad Z, Mayer EP, Kim K, Monsigny M. [http://www.ncbi.nlm.nih.gov/pubmed/9588889 Galectin-3 expression in human atherosclerotic lesions.] Am J Pathol. 1998 May;152(5):1199-208. PubMed PMID: 9588889; PubMed Central PMCID: PMC1858580.</ref> and contributes to the development of atherosclerosis in apolipoprotein (Apo)E-deficient mice<ref>Nachtigal M, Ghaffar A, Mayer EP. [http://www.ncbi.nlm.nih.gov/pubmed/18156214 Galectin-3 gene inactivation reduces atherosclerotic lesions and adventitial inflammation in ApoE-deficient mice.] Am J Pathol. 2008 Jan;172(1):247-55. Epub 2007 Dec 21. PubMed PMID: 18156214; PubMed Central PMCID: PMC2189631.</ref> 

''Infectious processes.'' 

The roles of galectin-3 in a large number of mouse models of infectious disease have been studied in ''Lgals3-/-'' mice, as follows:
:# suppresses LPS-induced shock accompanied by lower inflammatory cytokine and nitric oxide production, possibly a result of its ability to bind to this endotoxin. However, it enhances sensitivity to ''Salmonella'' infection<ref name="Li 2008"/>
:# contributes to recruitment of neutrophils to lungs of mice infected with ''S. pneumoniae'' and has a protective role in development of pneumonia after the infection, possibly by augmenting the function of neutrophils<ref>Nieminen J, St-Pierre C, Bhaumik P, Poirier F, Sato S. [http://www.ncbi.nlm.nih.gov/pubmed/18250456 Role of galectin-3 in leukocyte recruitment in a murine model of lung infection by Streptococcus pneumoniae.] J Immunol. 2008 Feb 15;180(4):2466-73. PubMed PMID: 18250456.</ref>
:# contributes to inflammatory responses in intestines, liver, and brain (but not in lungs) and a lower systemic Th1-polarized response in mice infected by ''Toxoplasma gondii''<ref name="Bernardes 2006"/>; galectin-3 suppresses parasite burden in the brain
:# promotes development of T and B responses in the spleen, as well formation of liver granulomas, but suppresses the Th1-polarized response in mice infected with ''Schistosoma mansoni''<ref name="Breuilh 2007"/>
:# contributes to sensitivity in lethal effects of ''Rhodococcus equi'', a facultative intracellular bacterium of macrophages<ref>Ferraz LC, Bernardes ES, Oliveira AF, Ruas LP, Fermino ML, Soares SG, Loyola AM, Oliver C, Jamur MC, Hsu DK, Liu FT, Chammas R, Roque-Barreira MC. [http://www.ncbi.nlm.nih.gov/pubmed/18825751 Lack of galectin-3 alters the balance of innate immune cytokines and confers resistance to Rhodococcus equi infection.] Eur J Immunol. 2008 Oct;38(10):2762-75. PubMed PMID: 18825751.</ref>. It suppresses inflammatory responses, including production of the Th1 cytokines IL-12 and IFN-γ, as well as IL-1β 
:# promotes resistance of mice to infection by “Paracoccidioides brasiliensis” and favors a Th1-polarized immune response<ref>Ruas LP, Bernardes ES, Fermino ML, de Oliveira LL, Hsu DK, Liu FT, Chammas R, Roque-Barreira MC. [http://www.ncbi.nlm.nih.gov/pubmed/19229338 Lack of galectin-3 drives response to Paracoccidioides brasiliensis toward a Th2-biased immunity.] PLoS One. 2009;4(2):e4519. Epub 2009 Feb 20. PubMed PMID: 19229338; PubMed Central PMCID: PMC2641003.</ref> 

Interestingly, recombinant Galectin-3 is able to induce cell death in the yeast Candida albicans in vitro<ref>Kohatsu L, Hsu DK, Jegalian AG, Liu FT, Baum LG. [http://www.ncbi.nlm.nih.gov/pubmed/16982911 Galectin-3 induces death of Candida species expressing specific beta-1,2-linked mannans.] J Immunol. 2006 Oct 1;177(7):4718-26. PubMed PMID: 16982911.</ref>. 

'''Tumor development/progression.''' 
Galectin-3 expression is altered in a variety of tumors in comparison to normal tissues<ref>Danguy A, Camby I, Kiss R. [http://www.ncbi.nlm.nih.gov/pubmed/12223276 Galectins and cancer.] Biochim Biophys Acta. 2002 Sep 19;1572(2-3):285-93. Review. PubMed PMID: 12223276.</ref>. The diagnostic utility of Galectin-3 expression in thyroid cancer has been extensively demonstrated (e.g., <ref>Chiu CG, Strugnell SS, Griffith OL, Jones SJ, Gown AM, Walker B, Nabi IR, Wiseman SM. [http://www.ncbi.nlm.nih.gov/pubmed/20363921 Diagnostic utility of galectin-3 in thyroid cancer.] Am J Pathol. 2010 May;176(5):2067-81. Epub 2010 Apr 2. PubMed PMID: 20363921; PubMed Central PMCID: PMC2861072.</ref><ref>Carpi A, Mechanick JI, Saussez S, Nicolini A. [http://www.ncbi.nlm.nih.gov/pubmed/20578236 Thyroid tumor marker genomics and proteomics: diagnostic and clinical implications.] J Cell Physiol. 2010 Sep;224(3):612-9. PubMed PMID: 20578236.</ref>). The role of Galectin-3 in tumor growth, progression, and metastasis has been comprehensively documented (reviewed in <ref name="Liu 2005"/>). There is evidence that Galectin-3 expression is necessary for the initiation of the transformed phenotype of tumors, possibly related to its ability to interact with oncogenic K-Ras<ref>Shalom-Feuerstein R, Plowman SJ, Rotblat B, Ariotti N, Tian T, Hancock JF, Kloog Y. [http://www.ncbi.nlm.nih.gov/pubmed/18701484 K-ras nanoclustering is subverted by overexpression of the scaffold protein galectin-3.] Cancer Res. 2008 Aug 15;68(16):6608-16. PubMed PMID: 18701484; PubMed Central PMCID: PMC2587079.</ref>. 

The most extensively studied function of Galectin-3 is its inhibition of apoptosis in a range of tumor cell types exposed to diverse apoptotic stimuli (reviewed in <ref>Yang RY, Rabinovich GA, Liu FT. [http://www.ncbi.nlm.nih.gov/pubmed/18549522 Galectins: structure, function and therapeutic potential.] Expert Rev Mol Med. 2008 Jun 13;10:e17. Review. PubMed PMID: 18549522.</ref>). The mechanism by which Galectin-3 inhibits apoptosis in tumor cells has been extensively studied <ref name="Liu 2005"/><ref>Nakahara S, Oka N, Raz A. [http://www.ncbi.nlm.nih.gov/pubmed/15843888 On the role of galectin-3 in cancer apoptosis.] Apoptosis. 2005; 10:267-75. PubMed PMID: 15843888.</ref>). Apoptosis induced by the tumor suppressor p53 involves repression of Galectin-3<ref>Cecchinelli B, et al. [http://www.ncbi.nlm.nih.gov/pubmed/16738336 Repression of the antiapoptotic molecule galectin-3 by homeodomain-interacting protein kinase 2-activated p53 is required for p53-induced apoptosis.] Mol Cell Biol. 2006; 26:4746-57. PubMed PMID: 16738336; PMCID: PubMed Central PMC1489111</ref>. 

Endogenous galectin-3 promotes tumor cell growth (reviewed in <ref name="Liu 2005"/>), one mechanism may involve interaction with transcription factors<ref>Paron I, et al. [http://www.ncbi.nlm.nih.gov/pubmed/12615069 Nuclear localization of Galectin-3 in transformed thyroid cells: a role in transcriptional regulation.] Biochem Biophys Res Commun. 2003; 302:545-53. PubMed PMID: 12615069.</ref>, another may be facilitation of the signaling of K-Ras to Raf and PI3 kinase<ref>Ashery U, et al. [http://www.ncbi.nlm.nih.gov/pubmed/16691442 Spatiotemporal organization of Ras signaling: rasosomes and the galectin switch.] Cell Mol Neurobiol. 2006; 26:471-95. PubMed PMID: 16691442.</ref>. Endogenous galectin-3 also regulates tumor progression by influencing cell cycling; its binds to β-catenin and stimulates the expression of cyclin D and c-Myc<ref>Shimura T, Takenaka Y, Tsutsumi S, Hogan V, Kikuchi A, Raz A. [http://www.ncbi.nlm.nih.gov/pubmed/15374939 Galectin-3, a novel binding partner of beta-catenin.] Cancer Res. 2004; 64:6363-7. PubMed PMID: 15374939.</ref>. 

Galectin-3 can affect tumor metastasis by exerting its effect in the tumor microenvironment, including angiogenesis and fibrosis<ref name="Liu 2005"/>. Galectin-3 plays a role in activation of myofibroblasts in the liver and contributes to liver fibrosis induced by carbon tetrachloride<ref>Henderson NC, et al. [http://www.ncbi.nlm.nih.gov/pubmed/16549783 Galectin-3 regulates myofibroblast activation and hepatic fibrosis.] Proc Natl Acad Sci U S A. 2006; 103:5060-5. PubMed PMID: 16549783; PubMed Central PMCID: PMC1458794.</ref>. 

In a human melanoma tumor model in immunodeficient mice, administration of galectin-3 results in suppressing the tumor killing effect of tumor-reactive T cells<ref>Peng W, Wang HY, Miyahara Y, Peng G, Wang RF. [http://www.ncbi.nlm.nih.gov/pubmed/18757439 Tumor-associated galectin-3 modulates the function of tumor-reactive T cells.] Cancer Res. 2008 Sep 1;68(17):7228-36. PubMed PMID: 18757439.</ref>. Tumor-associated galectin-3 may also contribute to tumor immune escape by rendering tumor-infiltrating cytolytic lymphocytes anergic<ref>Demotte N, Stroobant V, Courtoy PJ, Van Der Smissen P, Colau D, Luescher IF, Hivroz C, Nicaise J, Squifflet JL, Mourad M, Godelaine D, Boon T, van der Bruggen P. [http://www.ncbi.nlm.nih.gov/pubmed/18342010 Restoring the association of the T cell receptor with CD8 reverses anergy in human tumor-infiltrating lymphocytes.] Immunity. 2008 Mar;28(3):414-24. PubMed PMID: 18342010.</ref>. 

Galectin-3 affects the motility of tumor cells and influences their invasiveness in vitro. However, both positive and negative effects have been reported<ref>Le Marer N, Hughes RC. [http://www.ncbi.nlm.nih.gov/pubmed/8647922 Effects of the carbohydrate-binding protein galectin-3 on the invasiveness of human breast carcinoma cells.] J Cell Physiol. 1996; 168:51-8. PubMed PMID: 8647922.</ref><ref>Moisa A, et al. [http://www.ncbi.nlm.nih.gov/pubmed/17695496 Growth/adhesion-regulatory tissue lectin galectin-3: stromal presence but not cytoplasmic/nuclear expression in tumor cells as a negative prognostic factor in breast cancer.] Anticancer Res. 2007; 27:2131-9. PubMed PMID: 17695496.</ref>. Endogenous galectin-3 can also contribute to cell motility and in vitro invasiveness<ref>Matarrese P, et al. [http://www.ncbi.nlm.nih.gov/pubmed/10699929 Galectin-3 overexpression protects from apoptosis by improving cell adhesion properties.] Int J Cancer. 2000; 85:545-54. PubMed PMID: 10699929.</ref><ref>O'Driscoll L, Linehan R, Liang YH, Joyce H, Oglesby I, Clynes M. [http://www.ncbi.nlm.nih.gov/pubmed/12530054 Galectin-3 expression alters adhesion, motility and invasion in a lung cell line (DLKP), in vitro.] Anticancer Res. 2002; 22:3117-25. PubMed PMID: 12530054.</ref><ref>Shimura T, et al. [http://www.ncbi.nlm.nih.gov/pubmed/15867344 Implication of galectin-3 in Wnt signaling.] Cancer Res. 2005; 65:3535-7. PubMed PMID: 15867344.</ref>. Galectin-3 has angiogenic activity, which may be related to its ability to induce migration of endothelial cells<ref>Nangia-Makker P, et al. [http://www.ncbi.nlm.nih.gov/pubmed/10702407 Galectin-3 induces endothelial cell morphogenesis and angiogenesis.] Am J Pathol. 2000; 156:899-909. PubMed PMID: 10702407; PubMed Central PMCID: PMC1876842.</ref>. 

Studies with animal models have provided evidence for the role of galectins in tumor metastasis in vivo (reviewed in <ref name="Liu 2005"/>). For example, liver metastases of human adenocarcinoma xenotransplants in SCID mice are inhibitable by anti-galectin-3 antibody. Breast carcinoma cells overexpressing transgenic galectin-3 have higher metastatic potential. In an orthotopic nude mouse model of human breast cancer, tumor metastasis is inhibitable by C-terminal domain fragment of galectin-3 (galectin-3C)<ref>John CM, Leffler H, Kahl-Knutsson B, Svensson I, Jarvis GA. [http://www.ncbi.nlm.nih.gov/pubmed/12796408 Truncated galectin-3 inhibits tumor growth and metastasis in orthotopic nude mouse model of human breast cancer.] Clin Cancer Res. 2003; 9:2374-83. PubMed PMID: 12796408.</ref>. 

Galectin-3 contributes to chemotherapeutic resistance of thyroid cancer cells in vitro, the progression of disease in prostate cancer<ref>Wang Y, et al. [http://www.ncbi.nlm.nih.gov/pubmed/19286570 Regulation of prostate cancer progression by galectin-3.] Am J Pathol. 2009; 174:1515-23. PubMed PMID: 19286570; PubMed Central PMCID: PMC2671381.</ref> and development of carcinogen-induced lung tumorigenesis<ref>Abdel-Aziz HO, et al. [http://www.ncbi.nlm.nih.gov/pubmed/18204863 Targeted disruption of the galectin-3 gene results in decreased susceptibility to NNK-induced lung tumorigenesis: an oligonucleotide microarray study.] J Cancer Res Clin Oncol. 2008; 134:777-88. PubMed PMID: 18204863.</ref> in mouse models. However, the absence of galectin-3 may not affect the evolution of cancers<ref>Eude-Le Parco I, et al. [http://www.ncbi.nlm.nih.gov/pubmed/18849326 Genetic assessment of the importance of galectin-3 in cancer initiation, progression, and dissemination in mice.] Glycobiology. 2009; 19:68-75. PubMed PMID: 18849326.</ref>. Galectin-3-targeting small molecule inhibitors enhancs apoptosis induced by chemo- and radio-therapy in papillary thyroid cancer in vitro<ref>Lin CI, et al. [http://www.ncbi.nlm.nih.gov/pubmed/19825987 Galectin-3 targeted therapy with a small molecule inhibitor activates apoptosis and enhances both chemosensitivity and radiosensitivity in papillary thyroid cancer.] Mol Cancer Res. 2009; 7:1655-62. PubMed PMID: 19825987.</ref>. GCS-100, a galectin-3 antagonist, induces myeloma cell death in vitro<ref>Streetly MJ, Maharaj L, Joel S, Schey SA, Gribben JG, Cotter FE. [http://www.ncbi.nlm.nih.gov/pubmed/20190189 GCS-100, a novel galectin-3 antagonist, modulates MCL-1, NOXA, and cell cycle to induce myeloma cell death.] Blood. 2010; 115:3939-48. PubMed PMID: 20190189.</ref>). 

== CFG resources used in investigations ==
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=galectin-3&maxresults=20 CFG database search results for Galectin-3].

=== Glycan profiling ===
 

=== Glycogene microarray ===
Gene expression analyses have been performed on several cell types and tissues at [http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=galectin-3&cat=coree Core E] of the CFG. Probes for human galectin-3 have been included in all versions of the CFG glycogene chip, and probes for mouse galectin-3 are included on versions 2, 3, and 4.
 

=== Knockout mouse lines ===
Galectin-3 knockout mice were [https://www.functionalglycomics.org/glycomics/publicdata/phenotyping.jsp phenotyped by Core G] of the CFG and continue to be used by investigators to study the biological functions of Galectin-3.

=== Glycan array ===
Investigators have used CFG carbohydrate compounds and glycan arrays to study ligand binding specificity of Galectin-3 (for example, click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_GLYCAN_v2_10_02132003 here]). To see all glycan array results for Galectin-3, click [http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=galectin-3&cat=coreh here].

== Related GBPs ==
Structure unique among galectins in mammals; homologues in vertebrates & invertebrates.

== References ==
<references/>

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: Linda Baum, Richard Cummings, Michael Demetriou, Daniel Hsu, Fu-Tong Liu, David F. Smith

CD22

2012-01-20T19:56:16Z

Anna Crie: /* Biological roles of GBP-ligand interaction */

CD22 is predominantly expressed on B cells and is well documented as a regulator of B cell receptor (BCR) signaling<ref name="Crocker 2007">Crocker PR, Paulson JC, Varki A. [http://www.ncbi.nlm.nih.gov/pubmed/17380156 Siglecs and their roles in the immune system]. ''Nat Rev Immunol'' 2007 Apr;7(4):255-66. Review.</ref>. It is one of four siglecs that are highly conserved among mammals. This paradigm is unique among the siglecs in that the cytoplasmic domain has six conserved tyrosine motifs, including three immunoreceptor tyrosine inhibitory motifs (ITIM), one ITIM-like motif, and a growth factor receptor bound protein2 (GRB2) motif. These tyrosine motifs are involved in regulation of BCR signaling and also mediate its constitutive clathrin mediated endocytosis, an activity believed to be tied to its regulation of cell signaling. The preferred glycan ligand of CD22 differs significantly in humans and mice<ref name="Crocker 2007"/><ref name="Kimura 2007">Kimura N, Ohmori K, Miyazaki K, Izawa M, Matsuzaki Y, Yasuda Y, Takematsu H, Kozutsumi Y, Moriyama A, Kannagi R. [http://www.ncbi.nlm.nih.gov/pubmed/17728258 Human B-lymphocytes express alpha2-6-sialylated 6-sulfo-N-acetyllactosamine serving as a preferred ligand for CD22/Siglec-2]. J'' Biol Chem''. 2007 Nov 2;282(44):32200-7.</ref><ref name="Blixt 2004">Blixt O, Head S, Mondala T, Scanlan C, Huflejt ME, Alvarez R, Bryan MC, Fazio F, Calarese D, Stevens J, Razi N, Stevens DJ, Skehel JJ, van Die I, Burton DR, Wilson IA, Cummings R, Bovin N, Wong CH, Paulson JC. [http://www.ncbi.nlm.nih.gov/pubmed/15563589 Printed covalent glycan array for ligand profiling of diverse glycan binding proteins]. ''Proc Natl Acad Sci U S A''. 2004 Dec 7;101(49):17033-8.</ref>. While both recognize the sequence Siaα-2-6Galβ-1-4GlcNAc expressed abundantly on B cells, murine CD22 prefers Neu5Gc (not found in humans) over Neu5Ac, while human CD22 exhibits highest affinity for sulfated sialoside, Neu5Acα-2-6Galβ-1-4[6S]GlcNAc, demonstrating significant evolution of ligand specificity with conservation of function. Although CD22 recognizes ligands on the same cell in ''cis'', it also binds to ligands in ''trans'' if expressed on adjacent contacting cells. A major area of investigation is to understand the relative roles of ''cis'' and ''trans'' ligands in CD22 function.

[[Image:SiglecCD22.jpg|right|alt text]]
== CFG Participating Investigators contributing to the understanding of this paradigm ==

CFG Participating Investigators (PIs) have made major contributions to the understanding of the biology of human and murine CD22. These include: Nicolai Bovin, Paul Crocker, Jamey Marth, David Nemazee, Lars Nitschke, Jim Paulson, Ajit Varki

== Progress toward understanding this GBP paradigm ==
This section documents what is currently known about CD22, its carbohydrate ligand(s), and how they interact to mediate cell communication. Further information can be found in the GBP Molecule Page for [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_hum_Itlect_269&sideMenu=no human] and [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_mou_Itlect_194&sideMenu=no mouse] CD22 (aka Siglec-2) in the CFG database.
=== Carbohydrate ligands ===
Although CD22 is highly conserved throughout mammalian species, murine and human CD22 are known to exhibit significant differences in their specificities that appear to have evolved to compensate for changes in the glycan ligands expressed on B cells. While both bind Siaα2-6Gal terminated glycans, murine CD22 prefers NeuGc (NeuGcα2-6Galβ1-4GlcNAc), which is not found in humans. In contrast, human human CD22 recognizes NeuAc and NeuGc with equal affinity. In addition, however, human CD22 exhibits highest affinity for a ligand with sulfate at the 6 position of GlcNAc (NeuAcα2-6Galβ1-4[6S]GlcNAc).<ref name="Crocker 2007"/><ref name="Kimura 2007"/> 9-O-acetylation of sialic acid abrogates binding of CD22, which is thought to regulate the binding of ''cis'' ligands on B cells.
 
=== Cellular expression of GBP and ligands ===
CD22 is primarily expressed on mature B cells and to a lesser extent on memory B cells. However, it is not expressed on pre-B cells and differentiated plasma cells. Like many siglecs, CD22 interacts with endogenous ligands on B cells in ''cis'', and on other cells, such as T cells and bone marrow vessel endothelial cells in ''trans''. Although ''cis'' ligands of tend to mask the CD22 binding site, CD22 is able to interact with ''trans'' ligands on contacting cells (B cells and T cells), and to bind to synthetic multivalent ligands that have sufficient avidity.
 
=== Biosynthesis of ligands ===
The ligands of CD22 are predominately the product of a single sialyltransferase, ST6Gal I. Mice deficient in ST6Gal I express no ligands on B cells resulting in an immuno-deficient phenotype.
Differences in the specificity of human and murine siglec orthologs/paralogs also reflect adaptations to recognize self-ligands <ref name="Crocker 2007"/><ref name="Varki 2010">Varki, A. [http://www.ncbi.nlm.nih.gov/pubmed/20445087 Colloquium paper: uniquely human evolution of sialic acid genetics and biology]. ''Proc Natl Acad Sci U S A''. 2010 May 11;107 Suppl 2:8939-46.</ref>. In particular, murine CD22 preferentially recognizes NeuGc containing α2-6 sialosides (2) with over 10 fold higher affinity than NeuAc (1), but human CD22 exhibits equal affinity for both, consistent with the fact that mouse B cells preferentially express NeuGc, while human B cells express only NeuAc <ref name="Brinkman 2000">Brinkman-Van der Linden EC, Sjoberg ER, Juneja LR, Crocker PR, Varki N, Varki A. [http://www.ncbi.nlm.nih.gov/pubmed/10722703 Loss of N-glycolylneuraminic acid in human evolution. Implications for sialic acid recognition by siglecs]. .J'' Biol Chem''. 2000 Mar 24;275(12):8633-40.</ref><ref name="Kelm 1994">Kelm S, Schauer R, Manuguerra JC, Gross HJ, Crocker PR. [http://www.ncbi.nlm.nih.gov/pubmed/7696861 Modifications of cell surface sialic acids modulate cell adhesion mediated by sialoadhesin and CD22]. '' Glycoconj J''. 1994 Dec;11(6):576-85.</ref><ref name="Naito 2007">Naito Y, Takematsu H, Koyama S, Miyake S, Yamamoto H, Fujinawa R, Sugai M, Okuno Y, Tsujimoto G, Yamaji T, Hashimoto Y, Itohara S, Kawasaki T, Suzuki A, Kozutsumi Y. [http://www.ncbi.nlm.nih.gov/pubmed/17296732 Germinal center marker GL7 probes activation-dependent repression of N-glycolylneuraminic acid, a sialic acid species involved in the negative modulation of B-cell activation]. '' Mol Cell Biol''. 2007 Apr;27(8):3008-22.</ref><ref name="Blixt 2003">Blixt O, Collins BE, van den Nieuwenhof IM, Crocker PR, Paulson JC. [http://www.ncbi.nlm.nih.gov/pubmed/12773526 Sialoside specificity of the siglec family assessed using novel multivalent probes: identification of potent inhibitors of myelin-associated glycoprotein]. J'' Biol Chem''. 2003 Aug 15;278(33):31007-19.</ref>. Another difference is that human CD22 exhibits highest affinity for the 6-sulfo-NeuAcα2-6Galβ1-4GlcNAc (3) <ref name="Blixt 2004"/><ref name="Kimura 2007"/><ref name="CFG">Consortium for Functional Glycomics. [http://www.functionalglycomics.org http://www.functionalglycomics.org].</ref>. Despite these differences, activation of B cells in both species results in down regulation of the highest affinity ligand. In murine B cells, activation causes de novo synthesis of sialosides with NeuAc instead of NeuGc through down regulation of CMP-sialic acid hydroxylase <ref name="Naito 2007"/>, while in human B cells, differentiation of B cells in germinal centers coincides with loss of the sulfate from the high affinity sulfated ligand (3) <ref name="Kimura 2007"/>. Recent reports also document that 9-O-acetyl substitutions of sialic acids also play an important role in regulating the association of CD22 with cis ligands, which is an element of specificity conserved across the two species <ref name="Sjoberg 1994">Sjoberg ER, Powell LD, Klein A, Varki A. [http://www.ncbi.nlm.nih.gov/pubmed/18034751 Natural ligands of the B cell adhesion molecule CD22 beta can be masked by 9-O-acetylation of sialic acids]. J'' Cell Biol''. 1994 Jul;126(2):549-62.</ref><ref name="Cariappa 2009">Cariappa A, Takematsu H, Liu H, Diaz S, Haider K, Boboila C, Kalloo G, Connole M, Shi HN, Varki N, Varki A, Pillai S. [http://www.ncbi.nlm.nih.gov/pubmed/19103880 B cell antigen receptor signal strength and peripheral B cell development are regulated by a 9-O-acetyl sialic acid esterase]. J'' Exp Med''. 2009 Jan 16;206(1):125-38.</ref><ref name="Pillai 2009">Pillai S, Cariappa A, Pirnie SP. [http://www.ncbi.nlm.nih.gov/pubmed/19766537 Esterases and autoimmunity: the sialic acid acetylesterase pathway and the regulation of peripheral B cell tolerance]. '' Trends Immunol''. 2009 Oct;30(10):488-93.</ref><ref name="Surolia 2010">Surolia I, Pirnie SP, Chellappa V, Taylor KN, Cariappa A, Moya J, Liu H, Bell DW, Driscoll DR, Diederichs S, Haider K, Netravali I, Le S, Elia R, Dow E, Lee A, Freudenberg J, De Jager PL, Chretien Y, Varki A, Macdonald ME, Gillis T, Behrens TW, Bloch D, Collier D, Korzenik J, Podolsky DK, Hafler D, Murali M, Sands B, Stone JH, Gregersen PK, Pillai S. [http://www.ncbi.nlm.nih.gov/pubmed/20555325 Functionally defective germline variants of sialic acid acetylesterase in autoimmunity]. '' Nature''. 2010 Jul 8;466(7303):243-7.</ref>.

=== Structure ===
Although the crystal structure of CD22 has not yet been elucidated, structures of other siglecs, including sialoadhesin, siglec-5 and siglec-7 have shed insights into the nature of the ligand binding site of CD22.<ref name="Crocker 2007"/>
 
=== Biological roles of GBP-ligand interaction ===

CD22 is a co-receptor of the membrane IgM B cell receptor (BCR), and regulates BCR signaling via immunoreceptor tyrosine inhibitory motifs (ITIMs) in its cytoplasmic domain.<ref name="Tedder 2005">Tedder TF, Poe JC, Haas KM. [http://www.ncbi.nlm.nih.gov/pubmed/16227086 CD22: a multifunctional receptor that regulates B lymphocyte survival and signal transduction]. ''Adv Immunol''. 2005;88:1-50.</ref><ref name="Crocker 2007"/><ref name="Walker 2008">Walker JA, Smith KG. [http://www.ncbi.nlm.nih.gov/pubmed/18067554 CD22: an inhibitory enigma]. ''Immunology''. 2008;123(3):314-25.</ref><ref name="Nitschke 2009">Nitschke L. [http://www.ncbi.nlm.nih.gov/pubmed/19594633 CD22 and Siglec-G: B-cell inhibitory receptors with distinct functions]. ''Immunol Rev''. 2009;230(1):128-43.</ref>
CD22 is predominately localized in clathrin-coated pits on the surface of the cell, where it mediates constitutive recycling to endocytic compartments.<ref name="Collins 2006">Collins BE, Smith BA, Bengtson P, Paulson JC. . [http://www.ncbi.nlm.nih.gov/pubmed/16369536 Ablation of CD22 in ligand-deficient mice restores B cell receptor signaling]. ''Nat Immunol''. 2006;7(2):199-206.</ref><ref name="Grewal 2006">Grewal PK, Boton M, Ramirez K, Collins BE, Saito A, Green RS, Ohtsubo K, Chui D, Marth JD. [http://www.ncbi.nlm.nih.gov/pubmed/16782884 ST6Gal-I restrains CD22-dependent antigen receptor endocytosis and Shp-1 recruitment in normal and pathogenic immune signaling]. ''Mol Cell Biol''. 2006;26(13):4970-81.</ref><ref name="O'Reilly 2011">O'Reilly MK, Tian H, Paulson JC. [http://www.ncbi.nlm.nih.gov/pubmed/21178016 CD22 is a recycling receptor that can shuttle cargo between the cell surface and endosomal compartments of B cells]. ''J Immunol''. 2011;186(3):1554-63.</ref>
Following ligation of the BCR with antigen, phosphokinases phosphorylate the BCR complex, which in turn amplifies a signal to activate the cell to proliferate and produce antibody. As one of the co-receptors of the BCR, CD22 recruits cofactors that modulate the degree of BCR phosphorylation and downstream signaling. In particular, CD22 recruits the phsophatase SHP-1 that dephosphorylates the BCR complex and suppresses cell signaling. Thus, CD22 is often considered to be a negative regulator of BCR signaling.

The roles of ligands in BCR signaling have been extensively investigated. <ref name="Tedder 2005"/><ref name="Crocker 2007"/><ref name="Walker 2008"/><ref name="Collins 2006"/><ref name="Naito 2007"/><ref name="Cariappa 2009"/><ref name="Hennet 1998">Hennet T, Chui D, Paulson JC, Marth JD. [http://www.ncbi.nlm.nih.gov/pubmed/9539767 Immune regulation by the ST6Gal sialyltransferase]. ''Proc Natl Acad Sci U S A''. 1998;95(8):4504-9.</ref> Siglecs in general, and CD22 in particular, are known to interact with sialylated ligands on the same cell, “in cis”, and on opposing cells, “in trans”. Although many B cell glycoproteins carry the ligand of CD22, the predominant cis ligands appear to be CD22 itself. <ref name="Hans 2005">Han S, Collins BE, Bengtson P, Paulson JC. [http://www.ncbi.nlm.nih.gov/pubmed/16408005 Homomultimeric complexes of CD22 in B cells revealed by protein-glycan cross-linking]. ''Nat Chem Biol''. 2005;1(2):93-7.</ref> This is due in part to the fact that CD22 is preferentially concentrated in clathrin coated pits. Although there is agreement that cis ligand influence CD22 function as a regulator of BCR signaling, there is yet no consensus on the relevance of cis ligands to the constitutive regulation of the BCR. <ref name="Tedder 2005"/><ref name="Walker 2008"/><ref name="Collins 2006"/><ref name="Naito 2007"/><ref name="Cariappa 2009"/>

Despite the presence of cis ligands, CD22 can interact with trans ligands on opposing cells, and redistribute to the site of cell contact.<ref name="Collins 2004">Collins BE, Blixt O, DeSieno AR, Bovin N, Marth JD, Paulson JC. [http://www.ncbi.nlm.nih.gov/pubmed/15079087 Masking of CD22 by cis ligands does not prevent redistribution of CD22 to sites of cell contact]. ''Proc Natl Acad Sci U S A''. 2004;101(16):6104-9.</ref> This property is has been implicated in recirculation of B cells in the bone marrow,<ref name="Nitschke 1999">Nitschke L, Floyd H, Ferguson DJ, Crocker PR. [http://www.ncbi.nlm.nih.gov/pubmed/10224292 Identification of CD22 ligands on bone marrow sinusoidal endothelium implicated in CD22-dependent homing of recirculating B cells]. ''J Exp Med''. 1999;189(9):1513-8.</ref> and is believed to be relevant to innate recognition of self.
<ref name="Lanoue 2002">Lanoue A, Batista FD, Stewart M, Neuberger MS. [http://www.ncbi.nlm.nih.gov/pubmed/11807774 Interaction of CD22 with alpha2,6-linked sialoglycoconjugates: innate recognition of self to dampen B cell autoreactivity?]. ''Eur J Immunol''. 2002;32(2):348-55.</ref> <ref name="Duong 2010">Duong BH, Tian H, Ota T, Completo G, Han S, Vela JL, Ota M, Kubitz M, Bovin N, Paulson JC, Nemazee D. [http://www.ncbi.nlm.nih.gov/pubmed/20038598 Decoration of T-independent antigen with ligands for CD22 and Siglec-G can suppress immunity and induce B cell tolerance in vivo]. ''J Exp Med''. 2010;207(1):173-87.</ref> Indeed, Lanoue et al. demonstrated that B cell signaling is suppressed if the antigen is expressed on a cell that contains ligands of CD22. <ref name="Lanoue 2002"/> Several groups have demonstrated that co-presentation of an antigen and CD22 ligands results in suppressed activation of a B cell. <ref name="Lanoue 2002"/><ref name="Duong 2010"/><ref name="Courtney 2009">Courtney AH, Puffer EB, Pontrello JK, Yang ZQ, Kiessling LL. [http://www.ncbi.nlm.nih.gov/pubmed/19202057 Sialylated multivalent antigens engage CD22 in trans and inhibit B cell activation]. ''Proc Natl Acad Sci U S A''. 2009;106(8):2500-5.</ref> In fact, immunization of a mouse with a polymer containing both a T-independent antigen and a high affinity CD22 ligand induces activation and apoptosis of B cells recognizing the antigen, resulting in tolerization of the mouse to subsequent challenge with the antigen.<ref name="Duong 2010"/> The results suggest that trans ligands of CD22 and other B cell siglecs may serve as markers of self, and that CD22 participates in a mechanism of peripheral tolerance to self-antigens.

== CFG resources used in investigations ==
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=CD22&maxresults=20 CFG database search results for CD22].

=== Glycan profiling ===
Both murine and human CD22 recognize the sequence Siaα2-6Galβ1-4GlcNAc expressed abundantly on [http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=b%20AND%20cells&cat=corec B cells], which have been subjected to glycan profiling by the CFG.
 

=== Glycogene microarray ===

The CFG glycogene microarray has been used to show that ST6Gal I is downregulated [https://www.functionalglycomics.org/glycomics/publicdata/microarray.jsp?resReqId=cfg_rRequest_2 'on T cells] upon activation suggesting that B cell ''trans'' ligands are reduced on activated T cells. Probes for mouse and human CD22 have been included on all four versions of the CFG glycogene array.

=== Knockout mouse lines ===
Mice deficient in [https://www.functionalglycomics.org/static/consortium/resources/resourcecoref16.shtml CD22] and the sialyltransferase, ST6Gal I, responsible for synthesis of its ligands ([https://www.functionalglycomics.org/glycomics/publicdata/phenotyping.jsp ST6Gal I]) distributed by the CFG have been instrumental in understanding the biology of CD22.

=== Glycan array ===
The CFG's glycan array was instrumental in identification of the [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1792 high affinity ligands of CD22] as sialylated-sulfated glycans.<ref name="Kimura 2007"/><ref name="Blixt 2004"/>

== Related GBPs ==

This paradigm is unique among the siglecs in that the cytoplasmic domain has six conserved tyrosine motifs, including three immunoreceptor tyrosine inhibitory motifs (ITIM), one ITIM-like motif, and a growth factor receptor bound protein2 (GRB2) motif. However, other members of the homologous siglec family have contributed to an understanding of the glycan binding site of CD22, and general principles governing the interaction of CD22 with ''cis'' and ''trans'' ligands.

== References ==
<references/>

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: Paul Crocker, James Paulson

CD22

2012-01-20T19:54:49Z

Anna Crie: /* Biosynthesis of ligands */

CD22 is predominantly expressed on B cells and is well documented as a regulator of B cell receptor (BCR) signaling<ref name="Crocker 2007">Crocker PR, Paulson JC, Varki A. [http://www.ncbi.nlm.nih.gov/pubmed/17380156 Siglecs and their roles in the immune system]. ''Nat Rev Immunol'' 2007 Apr;7(4):255-66. Review.</ref>. It is one of four siglecs that are highly conserved among mammals. This paradigm is unique among the siglecs in that the cytoplasmic domain has six conserved tyrosine motifs, including three immunoreceptor tyrosine inhibitory motifs (ITIM), one ITIM-like motif, and a growth factor receptor bound protein2 (GRB2) motif. These tyrosine motifs are involved in regulation of BCR signaling and also mediate its constitutive clathrin mediated endocytosis, an activity believed to be tied to its regulation of cell signaling. The preferred glycan ligand of CD22 differs significantly in humans and mice<ref name="Crocker 2007"/><ref name="Kimura 2007">Kimura N, Ohmori K, Miyazaki K, Izawa M, Matsuzaki Y, Yasuda Y, Takematsu H, Kozutsumi Y, Moriyama A, Kannagi R. [http://www.ncbi.nlm.nih.gov/pubmed/17728258 Human B-lymphocytes express alpha2-6-sialylated 6-sulfo-N-acetyllactosamine serving as a preferred ligand for CD22/Siglec-2]. J'' Biol Chem''. 2007 Nov 2;282(44):32200-7.</ref><ref name="Blixt 2004">Blixt O, Head S, Mondala T, Scanlan C, Huflejt ME, Alvarez R, Bryan MC, Fazio F, Calarese D, Stevens J, Razi N, Stevens DJ, Skehel JJ, van Die I, Burton DR, Wilson IA, Cummings R, Bovin N, Wong CH, Paulson JC. [http://www.ncbi.nlm.nih.gov/pubmed/15563589 Printed covalent glycan array for ligand profiling of diverse glycan binding proteins]. ''Proc Natl Acad Sci U S A''. 2004 Dec 7;101(49):17033-8.</ref>. While both recognize the sequence Siaα-2-6Galβ-1-4GlcNAc expressed abundantly on B cells, murine CD22 prefers Neu5Gc (not found in humans) over Neu5Ac, while human CD22 exhibits highest affinity for sulfated sialoside, Neu5Acα-2-6Galβ-1-4[6S]GlcNAc, demonstrating significant evolution of ligand specificity with conservation of function. Although CD22 recognizes ligands on the same cell in ''cis'', it also binds to ligands in ''trans'' if expressed on adjacent contacting cells. A major area of investigation is to understand the relative roles of ''cis'' and ''trans'' ligands in CD22 function.

[[Image:SiglecCD22.jpg|right|alt text]]
== CFG Participating Investigators contributing to the understanding of this paradigm ==

CFG Participating Investigators (PIs) have made major contributions to the understanding of the biology of human and murine CD22. These include: Nicolai Bovin, Paul Crocker, Jamey Marth, David Nemazee, Lars Nitschke, Jim Paulson, Ajit Varki

== Progress toward understanding this GBP paradigm ==
This section documents what is currently known about CD22, its carbohydrate ligand(s), and how they interact to mediate cell communication. Further information can be found in the GBP Molecule Page for [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_hum_Itlect_269&sideMenu=no human] and [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_mou_Itlect_194&sideMenu=no mouse] CD22 (aka Siglec-2) in the CFG database.
=== Carbohydrate ligands ===
Although CD22 is highly conserved throughout mammalian species, murine and human CD22 are known to exhibit significant differences in their specificities that appear to have evolved to compensate for changes in the glycan ligands expressed on B cells. While both bind Siaα2-6Gal terminated glycans, murine CD22 prefers NeuGc (NeuGcα2-6Galβ1-4GlcNAc), which is not found in humans. In contrast, human human CD22 recognizes NeuAc and NeuGc with equal affinity. In addition, however, human CD22 exhibits highest affinity for a ligand with sulfate at the 6 position of GlcNAc (NeuAcα2-6Galβ1-4[6S]GlcNAc).<ref name="Crocker 2007"/><ref name="Kimura 2007"/> 9-O-acetylation of sialic acid abrogates binding of CD22, which is thought to regulate the binding of ''cis'' ligands on B cells.
 
=== Cellular expression of GBP and ligands ===
CD22 is primarily expressed on mature B cells and to a lesser extent on memory B cells. However, it is not expressed on pre-B cells and differentiated plasma cells. Like many siglecs, CD22 interacts with endogenous ligands on B cells in ''cis'', and on other cells, such as T cells and bone marrow vessel endothelial cells in ''trans''. Although ''cis'' ligands of tend to mask the CD22 binding site, CD22 is able to interact with ''trans'' ligands on contacting cells (B cells and T cells), and to bind to synthetic multivalent ligands that have sufficient avidity.
 
=== Biosynthesis of ligands ===
The ligands of CD22 are predominately the product of a single sialyltransferase, ST6Gal I. Mice deficient in ST6Gal I express no ligands on B cells resulting in an immuno-deficient phenotype.
Differences in the specificity of human and murine siglec orthologs/paralogs also reflect adaptations to recognize self-ligands <ref name="Crocker 2007"/><ref name="Varki 2010">Varki, A. [http://www.ncbi.nlm.nih.gov/pubmed/20445087 Colloquium paper: uniquely human evolution of sialic acid genetics and biology]. ''Proc Natl Acad Sci U S A''. 2010 May 11;107 Suppl 2:8939-46.</ref>. In particular, murine CD22 preferentially recognizes NeuGc containing α2-6 sialosides (2) with over 10 fold higher affinity than NeuAc (1), but human CD22 exhibits equal affinity for both, consistent with the fact that mouse B cells preferentially express NeuGc, while human B cells express only NeuAc <ref name="Brinkman 2000">Brinkman-Van der Linden EC, Sjoberg ER, Juneja LR, Crocker PR, Varki N, Varki A. [http://www.ncbi.nlm.nih.gov/pubmed/10722703 Loss of N-glycolylneuraminic acid in human evolution. Implications for sialic acid recognition by siglecs]. .J'' Biol Chem''. 2000 Mar 24;275(12):8633-40.</ref><ref name="Kelm 1994">Kelm S, Schauer R, Manuguerra JC, Gross HJ, Crocker PR. [http://www.ncbi.nlm.nih.gov/pubmed/7696861 Modifications of cell surface sialic acids modulate cell adhesion mediated by sialoadhesin and CD22]. '' Glycoconj J''. 1994 Dec;11(6):576-85.</ref><ref name="Naito 2007">Naito Y, Takematsu H, Koyama S, Miyake S, Yamamoto H, Fujinawa R, Sugai M, Okuno Y, Tsujimoto G, Yamaji T, Hashimoto Y, Itohara S, Kawasaki T, Suzuki A, Kozutsumi Y. [http://www.ncbi.nlm.nih.gov/pubmed/17296732 Germinal center marker GL7 probes activation-dependent repression of N-glycolylneuraminic acid, a sialic acid species involved in the negative modulation of B-cell activation]. '' Mol Cell Biol''. 2007 Apr;27(8):3008-22.</ref><ref name="Blixt 2003">Blixt O, Collins BE, van den Nieuwenhof IM, Crocker PR, Paulson JC. [http://www.ncbi.nlm.nih.gov/pubmed/12773526 Sialoside specificity of the siglec family assessed using novel multivalent probes: identification of potent inhibitors of myelin-associated glycoprotein]. J'' Biol Chem''. 2003 Aug 15;278(33):31007-19.</ref>. Another difference is that human CD22 exhibits highest affinity for the 6-sulfo-NeuAcα2-6Galβ1-4GlcNAc (3) <ref name="Blixt 2004"/><ref name="Kimura 2007"/><ref name="CFG">Consortium for Functional Glycomics. [http://www.functionalglycomics.org http://www.functionalglycomics.org].</ref>. Despite these differences, activation of B cells in both species results in down regulation of the highest affinity ligand. In murine B cells, activation causes de novo synthesis of sialosides with NeuAc instead of NeuGc through down regulation of CMP-sialic acid hydroxylase <ref name="Naito 2007"/>, while in human B cells, differentiation of B cells in germinal centers coincides with loss of the sulfate from the high affinity sulfated ligand (3) <ref name="Kimura 2007"/>. Recent reports also document that 9-O-acetyl substitutions of sialic acids also play an important role in regulating the association of CD22 with cis ligands, which is an element of specificity conserved across the two species <ref name="Sjoberg 1994">Sjoberg ER, Powell LD, Klein A, Varki A. [http://www.ncbi.nlm.nih.gov/pubmed/18034751 Natural ligands of the B cell adhesion molecule CD22 beta can be masked by 9-O-acetylation of sialic acids]. J'' Cell Biol''. 1994 Jul;126(2):549-62.</ref><ref name="Cariappa 2009">Cariappa A, Takematsu H, Liu H, Diaz S, Haider K, Boboila C, Kalloo G, Connole M, Shi HN, Varki N, Varki A, Pillai S. [http://www.ncbi.nlm.nih.gov/pubmed/19103880 B cell antigen receptor signal strength and peripheral B cell development are regulated by a 9-O-acetyl sialic acid esterase]. J'' Exp Med''. 2009 Jan 16;206(1):125-38.</ref><ref name="Pillai 2009">Pillai S, Cariappa A, Pirnie SP. [http://www.ncbi.nlm.nih.gov/pubmed/19766537 Esterases and autoimmunity: the sialic acid acetylesterase pathway and the regulation of peripheral B cell tolerance]. '' Trends Immunol''. 2009 Oct;30(10):488-93.</ref><ref name="Surolia 2010">Surolia I, Pirnie SP, Chellappa V, Taylor KN, Cariappa A, Moya J, Liu H, Bell DW, Driscoll DR, Diederichs S, Haider K, Netravali I, Le S, Elia R, Dow E, Lee A, Freudenberg J, De Jager PL, Chretien Y, Varki A, Macdonald ME, Gillis T, Behrens TW, Bloch D, Collier D, Korzenik J, Podolsky DK, Hafler D, Murali M, Sands B, Stone JH, Gregersen PK, Pillai S. [http://www.ncbi.nlm.nih.gov/pubmed/20555325 Functionally defective germline variants of sialic acid acetylesterase in autoimmunity]. '' Nature''. 2010 Jul 8;466(7303):243-7.</ref>.

=== Structure ===
Although the crystal structure of CD22 has not yet been elucidated, structures of other siglecs, including sialoadhesin, siglec-5 and siglec-7 have shed insights into the nature of the ligand binding site of CD22.<ref name="Crocker 2007"/>
 
=== Biological roles of GBP-ligand interaction ===

CD22 is a co-receptor of the membrane IgM B cell receptor (BCR), and regulates BCR signaling via immunoreceptor tyrosine inhibitory motifs (ITIMs) in its cytoplasmic domain.<ref name="Tedder 2005">Tedder TF, Poe JC, Haas KM. [http://www.ncbi.nlm.nih.gov/pubmed/16227086 CD22: a multifunctional receptor that regulates B lymphocyte survival and signal transduction]. ''Adv Immunol''. 2005;88:1-50.</ref><ref name="Crocker 2007"/><ref name="Walker 2008">Walker JA, Smith KG. [http://www.ncbi.nlm.nih.gov/pubmed/18067554 CD22: an inhibitory enigma]. ''Immunology''. 2008;123(3):314-25.</ref><ref name="Nitschke 2009">Nitschke L. [http://www.ncbi.nlm.nih.gov/pubmed/19594633 CD22 and Siglec-G: B-cell inhibitory receptors with distinct functions]. ''Immunol Rev''. 2009;230(1):128-43.</ref>
CD22 is predominately localized in clathrin-coated pits on the surface of the cell, where it mediates constitutive recycling to endocytic compartments.<ref name="Collins 2006">Collins BE, Smith BA, Bengtson P, Paulson JC. . [http://www.ncbi.nlm.nih.gov/pubmed/16369536 Ablation of CD22 in ligand-deficient mice restores B cell receptor signaling]. ''Nat Immunol''. 2006;7(2):199-206.</ref><ref name="Grewal 2006">Grewal PK, Boton M, Ramirez K, Collins BE, Saito A, Green RS, Ohtsubo K, Chui D, Marth JD. [http://www.ncbi.nlm.nih.gov/pubmed/16782884 ST6Gal-I restrains CD22-dependent antigen receptor endocytosis and Shp-1 recruitment in normal and pathogenic immune signaling]. ''Mol Cell Biol''. 2006;26(13):4970-81.</ref><ref name="O'Reilly 2011">O'Reilly MK, Tian H, Paulson JC. [http://www.ncbi.nlm.nih.gov/pubmed/21178016 CD22 is a recycling receptor that can shuttle cargo between the cell surface and endosomal compartments of B cells]. ''J Immunol''. 2011;186(3):1554-63.</ref>
Following ligation of the BCR with antigen, phosphokinases phosphorylate the BCR complex, which in turn amplifies a signal to activate the cell to proliferate and produce antibody. As one of the co-receptors of the BCR, CD22 recruits cofactors that modulate the degree of BCR phosphorylation and downstream signaling. In particular, CD22 recruits the phsophatase SHP-1 that dephosphorylates the BCR complex and suppresses cell signaling. Thus, CD22 is often considered to be a negative regulator of BCR signaling.

The roles of ligands in BCR signaling have been extensively investigated. <ref name="Tedder 2005"/><ref name="Crocker 2007"/><ref name="Walker 2008"/><ref name="Collins 2006"/><ref name="Naito 2007"/><ref name="Cariappa 2009"/><ref name="Hennet 1998">Hennet T, Chui D, Paulson JC, Marth JD. [http://www.ncbi.nlm.nih.gov/pubmed/9539767 Immune regulation by the ST6Gal sialyltransferase]. ''Proc Natl Acad Sci U S A''. 1998;95(8):4504-9.</ref> Siglecs in general, and CD22 in particular, are known to interact with sialylated ligands on the same cell, “in cis”, and on opposing cells, “in trans”. Although many B cell glycoproteins carry the ligand of CD22, the predominant cis ligands appear to be CD22 itself. <ref name="Hans 2005">Han S, Collins BE, Bengtson P, Paulson JC. [http://www.ncbi.nlm.nih.gov/pubmed/16408005 Homomultimeric complexes of CD22 in B cells revealed by protein-glycan cross-linking]. ''Nat Chem Biol''. 2005;1(2):93-7.</ref> This is due in part to the fact that CD22 is preferentially concentrated in clathrin coated pits. Although there is agreement that cis ligand influence CD22 function as a regulator of BCR signaling, there is yet no consensus on the relevance of cis ligands to the constitutive regulation of the BCR. <ref name="Tedder 2005"/><ref name="Walker 2008"/><ref name="Collins 2006"/><ref name="Naito 2007"/><ref name="Cariappa 2009"/>

Despite the presence of cis ligands, CD22 can interact with trans ligands on opposing cells, and redistribute to the site of cell contact.<ref name="Collins 2004">Collins BE, Blixt O, DeSieno AR, Bovin N, Marth JD, Paulson JC. [http://www.ncbi.nlm.nih.gov/pubmed/15079087 Masking of CD22 by cis ligands does not prevent redistribution of CD22 to sites of cell contact]. ''Proc Natl Acad Sci U S A''. 2004;101(16):6104-9.</ref> This property is has been implicated in recirculation of B cells in the bone marrow,<ref name="Nitschke 1999">Nitschke L, Floyd H, Ferguson DJ, Crocker PR. [http://www.ncbi.nlm.nih.gov/pubmed/10224292 Identification of CD22 ligands on bone marrow sinusoidal endothelium implicated in CD22-dependent homing of recirculating B cells]. ''J Exp Med''. 1999;189(9):1513-8.</ref> and is believed to be relevant to innate recognition of self.
<ref name="Lanoue 2002">Lanoue A, Batista FD, Stewart M, Neuberger MS. [http://www.ncbi.nlm.nih.gov/pubmed/11807774 Interaction of CD22 with alpha2,6-linked sialoglycoconjugates: innate recognition of self to dampen B cell autoreactivity?]. ''Eur J Immunol''. 2002;32(2):348-55.</ref> <ref name="Duong 2010">Duong BH, Tian H, Ota T, Completo G, Han S, Vela JL, Ota M, Kubitz M, Bovin N, Paulson JC, Nemazee D. [http://www.ncbi.nlm.nih.gov/pubmed/20038598 Decoration of T-independent antigen with ligands for CD22 and Siglec-G can suppress immunity and induce B cell tolerance in vivo]. ''J Exp Med''. 2010;207(1):173-87.</ref> Indeed, Lanoue et al. demonstrated that B cell signaling is suppressed if the antigen is expressed on a cell that contains ligands of CD22. <ref name="Lanoue 2002"/> Several groups have demonstrated that co-presentation of an antigen and CD22 ligands results in suppressed activation of a B cell.(14-16)
<ref name="Lanoue 2002"/><ref name="Duong 2010"/><ref name="Courtney 2009">Courtney AH, Puffer EB, Pontrello JK, Yang ZQ, Kiessling LL. [http://www.ncbi.nlm.nih.gov/pubmed/19202057 Sialylated multivalent antigens engage CD22 in trans and inhibit B cell activation]. 'Proc Natl Acad Sci U S A''. 2009;106(8):2500-5.</ref> In fact, immunization of a mouse with a polymer containing both a T-independent antigen and a high affinity CD22 ligand induces activation and apoptosis of B cells recognizing the antigen, resulting in tolerization of the mouse to subsequent challenge with the antigen.<ref name="Duong 2010"/> The results suggest that trans ligands of CD22 and other B cell siglecs may serve as markers of self, and that CD22 participates in a mechanism of peripheral tolerance to self-antigens.

== CFG resources used in investigations ==
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=CD22&maxresults=20 CFG database search results for CD22].

=== Glycan profiling ===
Both murine and human CD22 recognize the sequence Siaα2-6Galβ1-4GlcNAc expressed abundantly on [http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=b%20AND%20cells&cat=corec B cells], which have been subjected to glycan profiling by the CFG.
 

=== Glycogene microarray ===

The CFG glycogene microarray has been used to show that ST6Gal I is downregulated [https://www.functionalglycomics.org/glycomics/publicdata/microarray.jsp?resReqId=cfg_rRequest_2 'on T cells] upon activation suggesting that B cell ''trans'' ligands are reduced on activated T cells. Probes for mouse and human CD22 have been included on all four versions of the CFG glycogene array.

=== Knockout mouse lines ===
Mice deficient in [https://www.functionalglycomics.org/static/consortium/resources/resourcecoref16.shtml CD22] and the sialyltransferase, ST6Gal I, responsible for synthesis of its ligands ([https://www.functionalglycomics.org/glycomics/publicdata/phenotyping.jsp ST6Gal I]) distributed by the CFG have been instrumental in understanding the biology of CD22.

=== Glycan array ===
The CFG's glycan array was instrumental in identification of the [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1792 high affinity ligands of CD22] as sialylated-sulfated glycans.<ref name="Kimura 2007"/><ref name="Blixt 2004"/>

== Related GBPs ==

This paradigm is unique among the siglecs in that the cytoplasmic domain has six conserved tyrosine motifs, including three immunoreceptor tyrosine inhibitory motifs (ITIM), one ITIM-like motif, and a growth factor receptor bound protein2 (GRB2) motif. However, other members of the homologous siglec family have contributed to an understanding of the glycan binding site of CD22, and general principles governing the interaction of CD22 with ''cis'' and ''trans'' ligands.

== References ==
<references/>

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: Paul Crocker, James Paulson

CD22

2012-01-20T19:51:53Z

Anna Crie: /* Biological roles of GBP-ligand interaction */

CD22 is predominantly expressed on B cells and is well documented as a regulator of B cell receptor (BCR) signaling<ref name="Crocker 2007">Crocker PR, Paulson JC, Varki A. [http://www.ncbi.nlm.nih.gov/pubmed/17380156 Siglecs and their roles in the immune system]. ''Nat Rev Immunol'' 2007 Apr;7(4):255-66. Review.</ref>. It is one of four siglecs that are highly conserved among mammals. This paradigm is unique among the siglecs in that the cytoplasmic domain has six conserved tyrosine motifs, including three immunoreceptor tyrosine inhibitory motifs (ITIM), one ITIM-like motif, and a growth factor receptor bound protein2 (GRB2) motif. These tyrosine motifs are involved in regulation of BCR signaling and also mediate its constitutive clathrin mediated endocytosis, an activity believed to be tied to its regulation of cell signaling. The preferred glycan ligand of CD22 differs significantly in humans and mice<ref name="Crocker 2007"/><ref name="Kimura 2007">Kimura N, Ohmori K, Miyazaki K, Izawa M, Matsuzaki Y, Yasuda Y, Takematsu H, Kozutsumi Y, Moriyama A, Kannagi R. [http://www.ncbi.nlm.nih.gov/pubmed/17728258 Human B-lymphocytes express alpha2-6-sialylated 6-sulfo-N-acetyllactosamine serving as a preferred ligand for CD22/Siglec-2]. J'' Biol Chem''. 2007 Nov 2;282(44):32200-7.</ref><ref name="Blixt 2004">Blixt O, Head S, Mondala T, Scanlan C, Huflejt ME, Alvarez R, Bryan MC, Fazio F, Calarese D, Stevens J, Razi N, Stevens DJ, Skehel JJ, van Die I, Burton DR, Wilson IA, Cummings R, Bovin N, Wong CH, Paulson JC. [http://www.ncbi.nlm.nih.gov/pubmed/15563589 Printed covalent glycan array for ligand profiling of diverse glycan binding proteins]. ''Proc Natl Acad Sci U S A''. 2004 Dec 7;101(49):17033-8.</ref>. While both recognize the sequence Siaα-2-6Galβ-1-4GlcNAc expressed abundantly on B cells, murine CD22 prefers Neu5Gc (not found in humans) over Neu5Ac, while human CD22 exhibits highest affinity for sulfated sialoside, Neu5Acα-2-6Galβ-1-4[6S]GlcNAc, demonstrating significant evolution of ligand specificity with conservation of function. Although CD22 recognizes ligands on the same cell in ''cis'', it also binds to ligands in ''trans'' if expressed on adjacent contacting cells. A major area of investigation is to understand the relative roles of ''cis'' and ''trans'' ligands in CD22 function.

[[Image:SiglecCD22.jpg|right|alt text]]
== CFG Participating Investigators contributing to the understanding of this paradigm ==

CFG Participating Investigators (PIs) have made major contributions to the understanding of the biology of human and murine CD22. These include: Nicolai Bovin, Paul Crocker, Jamey Marth, David Nemazee, Lars Nitschke, Jim Paulson, Ajit Varki

== Progress toward understanding this GBP paradigm ==
This section documents what is currently known about CD22, its carbohydrate ligand(s), and how they interact to mediate cell communication. Further information can be found in the GBP Molecule Page for [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_hum_Itlect_269&sideMenu=no human] and [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_mou_Itlect_194&sideMenu=no mouse] CD22 (aka Siglec-2) in the CFG database.
=== Carbohydrate ligands ===
Although CD22 is highly conserved throughout mammalian species, murine and human CD22 are known to exhibit significant differences in their specificities that appear to have evolved to compensate for changes in the glycan ligands expressed on B cells. While both bind Siaα2-6Gal terminated glycans, murine CD22 prefers NeuGc (NeuGcα2-6Galβ1-4GlcNAc), which is not found in humans. In contrast, human human CD22 recognizes NeuAc and NeuGc with equal affinity. In addition, however, human CD22 exhibits highest affinity for a ligand with sulfate at the 6 position of GlcNAc (NeuAcα2-6Galβ1-4[6S]GlcNAc).<ref name="Crocker 2007"/><ref name="Kimura 2007"/> 9-O-acetylation of sialic acid abrogates binding of CD22, which is thought to regulate the binding of ''cis'' ligands on B cells.
 
=== Cellular expression of GBP and ligands ===
CD22 is primarily expressed on mature B cells and to a lesser extent on memory B cells. However, it is not expressed on pre-B cells and differentiated plasma cells. Like many siglecs, CD22 interacts with endogenous ligands on B cells in ''cis'', and on other cells, such as T cells and bone marrow vessel endothelial cells in ''trans''. Although ''cis'' ligands of tend to mask the CD22 binding site, CD22 is able to interact with ''trans'' ligands on contacting cells (B cells and T cells), and to bind to synthetic multivalent ligands that have sufficient avidity.
 
=== Biosynthesis of ligands ===
The ligands of CD22 are predominately the product of a single sialyltransferase, ST6Gal I. Mice deficient in ST6Gal I express no ligands on B cells resulting in an immuno-deficient phenotype.
Differences in the specificity of human and murine siglec orthologs/paralogs also reflect adaptations to recognize self-ligands <ref name="Crocker 2007"/><ref name="Varki 2010">Varki, A. [http://www.ncbi.nlm.nih.gov/pubmed/20445087 Colloquium paper: uniquely human evolution of sialic acid genetics and biology]. "Proc Natl Acad Sci U S A''. 2010 May 11;107 Suppl 2:8939-46.</ref>. In particular, murine CD22 preferentially recognizes NeuGc containing α2-6 sialosides (2) with over 10 fold higher affinity than NeuAc (1), but human CD22 exhibits equal affinity for both, consistent with the fact that mouse B cells preferentially express NeuGc, while human B cells express only NeuAc <ref name="Brinkman 2000">Brinkman-Van der Linden EC, Sjoberg ER, Juneja LR, Crocker PR, Varki N, Varki A. [http://www.ncbi.nlm.nih.gov/pubmed/10722703 Loss of N-glycolylneuraminic acid in human evolution. Implications for sialic acid recognition by siglecs]. .J'' Biol Chem''. 2000 Mar 24;275(12):8633-40.</ref><ref name="Kelm 1994">Kelm S, Schauer R, Manuguerra JC, Gross HJ, Crocker PR. [http://www.ncbi.nlm.nih.gov/pubmed/7696861 Modifications of cell surface sialic acids modulate cell adhesion mediated by sialoadhesin and CD22]. '' Glycoconj J''. 1994 Dec;11(6):576-85.</ref><ref name="Naito 2007">Naito Y, Takematsu H, Koyama S, Miyake S, Yamamoto H, Fujinawa R, Sugai M, Okuno Y, Tsujimoto G, Yamaji T, Hashimoto Y, Itohara S, Kawasaki T, Suzuki A, Kozutsumi Y. [http://www.ncbi.nlm.nih.gov/pubmed/17296732 Germinal center marker GL7 probes activation-dependent repression of N-glycolylneuraminic acid, a sialic acid species involved in the negative modulation of B-cell activation]. '' Mol Cell Biol''. 2007 Apr;27(8):3008-22.</ref><ref name="Blixt 2003">Blixt O, Collins BE, van den Nieuwenhof IM, Crocker PR, Paulson JC. [http://www.ncbi.nlm.nih.gov/pubmed/12773526 Sialoside specificity of the siglec family assessed using novel multivalent probes: identification of potent inhibitors of myelin-associated glycoprotein]. J'' Biol Chem''. 2003 Aug 15;278(33):31007-19.</ref>. Another difference is that human CD22 exhibits highest affinity for the 6-sulfo-NeuAcα2-6Galβ1-4GlcNAc (3) <ref name="Blixt 2004"/><ref name="Kimura 2007"/><ref name="CFG">Consortium for Functional Glycomics. [http://www.functionalglycomics.org http://www.functionalglycomics.org].</ref>. Despite these differences, activation of B cells in both species results in down regulation of the highest affinity ligand. In murine B cells, activation causes de novo synthesis of sialosides with NeuAc instead of NeuGc through down regulation of CMP-sialic acid hydroxylase <ref name="Naito 2007"/>, while in human B cells, differentiation of B cells in germinal centers coincides with loss of the sulfate from the high affinity sulfated ligand (3) <ref name="Kimura 2007"/>. Recent reports also document that 9-O-acetyl substitutions of sialic acids also play an important role in regulating the association of CD22 with cis ligands, which is an element of specificity conserved across the two species <ref name="Sjoberg 1994">Sjoberg ER, Powell LD, Klein A, Varki A. [http://www.ncbi.nlm.nih.gov/pubmed/18034751 Natural ligands of the B cell adhesion molecule CD22 beta can be masked by 9-O-acetylation of sialic acids]. J'' Cell Biol''. 1994 Jul;126(2):549-62.</ref><ref name="Cariappa 2009">Cariappa A, Takematsu H, Liu H, Diaz S, Haider K, Boboila C, Kalloo G, Connole M, Shi HN, Varki N, Varki A, Pillai S. [http://www.ncbi.nlm.nih.gov/pubmed/19103880 B cell antigen receptor signal strength and peripheral B cell development are regulated by a 9-O-acetyl sialic acid esterase]. J'' Exp Med''. 2009 Jan 16;206(1):125-38.</ref><ref name="Pillai 2009">Pillai S, Cariappa A, Pirnie SP. [http://www.ncbi.nlm.nih.gov/pubmed/19766537 Esterases and autoimmunity: the sialic acid acetylesterase pathway and the regulation of peripheral B cell tolerance]. '' Trends Immunol''. 2009 Oct;30(10):488-93.</ref><ref name="Surolia 2010">Surolia I, Pirnie SP, Chellappa V, Taylor KN, Cariappa A, Moya J, Liu H, Bell DW, Driscoll DR, Diederichs S, Haider K, Netravali I, Le S, Elia R, Dow E, Lee A, Freudenberg J, De Jager PL, Chretien Y, Varki A, Macdonald ME, Gillis T, Behrens TW, Bloch D, Collier D, Korzenik J, Podolsky DK, Hafler D, Murali M, Sands B, Stone JH, Gregersen PK, Pillai S. [http://www.ncbi.nlm.nih.gov/pubmed/20555325 Functionally defective germline variants of sialic acid acetylesterase in autoimmunity]. '' Nature''. 2010 Jul 8;466(7303):243-7.</ref>.

=== Structure ===
Although the crystal structure of CD22 has not yet been elucidated, structures of other siglecs, including sialoadhesin, siglec-5 and siglec-7 have shed insights into the nature of the ligand binding site of CD22.<ref name="Crocker 2007"/>
 
=== Biological roles of GBP-ligand interaction ===

CD22 is a co-receptor of the membrane IgM B cell receptor (BCR), and regulates BCR signaling via immunoreceptor tyrosine inhibitory motifs (ITIMs) in its cytoplasmic domain.<ref name="Tedder 2005">Tedder TF, Poe JC, Haas KM. [http://www.ncbi.nlm.nih.gov/pubmed/16227086 CD22: a multifunctional receptor that regulates B lymphocyte survival and signal transduction]. ''Adv Immunol''. 2005;88:1-50.</ref><ref name="Crocker 2007"/><ref name="Walker 2008">Walker JA, Smith KG. [http://www.ncbi.nlm.nih.gov/pubmed/18067554 CD22: an inhibitory enigma]. ''Immunology''. 2008;123(3):314-25.</ref><ref name="Nitschke 2009">Nitschke L. [http://www.ncbi.nlm.nih.gov/pubmed/19594633 CD22 and Siglec-G: B-cell inhibitory receptors with distinct functions]. ''Immunol Rev''. 2009;230(1):128-43.</ref>
CD22 is predominately localized in clathrin-coated pits on the surface of the cell, where it mediates constitutive recycling to endocytic compartments.<ref name="Collins 2006">Collins BE, Smith BA, Bengtson P, Paulson JC. . [http://www.ncbi.nlm.nih.gov/pubmed/16369536 Ablation of CD22 in ligand-deficient mice restores B cell receptor signaling]. ''Nat Immunol''. 2006;7(2):199-206.</ref><ref name="Grewal 2006">Grewal PK, Boton M, Ramirez K, Collins BE, Saito A, Green RS, Ohtsubo K, Chui D, Marth JD. [http://www.ncbi.nlm.nih.gov/pubmed/16782884 ST6Gal-I restrains CD22-dependent antigen receptor endocytosis and Shp-1 recruitment in normal and pathogenic immune signaling]. ''Mol Cell Biol''. 2006;26(13):4970-81.</ref><ref name="O'Reilly 2011">O'Reilly MK, Tian H, Paulson JC. [http://www.ncbi.nlm.nih.gov/pubmed/21178016 CD22 is a recycling receptor that can shuttle cargo between the cell surface and endosomal compartments of B cells]. ''J Immunol''. 2011;186(3):1554-63.</ref>
Following ligation of the BCR with antigen, phosphokinases phosphorylate the BCR complex, which in turn amplifies a signal to activate the cell to proliferate and produce antibody. As one of the co-receptors of the BCR, CD22 recruits cofactors that modulate the degree of BCR phosphorylation and downstream signaling. In particular, CD22 recruits the phsophatase SHP-1 that dephosphorylates the BCR complex and suppresses cell signaling. Thus, CD22 is often considered to be a negative regulator of BCR signaling.

The roles of ligands in BCR signaling have been extensively investigated. <ref name="Tedder 2005"/><ref name="Crocker 2007"/><ref name="Walker 2008"/><ref name="Collins 2006"/><ref name="Naito 2007"/><ref name="Cariappa 2009"/><ref name="Hennet 1998">Hennet T, Chui D, Paulson JC, Marth JD. [http://www.ncbi.nlm.nih.gov/pubmed/9539767 Immune regulation by the ST6Gal sialyltransferase]. ''Proc Natl Acad Sci U S A''. 1998;95(8):4504-9.</ref> Siglecs in general, and CD22 in particular, are known to interact with sialylated ligands on the same cell, “in cis”, and on opposing cells, “in trans”. Although many B cell glycoproteins carry the ligand of CD22, the predominant cis ligands appear to be CD22 itself. <ref name="Hans 2005">Han S, Collins BE, Bengtson P, Paulson JC. [http://www.ncbi.nlm.nih.gov/pubmed/16408005 Homomultimeric complexes of CD22 in B cells revealed by protein-glycan cross-linking]. ''Nat Chem Biol''. 2005;1(2):93-7.</ref> This is due in part to the fact that CD22 is preferentially concentrated in clathrin coated pits. Although there is agreement that cis ligand influence CD22 function as a regulator of BCR signaling, there is yet no consensus on the relevance of cis ligands to the constitutive regulation of the BCR. <ref name="Tedder 2005"/><ref name="Walker 2008"/><ref name="Collins 2006"/><ref name="Naito 2007"/><ref name="Cariappa 2009"/>

Despite the presence of cis ligands, CD22 can interact with trans ligands on opposing cells, and redistribute to the site of cell contact.<ref name="Collins 2004">Collins BE, Blixt O, DeSieno AR, Bovin N, Marth JD, Paulson JC. [http://www.ncbi.nlm.nih.gov/pubmed/15079087 Masking of CD22 by cis ligands does not prevent redistribution of CD22 to sites of cell contact]. ''Proc Natl Acad Sci U S A''. 2004;101(16):6104-9.</ref> This property is has been implicated in recirculation of B cells in the bone marrow,<ref name="Nitschke 1999">Nitschke L, Floyd H, Ferguson DJ, Crocker PR. [http://www.ncbi.nlm.nih.gov/pubmed/10224292 Identification of CD22 ligands on bone marrow sinusoidal endothelium implicated in CD22-dependent homing of recirculating B cells]. ''J Exp Med''. 1999;189(9):1513-8.</ref> and is believed to be relevant to innate recognition of self.
<ref name="Lanoue 2002">Lanoue A, Batista FD, Stewart M, Neuberger MS. [http://www.ncbi.nlm.nih.gov/pubmed/11807774 Interaction of CD22 with alpha2,6-linked sialoglycoconjugates: innate recognition of self to dampen B cell autoreactivity?]. ''Eur J Immunol''. 2002;32(2):348-55.</ref> <ref name="Duong 2010">Duong BH, Tian H, Ota T, Completo G, Han S, Vela JL, Ota M, Kubitz M, Bovin N, Paulson JC, Nemazee D. [http://www.ncbi.nlm.nih.gov/pubmed/20038598 Decoration of T-independent antigen with ligands for CD22 and Siglec-G can suppress immunity and induce B cell tolerance in vivo]. ''J Exp Med''. 2010;207(1):173-87.</ref> Indeed, Lanoue et al. demonstrated that B cell signaling is suppressed if the antigen is expressed on a cell that contains ligands of CD22. <ref name="Lanoue 2002"/> Several groups have demonstrated that co-presentation of an antigen and CD22 ligands results in suppressed activation of a B cell.(14-16)
<ref name="Lanoue 2002"/><ref name="Duong 2010"/><ref name="Courtney 2009">Courtney AH, Puffer EB, Pontrello JK, Yang ZQ, Kiessling LL. [http://www.ncbi.nlm.nih.gov/pubmed/19202057 Sialylated multivalent antigens engage CD22 in trans and inhibit B cell activation]. 'Proc Natl Acad Sci U S A''. 2009;106(8):2500-5.</ref> In fact, immunization of a mouse with a polymer containing both a T-independent antigen and a high affinity CD22 ligand induces activation and apoptosis of B cells recognizing the antigen, resulting in tolerization of the mouse to subsequent challenge with the antigen.<ref name="Duong 2010"/> The results suggest that trans ligands of CD22 and other B cell siglecs may serve as markers of self, and that CD22 participates in a mechanism of peripheral tolerance to self-antigens.

== CFG resources used in investigations ==
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=CD22&maxresults=20 CFG database search results for CD22].

=== Glycan profiling ===
Both murine and human CD22 recognize the sequence Siaα2-6Galβ1-4GlcNAc expressed abundantly on [http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=b%20AND%20cells&cat=corec B cells], which have been subjected to glycan profiling by the CFG.
 

=== Glycogene microarray ===

The CFG glycogene microarray has been used to show that ST6Gal I is downregulated [https://www.functionalglycomics.org/glycomics/publicdata/microarray.jsp?resReqId=cfg_rRequest_2 'on T cells] upon activation suggesting that B cell ''trans'' ligands are reduced on activated T cells. Probes for mouse and human CD22 have been included on all four versions of the CFG glycogene array.

=== Knockout mouse lines ===
Mice deficient in [https://www.functionalglycomics.org/static/consortium/resources/resourcecoref16.shtml CD22] and the sialyltransferase, ST6Gal I, responsible for synthesis of its ligands ([https://www.functionalglycomics.org/glycomics/publicdata/phenotyping.jsp ST6Gal I]) distributed by the CFG have been instrumental in understanding the biology of CD22.

=== Glycan array ===
The CFG's glycan array was instrumental in identification of the [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1792 high affinity ligands of CD22] as sialylated-sulfated glycans.<ref name="Kimura 2007"/><ref name="Blixt 2004"/>

== Related GBPs ==

This paradigm is unique among the siglecs in that the cytoplasmic domain has six conserved tyrosine motifs, including three immunoreceptor tyrosine inhibitory motifs (ITIM), one ITIM-like motif, and a growth factor receptor bound protein2 (GRB2) motif. However, other members of the homologous siglec family have contributed to an understanding of the glycan binding site of CD22, and general principles governing the interaction of CD22 with ''cis'' and ''trans'' ligands.

== References ==
<references/>

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: Paul Crocker, James Paulson

CD22

2012-01-20T19:50:25Z

Anna Crie: /* Biological roles of GBP-ligand interaction */

CD22 is predominantly expressed on B cells and is well documented as a regulator of B cell receptor (BCR) signaling<ref name="Crocker 2007">Crocker PR, Paulson JC, Varki A. [http://www.ncbi.nlm.nih.gov/pubmed/17380156 Siglecs and their roles in the immune system]. ''Nat Rev Immunol'' 2007 Apr;7(4):255-66. Review.</ref>. It is one of four siglecs that are highly conserved among mammals. This paradigm is unique among the siglecs in that the cytoplasmic domain has six conserved tyrosine motifs, including three immunoreceptor tyrosine inhibitory motifs (ITIM), one ITIM-like motif, and a growth factor receptor bound protein2 (GRB2) motif. These tyrosine motifs are involved in regulation of BCR signaling and also mediate its constitutive clathrin mediated endocytosis, an activity believed to be tied to its regulation of cell signaling. The preferred glycan ligand of CD22 differs significantly in humans and mice<ref name="Crocker 2007"/><ref name="Kimura 2007">Kimura N, Ohmori K, Miyazaki K, Izawa M, Matsuzaki Y, Yasuda Y, Takematsu H, Kozutsumi Y, Moriyama A, Kannagi R. [http://www.ncbi.nlm.nih.gov/pubmed/17728258 Human B-lymphocytes express alpha2-6-sialylated 6-sulfo-N-acetyllactosamine serving as a preferred ligand for CD22/Siglec-2]. J'' Biol Chem''. 2007 Nov 2;282(44):32200-7.</ref><ref name="Blixt 2004">Blixt O, Head S, Mondala T, Scanlan C, Huflejt ME, Alvarez R, Bryan MC, Fazio F, Calarese D, Stevens J, Razi N, Stevens DJ, Skehel JJ, van Die I, Burton DR, Wilson IA, Cummings R, Bovin N, Wong CH, Paulson JC. [http://www.ncbi.nlm.nih.gov/pubmed/15563589 Printed covalent glycan array for ligand profiling of diverse glycan binding proteins]. ''Proc Natl Acad Sci U S A''. 2004 Dec 7;101(49):17033-8.</ref>. While both recognize the sequence Siaα-2-6Galβ-1-4GlcNAc expressed abundantly on B cells, murine CD22 prefers Neu5Gc (not found in humans) over Neu5Ac, while human CD22 exhibits highest affinity for sulfated sialoside, Neu5Acα-2-6Galβ-1-4[6S]GlcNAc, demonstrating significant evolution of ligand specificity with conservation of function. Although CD22 recognizes ligands on the same cell in ''cis'', it also binds to ligands in ''trans'' if expressed on adjacent contacting cells. A major area of investigation is to understand the relative roles of ''cis'' and ''trans'' ligands in CD22 function.

[[Image:SiglecCD22.jpg|right|alt text]]
== CFG Participating Investigators contributing to the understanding of this paradigm ==

CFG Participating Investigators (PIs) have made major contributions to the understanding of the biology of human and murine CD22. These include: Nicolai Bovin, Paul Crocker, Jamey Marth, David Nemazee, Lars Nitschke, Jim Paulson, Ajit Varki

== Progress toward understanding this GBP paradigm ==
This section documents what is currently known about CD22, its carbohydrate ligand(s), and how they interact to mediate cell communication. Further information can be found in the GBP Molecule Page for [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_hum_Itlect_269&sideMenu=no human] and [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_mou_Itlect_194&sideMenu=no mouse] CD22 (aka Siglec-2) in the CFG database.
=== Carbohydrate ligands ===
Although CD22 is highly conserved throughout mammalian species, murine and human CD22 are known to exhibit significant differences in their specificities that appear to have evolved to compensate for changes in the glycan ligands expressed on B cells. While both bind Siaα2-6Gal terminated glycans, murine CD22 prefers NeuGc (NeuGcα2-6Galβ1-4GlcNAc), which is not found in humans. In contrast, human human CD22 recognizes NeuAc and NeuGc with equal affinity. In addition, however, human CD22 exhibits highest affinity for a ligand with sulfate at the 6 position of GlcNAc (NeuAcα2-6Galβ1-4[6S]GlcNAc).<ref name="Crocker 2007"/><ref name="Kimura 2007"/> 9-O-acetylation of sialic acid abrogates binding of CD22, which is thought to regulate the binding of ''cis'' ligands on B cells.
 
=== Cellular expression of GBP and ligands ===
CD22 is primarily expressed on mature B cells and to a lesser extent on memory B cells. However, it is not expressed on pre-B cells and differentiated plasma cells. Like many siglecs, CD22 interacts with endogenous ligands on B cells in ''cis'', and on other cells, such as T cells and bone marrow vessel endothelial cells in ''trans''. Although ''cis'' ligands of tend to mask the CD22 binding site, CD22 is able to interact with ''trans'' ligands on contacting cells (B cells and T cells), and to bind to synthetic multivalent ligands that have sufficient avidity.
 
=== Biosynthesis of ligands ===
The ligands of CD22 are predominately the product of a single sialyltransferase, ST6Gal I. Mice deficient in ST6Gal I express no ligands on B cells resulting in an immuno-deficient phenotype.
Differences in the specificity of human and murine siglec orthologs/paralogs also reflect adaptations to recognize self-ligands <ref name="Crocker 2007"/><ref name="Varki 2010">Varki, A. [http://www.ncbi.nlm.nih.gov/pubmed/20445087 Colloquium paper: uniquely human evolution of sialic acid genetics and biology]. "Proc Natl Acad Sci U S A''. 2010 May 11;107 Suppl 2:8939-46.</ref>. In particular, murine CD22 preferentially recognizes NeuGc containing α2-6 sialosides (2) with over 10 fold higher affinity than NeuAc (1), but human CD22 exhibits equal affinity for both, consistent with the fact that mouse B cells preferentially express NeuGc, while human B cells express only NeuAc <ref name="Brinkman 2000">Brinkman-Van der Linden EC, Sjoberg ER, Juneja LR, Crocker PR, Varki N, Varki A. [http://www.ncbi.nlm.nih.gov/pubmed/10722703 Loss of N-glycolylneuraminic acid in human evolution. Implications for sialic acid recognition by siglecs]. .J'' Biol Chem''. 2000 Mar 24;275(12):8633-40.</ref><ref name="Kelm 1994">Kelm S, Schauer R, Manuguerra JC, Gross HJ, Crocker PR. [http://www.ncbi.nlm.nih.gov/pubmed/7696861 Modifications of cell surface sialic acids modulate cell adhesion mediated by sialoadhesin and CD22]. '' Glycoconj J''. 1994 Dec;11(6):576-85.</ref><ref name="Naito 2007">Naito Y, Takematsu H, Koyama S, Miyake S, Yamamoto H, Fujinawa R, Sugai M, Okuno Y, Tsujimoto G, Yamaji T, Hashimoto Y, Itohara S, Kawasaki T, Suzuki A, Kozutsumi Y. [http://www.ncbi.nlm.nih.gov/pubmed/17296732 Germinal center marker GL7 probes activation-dependent repression of N-glycolylneuraminic acid, a sialic acid species involved in the negative modulation of B-cell activation]. '' Mol Cell Biol''. 2007 Apr;27(8):3008-22.</ref><ref name="Blixt 2003">Blixt O, Collins BE, van den Nieuwenhof IM, Crocker PR, Paulson JC. [http://www.ncbi.nlm.nih.gov/pubmed/12773526 Sialoside specificity of the siglec family assessed using novel multivalent probes: identification of potent inhibitors of myelin-associated glycoprotein]. J'' Biol Chem''. 2003 Aug 15;278(33):31007-19.</ref>. Another difference is that human CD22 exhibits highest affinity for the 6-sulfo-NeuAcα2-6Galβ1-4GlcNAc (3) <ref name="Blixt 2004"/><ref name="Kimura 2007"/><ref name="CFG">Consortium for Functional Glycomics. [http://www.functionalglycomics.org http://www.functionalglycomics.org].</ref>. Despite these differences, activation of B cells in both species results in down regulation of the highest affinity ligand. In murine B cells, activation causes de novo synthesis of sialosides with NeuAc instead of NeuGc through down regulation of CMP-sialic acid hydroxylase <ref name="Naito 2007"/>, while in human B cells, differentiation of B cells in germinal centers coincides with loss of the sulfate from the high affinity sulfated ligand (3) <ref name="Kimura 2007"/>. Recent reports also document that 9-O-acetyl substitutions of sialic acids also play an important role in regulating the association of CD22 with cis ligands, which is an element of specificity conserved across the two species <ref name="Sjoberg 1994">Sjoberg ER, Powell LD, Klein A, Varki A. [http://www.ncbi.nlm.nih.gov/pubmed/18034751 Natural ligands of the B cell adhesion molecule CD22 beta can be masked by 9-O-acetylation of sialic acids]. J'' Cell Biol''. 1994 Jul;126(2):549-62.</ref><ref name="Cariappa 2009">Cariappa A, Takematsu H, Liu H, Diaz S, Haider K, Boboila C, Kalloo G, Connole M, Shi HN, Varki N, Varki A, Pillai S. [http://www.ncbi.nlm.nih.gov/pubmed/19103880 B cell antigen receptor signal strength and peripheral B cell development are regulated by a 9-O-acetyl sialic acid esterase]. J'' Exp Med''. 2009 Jan 16;206(1):125-38.</ref><ref name="Pillai 2009">Pillai S, Cariappa A, Pirnie SP. [http://www.ncbi.nlm.nih.gov/pubmed/19766537 Esterases and autoimmunity: the sialic acid acetylesterase pathway and the regulation of peripheral B cell tolerance]. '' Trends Immunol''. 2009 Oct;30(10):488-93.</ref><ref name="Surolia 2010">Surolia I, Pirnie SP, Chellappa V, Taylor KN, Cariappa A, Moya J, Liu H, Bell DW, Driscoll DR, Diederichs S, Haider K, Netravali I, Le S, Elia R, Dow E, Lee A, Freudenberg J, De Jager PL, Chretien Y, Varki A, Macdonald ME, Gillis T, Behrens TW, Bloch D, Collier D, Korzenik J, Podolsky DK, Hafler D, Murali M, Sands B, Stone JH, Gregersen PK, Pillai S. [http://www.ncbi.nlm.nih.gov/pubmed/20555325 Functionally defective germline variants of sialic acid acetylesterase in autoimmunity]. '' Nature''. 2010 Jul 8;466(7303):243-7.</ref>.

=== Structure ===
Although the crystal structure of CD22 has not yet been elucidated, structures of other siglecs, including sialoadhesin, siglec-5 and siglec-7 have shed insights into the nature of the ligand binding site of CD22.<ref name="Crocker 2007"/>
 
=== Biological roles of GBP-ligand interaction ===

CD22 is a co-receptor of the membrane IgM B cell receptor (BCR), and regulates BCR signaling via immunoreceptor tyrosine inhibitory motifs (ITIMs) in its cytoplasmic domain.<ref name="Tedder 2005">Tedder TF, Poe JC, Haas KM. [http://www.ncbi.nlm.nih.gov/pubmed/16227086 CD22: a multifunctional receptor that regulates B lymphocyte survival and signal transduction]. ''Adv Immunol''. 2005;88:1-50.</ref><ref name="Crocker 2007"/><ref name="Walker 2008">Walker JA, Smith KG. [http://www.ncbi.nlm.nih.gov/pubmed/18067554 CD22: an inhibitory enigma]. ''Immunology''. 2008;123(3):314-25.</ref><ref name="Nitschke 2009">Nitschke L. [http://www.ncbi.nlm.nih.gov/pubmed/19594633 CD22 and Siglec-G: B-cell inhibitory receptors with distinct functions]. ''Immunol Rev''. 2009;230(1):128-43.</ref>
CD22 is predominately localized in clathrin-coated pits on the surface of the cell, where it mediates constitutive recycling to endocytic compartments.<ref name="Collins 2006">Collins BE, Smith BA, Bengtson P, Paulson JC. . [http://www.ncbi.nlm.nih.gov/pubmed/16369536 Ablation of CD22 in ligand-deficient mice restores B cell receptor signaling]. ''Nat Immunol''. 2006;7(2):199-206.</ref><ref name="Grewal 2006">Grewal PK, Boton M, Ramirez K, Collins BE, Saito A, Green RS, Ohtsubo K, Chui D, Marth JD. [http://www.ncbi.nlm.nih.gov/pubmed/16782884 ST6Gal-I restrains CD22-dependent antigen receptor endocytosis and Shp-1 recruitment in normal and pathogenic immune signaling]. ''Mol Cell Biol''. 2006;26(13):4970-81.</ref><ref name="O'Reilly 2011">O'Reilly MK, Tian H, Paulson JC. [http://www.ncbi.nlm.nih.gov/pubmed/21178016 CD22 is a recycling receptor that can shuttle cargo between the cell surface and endosomal compartments of B cells]. ''J Immunol''. 2011;186(3):1554-63.</ref>
Following ligation of the BCR with antigen, phosphokinases phosphorylate the BCR complex, which in turn amplifies a signal to activate the cell to proliferate and produce antibody. As one of the co-receptors of the BCR, CD22 recruits cofactors that modulate the degree of BCR phosphorylation and downstream signaling. In particular, CD22 recruits the phsophatase SHP-1 that dephosphorylates the BCR complex and suppresses cell signaling. Thus, CD22 is often considered to be a negative regulator of BCR signaling.

The roles of ligands in BCR signaling have been extensively investigated. <ref name="Tedder 2005"/><ref name="Crocker 2007"/><ref name="Walker 2008"/><ref name="Collins 2006"/><ref name="Naito 2007"/><ref name="Cariappa 2009"/><ref name="Hennet 1998">Hennet T, Chui D, Paulson JC, Marth JD. [http://www.ncbi.nlm.nih.gov/pubmed/9539767 Immune regulation by the ST6Gal sialyltransferase]. ''Proc Natl Acad Sci U S A''. 1998;95(8):4504-9.</ref>
Siglecs in general, and CD22 in particular, are known to interact with sialylated ligands on the same cell, “in cis”, and on opposing cells, “in trans”. Although many B cell glycoproteins carry the ligand of CD22, the predominant cis ligands appear to be CD22 itself.
<ref name="Hans 2005">Han S, Collins BE, Bengtson P, Paulson JC. [http://www.ncbi.nlm.nih.gov/pubmed/16408005 Homomultimeric complexes of CD22 in B cells revealed by protein-glycan cross-linking]. ''Nat Chem Biol''. 2005;1(2):93-7.</ref>
This is due in part to the fact that CD22 is preferentially concentrated in clathrin coated pits. Although there is agreement that cis ligand influence CD22 function as a regulator of BCR signaling, there is yet no consensus on the relevance of cis ligands to the constitutive regulation of the BCR. <ref name="Tedder 2005"/><ref name="Walker 2008"/><ref name="Collins 2006"/><ref name="Naito 2007"/><ref name="Cariappa 2009"/>

Despite the presence of cis ligands, CD22 can interact with trans ligands on opposing cells, and redistribute to the site of cell contact.<ref name="Collins 2004">Collins BE, Blixt O, DeSieno AR, Bovin N, Marth JD, Paulson JC. [http://www.ncbi.nlm.nih.gov/pubmed/15079087 Masking of CD22 by cis ligands does not prevent redistribution of CD22 to sites of cell contact]. ''Proc Natl Acad Sci U S A''. 2004;101(16):6104-9.</ref> This property is has been implicated in recirculation of B cells in the bone marrow,<ref name="Nitschke 1999">Nitschke L, Floyd H, Ferguson DJ, Crocker PR. [http://www.ncbi.nlm.nih.gov/pubmed/10224292 Identification of CD22 ligands on bone marrow sinusoidal endothelium implicated in CD22-dependent homing of recirculating B cells]. ''J Exp Med''. 1999;189(9):1513-8.</ref> and is believed to be relevant to innate recognition of self.
<ref name="Lanoue 2002">Lanoue A, Batista FD, Stewart M, Neuberger MS. [http://www.ncbi.nlm.nih.gov/pubmed/11807774 Interaction of CD22 with alpha2,6-linked sialoglycoconjugates: innate recognition of self to dampen B cell autoreactivity?]. ''Eur J Immunol''. 2002;32(2):348-55.</ref> <ref name="Duong 2010">Duong BH, Tian H, Ota T, Completo G, Han S, Vela JL, Ota M, Kubitz M, Bovin N, Paulson JC, Nemazee D. [http://www.ncbi.nlm.nih.gov/pubmed/20038598 Decoration of T-independent antigen with ligands for CD22 and Siglec-G can suppress immunity and induce B cell tolerance in vivo]. ''J Exp Med''. 2010;207(1):173-87.</ref> Indeed, Lanoue et al. demonstrated that B cell signaling is suppressed if the antigen is expressed on a cell that contains ligands of CD22. <ref name="Lanoue 2002"/> Several groups have demonstrated that co-presentation of an antigen and CD22 ligands results in suppressed activation of a B cell.(14-16)
<ref name="Lanoue 2002"/><ref name="Duong 2010"/><ref name="Courtney 2009">Courtney AH, Puffer EB, Pontrello JK, Yang ZQ, Kiessling LL. [http://www.ncbi.nlm.nih.gov/pubmed/19202057 Sialylated multivalent antigens engage CD22 in trans and inhibit B cell activation]. 'Proc Natl Acad Sci U S A''. 2009;106(8):2500-5.</ref> In fact, immunization of a mouse with a polymer containing both a T-independent antigen and a high affinity CD22 ligand induces activation and apoptosis of B cells recognizing the antigen, resulting in tolerization of the mouse to subsequent challenge with the antigen.<ref name="Duong 2010"/> The results suggest that trans ligands of CD22 and other B cell siglecs may serve as markers of self, and that CD22 participates in a mechanism of peripheral tolerance to self-antigens.

== CFG resources used in investigations ==
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=CD22&maxresults=20 CFG database search results for CD22].

=== Glycan profiling ===
Both murine and human CD22 recognize the sequence Siaα2-6Galβ1-4GlcNAc expressed abundantly on [http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=b%20AND%20cells&cat=corec B cells], which have been subjected to glycan profiling by the CFG.
 

=== Glycogene microarray ===

The CFG glycogene microarray has been used to show that ST6Gal I is downregulated [https://www.functionalglycomics.org/glycomics/publicdata/microarray.jsp?resReqId=cfg_rRequest_2 'on T cells] upon activation suggesting that B cell ''trans'' ligands are reduced on activated T cells. Probes for mouse and human CD22 have been included on all four versions of the CFG glycogene array.

=== Knockout mouse lines ===
Mice deficient in [https://www.functionalglycomics.org/static/consortium/resources/resourcecoref16.shtml CD22] and the sialyltransferase, ST6Gal I, responsible for synthesis of its ligands ([https://www.functionalglycomics.org/glycomics/publicdata/phenotyping.jsp ST6Gal I]) distributed by the CFG have been instrumental in understanding the biology of CD22.

=== Glycan array ===
The CFG's glycan array was instrumental in identification of the [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1792 high affinity ligands of CD22] as sialylated-sulfated glycans.<ref name="Kimura 2007"/><ref name="Blixt 2004"/>

== Related GBPs ==

This paradigm is unique among the siglecs in that the cytoplasmic domain has six conserved tyrosine motifs, including three immunoreceptor tyrosine inhibitory motifs (ITIM), one ITIM-like motif, and a growth factor receptor bound protein2 (GRB2) motif. However, other members of the homologous siglec family have contributed to an understanding of the glycan binding site of CD22, and general principles governing the interaction of CD22 with ''cis'' and ''trans'' ligands.

== References ==
<references/>

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: Paul Crocker, James Paulson

CD22

2012-01-20T19:48:21Z

Anna Crie: /* Biological roles of GBP-ligand interaction */

CD22 is predominantly expressed on B cells and is well documented as a regulator of B cell receptor (BCR) signaling<ref name="Crocker 2007">Crocker PR, Paulson JC, Varki A. [http://www.ncbi.nlm.nih.gov/pubmed/17380156 Siglecs and their roles in the immune system]. ''Nat Rev Immunol'' 2007 Apr;7(4):255-66. Review.</ref>. It is one of four siglecs that are highly conserved among mammals. This paradigm is unique among the siglecs in that the cytoplasmic domain has six conserved tyrosine motifs, including three immunoreceptor tyrosine inhibitory motifs (ITIM), one ITIM-like motif, and a growth factor receptor bound protein2 (GRB2) motif. These tyrosine motifs are involved in regulation of BCR signaling and also mediate its constitutive clathrin mediated endocytosis, an activity believed to be tied to its regulation of cell signaling. The preferred glycan ligand of CD22 differs significantly in humans and mice<ref name="Crocker 2007"/><ref name="Kimura 2007">Kimura N, Ohmori K, Miyazaki K, Izawa M, Matsuzaki Y, Yasuda Y, Takematsu H, Kozutsumi Y, Moriyama A, Kannagi R. [http://www.ncbi.nlm.nih.gov/pubmed/17728258 Human B-lymphocytes express alpha2-6-sialylated 6-sulfo-N-acetyllactosamine serving as a preferred ligand for CD22/Siglec-2]. J'' Biol Chem''. 2007 Nov 2;282(44):32200-7.</ref><ref name="Blixt 2004">Blixt O, Head S, Mondala T, Scanlan C, Huflejt ME, Alvarez R, Bryan MC, Fazio F, Calarese D, Stevens J, Razi N, Stevens DJ, Skehel JJ, van Die I, Burton DR, Wilson IA, Cummings R, Bovin N, Wong CH, Paulson JC. [http://www.ncbi.nlm.nih.gov/pubmed/15563589 Printed covalent glycan array for ligand profiling of diverse glycan binding proteins]. ''Proc Natl Acad Sci U S A''. 2004 Dec 7;101(49):17033-8.</ref>. While both recognize the sequence Siaα-2-6Galβ-1-4GlcNAc expressed abundantly on B cells, murine CD22 prefers Neu5Gc (not found in humans) over Neu5Ac, while human CD22 exhibits highest affinity for sulfated sialoside, Neu5Acα-2-6Galβ-1-4[6S]GlcNAc, demonstrating significant evolution of ligand specificity with conservation of function. Although CD22 recognizes ligands on the same cell in ''cis'', it also binds to ligands in ''trans'' if expressed on adjacent contacting cells. A major area of investigation is to understand the relative roles of ''cis'' and ''trans'' ligands in CD22 function.

[[Image:SiglecCD22.jpg|right|alt text]]
== CFG Participating Investigators contributing to the understanding of this paradigm ==

CFG Participating Investigators (PIs) have made major contributions to the understanding of the biology of human and murine CD22. These include: Nicolai Bovin, Paul Crocker, Jamey Marth, David Nemazee, Lars Nitschke, Jim Paulson, Ajit Varki

== Progress toward understanding this GBP paradigm ==
This section documents what is currently known about CD22, its carbohydrate ligand(s), and how they interact to mediate cell communication. Further information can be found in the GBP Molecule Page for [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_hum_Itlect_269&sideMenu=no human] and [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_mou_Itlect_194&sideMenu=no mouse] CD22 (aka Siglec-2) in the CFG database.
=== Carbohydrate ligands ===
Although CD22 is highly conserved throughout mammalian species, murine and human CD22 are known to exhibit significant differences in their specificities that appear to have evolved to compensate for changes in the glycan ligands expressed on B cells. While both bind Siaα2-6Gal terminated glycans, murine CD22 prefers NeuGc (NeuGcα2-6Galβ1-4GlcNAc), which is not found in humans. In contrast, human human CD22 recognizes NeuAc and NeuGc with equal affinity. In addition, however, human CD22 exhibits highest affinity for a ligand with sulfate at the 6 position of GlcNAc (NeuAcα2-6Galβ1-4[6S]GlcNAc).<ref name="Crocker 2007"/><ref name="Kimura 2007"/> 9-O-acetylation of sialic acid abrogates binding of CD22, which is thought to regulate the binding of ''cis'' ligands on B cells.
 
=== Cellular expression of GBP and ligands ===
CD22 is primarily expressed on mature B cells and to a lesser extent on memory B cells. However, it is not expressed on pre-B cells and differentiated plasma cells. Like many siglecs, CD22 interacts with endogenous ligands on B cells in ''cis'', and on other cells, such as T cells and bone marrow vessel endothelial cells in ''trans''. Although ''cis'' ligands of tend to mask the CD22 binding site, CD22 is able to interact with ''trans'' ligands on contacting cells (B cells and T cells), and to bind to synthetic multivalent ligands that have sufficient avidity.
 
=== Biosynthesis of ligands ===
The ligands of CD22 are predominately the product of a single sialyltransferase, ST6Gal I. Mice deficient in ST6Gal I express no ligands on B cells resulting in an immuno-deficient phenotype.
Differences in the specificity of human and murine siglec orthologs/paralogs also reflect adaptations to recognize self-ligands <ref name="Crocker 2007"/><ref name="Varki 2010">Varki, A. [http://www.ncbi.nlm.nih.gov/pubmed/20445087 Colloquium paper: uniquely human evolution of sialic acid genetics and biology]. "Proc Natl Acad Sci U S A''. 2010 May 11;107 Suppl 2:8939-46.</ref>. In particular, murine CD22 preferentially recognizes NeuGc containing α2-6 sialosides (2) with over 10 fold higher affinity than NeuAc (1), but human CD22 exhibits equal affinity for both, consistent with the fact that mouse B cells preferentially express NeuGc, while human B cells express only NeuAc <ref name="Brinkman 2000">Brinkman-Van der Linden EC, Sjoberg ER, Juneja LR, Crocker PR, Varki N, Varki A. [http://www.ncbi.nlm.nih.gov/pubmed/10722703 Loss of N-glycolylneuraminic acid in human evolution. Implications for sialic acid recognition by siglecs]. .J'' Biol Chem''. 2000 Mar 24;275(12):8633-40.</ref><ref name="Kelm 1994">Kelm S, Schauer R, Manuguerra JC, Gross HJ, Crocker PR. [http://www.ncbi.nlm.nih.gov/pubmed/7696861 Modifications of cell surface sialic acids modulate cell adhesion mediated by sialoadhesin and CD22]. '' Glycoconj J''. 1994 Dec;11(6):576-85.</ref><ref name="Naito 2007">Naito Y, Takematsu H, Koyama S, Miyake S, Yamamoto H, Fujinawa R, Sugai M, Okuno Y, Tsujimoto G, Yamaji T, Hashimoto Y, Itohara S, Kawasaki T, Suzuki A, Kozutsumi Y. [http://www.ncbi.nlm.nih.gov/pubmed/17296732 Germinal center marker GL7 probes activation-dependent repression of N-glycolylneuraminic acid, a sialic acid species involved in the negative modulation of B-cell activation]. '' Mol Cell Biol''. 2007 Apr;27(8):3008-22.</ref><ref name="Blixt 2003">Blixt O, Collins BE, van den Nieuwenhof IM, Crocker PR, Paulson JC. [http://www.ncbi.nlm.nih.gov/pubmed/12773526 Sialoside specificity of the siglec family assessed using novel multivalent probes: identification of potent inhibitors of myelin-associated glycoprotein]. J'' Biol Chem''. 2003 Aug 15;278(33):31007-19.</ref>. Another difference is that human CD22 exhibits highest affinity for the 6-sulfo-NeuAcα2-6Galβ1-4GlcNAc (3) <ref name="Blixt 2004"/><ref name="Kimura 2007"/><ref name="CFG">Consortium for Functional Glycomics. [http://www.functionalglycomics.org http://www.functionalglycomics.org].</ref>. Despite these differences, activation of B cells in both species results in down regulation of the highest affinity ligand. In murine B cells, activation causes de novo synthesis of sialosides with NeuAc instead of NeuGc through down regulation of CMP-sialic acid hydroxylase <ref name="Naito 2007"/>, while in human B cells, differentiation of B cells in germinal centers coincides with loss of the sulfate from the high affinity sulfated ligand (3) <ref name="Kimura 2007"/>. Recent reports also document that 9-O-acetyl substitutions of sialic acids also play an important role in regulating the association of CD22 with cis ligands, which is an element of specificity conserved across the two species <ref name="Sjoberg 1994">Sjoberg ER, Powell LD, Klein A, Varki A. [http://www.ncbi.nlm.nih.gov/pubmed/18034751 Natural ligands of the B cell adhesion molecule CD22 beta can be masked by 9-O-acetylation of sialic acids]. J'' Cell Biol''. 1994 Jul;126(2):549-62.</ref><ref name="Cariappa 2009">Cariappa A, Takematsu H, Liu H, Diaz S, Haider K, Boboila C, Kalloo G, Connole M, Shi HN, Varki N, Varki A, Pillai S. [http://www.ncbi.nlm.nih.gov/pubmed/19103880 B cell antigen receptor signal strength and peripheral B cell development are regulated by a 9-O-acetyl sialic acid esterase]. J'' Exp Med''. 2009 Jan 16;206(1):125-38.</ref><ref name="Pillai 2009">Pillai S, Cariappa A, Pirnie SP. [http://www.ncbi.nlm.nih.gov/pubmed/19766537 Esterases and autoimmunity: the sialic acid acetylesterase pathway and the regulation of peripheral B cell tolerance]. '' Trends Immunol''. 2009 Oct;30(10):488-93.</ref><ref name="Surolia 2010">Surolia I, Pirnie SP, Chellappa V, Taylor KN, Cariappa A, Moya J, Liu H, Bell DW, Driscoll DR, Diederichs S, Haider K, Netravali I, Le S, Elia R, Dow E, Lee A, Freudenberg J, De Jager PL, Chretien Y, Varki A, Macdonald ME, Gillis T, Behrens TW, Bloch D, Collier D, Korzenik J, Podolsky DK, Hafler D, Murali M, Sands B, Stone JH, Gregersen PK, Pillai S. [http://www.ncbi.nlm.nih.gov/pubmed/20555325 Functionally defective germline variants of sialic acid acetylesterase in autoimmunity]. '' Nature''. 2010 Jul 8;466(7303):243-7.</ref>.

=== Structure ===
Although the crystal structure of CD22 has not yet been elucidated, structures of other siglecs, including sialoadhesin, siglec-5 and siglec-7 have shed insights into the nature of the ligand binding site of CD22.<ref name="Crocker 2007"/>
 
=== Biological roles of GBP-ligand interaction ===
CD22 is a co-receptor of the membrane IgM B cell receptor (BCR), and regulates BCR signaling via immunoreceptor tyrosine inhibitory motifs (ITIMs) in its cytoplasmic domain.<ref name="Tedder 2005">Tedder TF, Poe JC, Haas KM. [http://www.ncbi.nlm.nih.gov/pubmed/16227086 CD22: a multifunctional receptor that regulates B lymphocyte survival and signal transduction]. ''Adv Immunol''. 2005;88:1-50.</ref><ref name="Crocker 2007"/><ref name="Walker 2008">Walker JA, Smith KG. [http://www.ncbi.nlm.nih.gov/pubmed/18067554 CD22: an inhibitory enigma]. ''Immunology''. 2008;123(3):314-25.</ref><ref name="Nitschke 2009">Nitschke L. [http://www.ncbi.nlm.nih.gov/pubmed/19594633 CD22 and Siglec-G: B-cell inhibitory receptors with distinct functions]. ''Immunol Rev''. 2009;230(1):128-43.</ref>
CD22 is predominately localized in clathrin-coated pits on the surface of the cell, where it mediates constitutive recycling to endocytic compartments.<ref name="Collins 2006">Collins BE, Smith BA, Bengtson P, Paulson JC. . [http://www.ncbi.nlm.nih.gov/pubmed/16369536 Ablation of CD22 in ligand-deficient mice restores B cell receptor signaling]. ''Nat Immunol''. 2006;7(2):199-206.</ref><ref name="Grewal 2006">Grewal PK, Boton M, Ramirez K, Collins BE, Saito A, Green RS, Ohtsubo K, Chui D, Marth JD. [http://www.ncbi.nlm.nih.gov/pubmed/16782884 ST6Gal-I restrains CD22-dependent antigen receptor endocytosis and Shp-1 recruitment in normal and pathogenic immune signaling]. ''Mol Cell Biol''. 2006;26(13):4970-81.</ref><ref name="O'Reilly 2011">O'Reilly MK, Tian H, Paulson JC. [http://www.ncbi.nlm.nih.gov/pubmed/21178016 CD22 is a recycling receptor that can shuttle cargo between the cell surface and endosomal compartments of B cells]. ''J Immunol''. 2011;186(3):1554-63.</ref>
Following ligation of the BCR with antigen, phosphokinases phosphorylate the BCR complex, which in turn amplifies a signal to activate the cell to proliferate and produce antibody. As one of the co-receptors of the BCR, CD22 recruits cofactors that modulate the degree of BCR phosphorylation and downstream signaling. In particular, CD22 recruits the phsophatase SHP-1 that dephosphorylates the BCR complex and suppresses cell signaling. Thus, CD22 is often considered to be a negative regulator of BCR signaling.

The roles of ligands in BCR signaling have been extensively investigated. <ref name="Tedder 2005"/><ref name="Crocker 2007"/><ref name="Walker 2008"/><ref name="Collins 2006"/><ref name="Naito 2007"/><ref name="Cariappa 2009"/><ref name="Hennet 1998">Hennet T, Chui D, Paulson JC, Marth JD. [http://www.ncbi.nlm.nih.gov/pubmed/9539767 Immune regulation by the ST6Gal sialyltransferase]. ''Proc Natl Acad Sci U S A''. 1998;95(8):4504-9.</ref>
Siglecs in general, and CD22 in particular, are known to interact with sialylated ligands on the same cell, “in cis”, and on opposing cells, “in trans”. Although many B cell glycoproteins carry the ligand of CD22, the predominant cis ligands appear to be CD22 itself.
<ref name="Hans 2005">Han S, Collins BE, Bengtson P, Paulson JC. [http://www.ncbi.nlm.nih.gov/pubmed/16408005 Homomultimeric complexes of CD22 in B cells revealed by protein-glycan cross-linking]. ''Nat Chem Biol''. 2005;1(2):93-7.</ref>
This is due in part to the fact that CD22 is preferentially concentrated in clathrin coated pits. Although there is agreement that cis ligand influence CD22 function as a regulator of BCR signaling, there is yet no consensus on the relevance of cis ligands to the constitutive regulation of the BCR. <ref name="Tedder 2005"/><ref name="Walker 2008"/><ref name="Collins 2006"/><ref name="Naito 2007"/><ref name="Cariappa 2009"/>

Despite the presence of cis ligands, CD22 can interact with trans ligands on opposing cells, and redistribute to the site of cell contact.<ref name="Collins 2004">Collins BE, Blixt O, DeSieno AR, Bovin N, Marth JD, Paulson JC. [http://www.ncbi.nlm.nih.gov/pubmed/15079087 Masking of CD22 by cis ligands does not prevent redistribution of CD22 to sites of cell contact]. ''Proc Natl Acad Sci U S A''. 2004;101(16):6104-9.</ref> This property is has been implicated in recirculation of B cells in the bone marrow,<ref name="Nitschke 1999">Nitschke L, Floyd H, Ferguson DJ, Crocker PR. [http://www.ncbi.nlm.nih.gov/pubmed/10224292 Identification of CD22 ligands on bone marrow sinusoidal endothelium implicated in CD22-dependent homing of recirculating B cells]. ''J Exp Med''. 1999;189(9):1513-8.</ref> and is believed to be relevant to innate recognition of self.
<ref name="Lanoue 2002">Lanoue A, Batista FD, Stewart M, Neuberger MS. [http://www.ncbi.nlm.nih.gov/pubmed/11807774 Interaction of CD22 with alpha2,6-linked sialoglycoconjugates: innate recognition of self to dampen B cell autoreactivity?]. ''Eur J Immunol''. 2002;32(2):348-55.</ref> <ref name="Duong 2010">Duong BH, Tian H, Ota T, Completo G, Han S, Vela JL, Ota M, Kubitz M, Bovin N, Paulson JC, Nemazee D. [http://www.ncbi.nlm.nih.gov/pubmed/20038598 Decoration of T-independent antigen with ligands for CD22 and Siglec-G can suppress immunity and induce B cell tolerance in vivo]. ''J Exp Med''. 2010;207(1):173-87.</ref> Indeed, Lanoue et al. demonstrated that B cell signaling is suppressed if the antigen is expressed on a cell that contains ligands of CD22. <ref name="Lanoue 2002"/> Several groups have demonstrated that co-presentation of an antigen and CD22 ligands results in suppressed activation of a B cell.(14-16)
<ref name="Lanoue 2002"/><ref name="Duong 2010"/><ref name="Courtney 2009">Courtney AH, Puffer EB, Pontrello JK, Yang ZQ, Kiessling LL. [http://www.ncbi.nlm.nih.gov/pubmed/19202057 Sialylated multivalent antigens engage CD22 in trans and inhibit B cell activation]. 'Proc Natl Acad Sci U S A''. 2009;106(8):2500-5.</ref> In fact, immunization of a mouse with a polymer containing both a T-independent antigen and a high affinity CD22 ligand induces activation and apoptosis of B cells recognizing the antigen, resulting in tolerization of the mouse to subsequent challenge with the antigen.<ref name="Duong 2010"/> The results suggest that trans ligands of CD22 and other B cell siglecs may serve as markers of self, and that CD22 participates in a mechanism of peripheral tolerance to self-antigens.

== CFG resources used in investigations ==
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=CD22&maxresults=20 CFG database search results for CD22].

=== Glycan profiling ===
Both murine and human CD22 recognize the sequence Siaα2-6Galβ1-4GlcNAc expressed abundantly on [http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=b%20AND%20cells&cat=corec B cells], which have been subjected to glycan profiling by the CFG.
 

=== Glycogene microarray ===

The CFG glycogene microarray has been used to show that ST6Gal I is downregulated [https://www.functionalglycomics.org/glycomics/publicdata/microarray.jsp?resReqId=cfg_rRequest_2 'on T cells] upon activation suggesting that B cell ''trans'' ligands are reduced on activated T cells. Probes for mouse and human CD22 have been included on all four versions of the CFG glycogene array.

=== Knockout mouse lines ===
Mice deficient in [https://www.functionalglycomics.org/static/consortium/resources/resourcecoref16.shtml CD22] and the sialyltransferase, ST6Gal I, responsible for synthesis of its ligands ([https://www.functionalglycomics.org/glycomics/publicdata/phenotyping.jsp ST6Gal I]) distributed by the CFG have been instrumental in understanding the biology of CD22.

=== Glycan array ===
The CFG's glycan array was instrumental in identification of the [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1792 high affinity ligands of CD22] as sialylated-sulfated glycans.<ref name="Kimura 2007"/><ref name="Blixt 2004"/>

== Related GBPs ==

This paradigm is unique among the siglecs in that the cytoplasmic domain has six conserved tyrosine motifs, including three immunoreceptor tyrosine inhibitory motifs (ITIM), one ITIM-like motif, and a growth factor receptor bound protein2 (GRB2) motif. However, other members of the homologous siglec family have contributed to an understanding of the glycan binding site of CD22, and general principles governing the interaction of CD22 with ''cis'' and ''trans'' ligands.

== References ==
<references/>

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: Paul Crocker, James Paulson

CD22

2012-01-20T16:39:07Z

Anna Crie: /* Biosynthesis of ligands */

CD22

2012-01-20T16:38:40Z

Anna Crie: /* Biological roles of GBP-ligand interaction */

CD22

2012-01-20T05:10:43Z

Anna Crie: /* Biological roles of GBP-ligand interaction */

CD22

2012-01-20T05:08:24Z

Anna Crie:

CD22

2012-01-20T04:44:42Z

Anna Crie: /* Biological roles of GBP-ligand interaction */

CD22

2012-01-20T04:44:15Z

Anna Crie: /* Biological roles of GBP-ligand interaction */

CD22

2012-01-20T04:43:30Z

Anna Crie: /* Biological roles of GBP-ligand interaction */

File:C-type lectin.jpg

2011-12-20T05:15:21Z

Anna Crie: uploaded a new version of "File:C-type lectin.jpg"

File:C-type lectin.jpg

2011-12-20T05:13:55Z

Anna Crie: uploaded a new version of "File:C-type lectin.jpg"

User talk:Vitaly Balan

2011-09-08T15:10:58Z

Anna Crie: Welcome!

'''Welcome to ''CFGparadigms''!''' We hope you will contribute much and well.
You'll probably want to read the [[Help:Contents|help pages]]. Again, welcome and have fun! [[User:Anna Crie|Anna Crie]] 15:10, 8 September 2011 (UTC)

User:Vitaly Balan

2011-09-08T15:10:58Z

Anna Crie: Creating user page with biography of new user.

CURRICULUM VITAE of VITALY BALAN

EDUCATION
1999 – 2004 Ph.D. in Molecular Biology & Biochemistry
University of Ben-Gurion, Israel (Advisors: Prof. Ze’ev Barak and Prof. David Chipman)
1995 – 1998 M.Sc. in Molecular Biology & Biochemistry
University of Ben-Gurion, Israel (Advisors: Prof. Ze’ev Barak and Prof. David Chipman)
1988 – 1993 B.Sc. in Biology & Chemistry
Tiraspol State University,
Moldova
POSITIONS AND EMPLOYMENT
2011-present Assistant Professor, Department of Oncology, Wayne State University, Karmanos Cancer Institute, Detroit, MI USA

2006-2011 Research Associate, Karmanos Cancer Institute, Department of Pathology, Wayne State University, Detroit, MI USA (supervisor Dr. Avraham Raz)

2004-2006 Postdoctoral Research Fellow, Karmanos Cancer Institute, Department of Pathology, Wayne State University, Detroit, MI USA (supervisor Dr. Guri Tzivion)
2003-2004 Postdoctoral Research Fellow, CVRI, Texas A&M University, Temple, TX (supervisor Dr. Guri Tzivion)
1998-2003 Research Graduate/Assistant Teacher, Department of Life Sciences, University of Ben-Gurion, Israel.
1996-1998 Research Assistant/Assistant Teacher, Department of Life Sciences, University of Ben-Gurion, Israel.

PUBLICATIONS

Dobson, M., Ramakrishnan, G., Ma, S., Kaplun, L., Balan, V., Fridman, R., Tzivion, G. Bimodal Regulation of FoxO3 by AKT and 14-3-3. Biochimica et Biophysica Acta Mol Cell Research, 2011 Aug; 1813 (8): p. 1453-64

Wang, Y., Nangia-Makker, P, Balan, V., Hogan, V., Raz, A. Calpain activation through galectin-3 inhibition sensitizes prostate cancer cells to cisplatin treatment. Cell Death & Disease, 2010 Nov; vol. 1 (11) pp. e101, doi: 10.1038/cddis.2010.79

Balan, V1., Nangia-Makker, P., Jung, Y.S., Wang, Y., and Raz, A. Galectin-3: A novel substrate for c-Abl kinase. Biochimica et Biophysica Acta Mol Cell Research, 2010 June; 1803 (10): p. 1198-205.
1 Corresponding author

Balan, V., Nangia-Makker, P., Raz, A. Galectins as biomarkers. Cancers 2010 Apr; 2 (2): p. 592-610

Nangia-Makker, P., Wang, Y., Raz, T., Tait, L., Balan, V., Hogan, V., Raz, A. Cleavage of galectin-3 by matrix metalloproteases induces angiogenesis in breast cancer. Int J Cancer, 2010 Dec; 1; 127 (11): p. 2530-41 Featured paper

Wang, Y., Nangia-Makker, P., Tait, L., Balan, V., Hogan, V., Pienta, KJ., Raz, A. Regulation of prostate cancer progression by galectin-3. Am J Pathol 2009 Apr; 174 (4): (1515-1523)

Balan, V., Nangia-Makker, P., Schwartz, A. G., Jung, Y. S., Tait, L., Hogan, V., Raz, T., Wang, Y., Yang, Z. Q., Wu, G. S., Guo, Y., Li, H., Abrams, J., Couch, F. J., Lingle, W. L., Lloyd, R. V., Ethier, S. P., Tainsky, M. A., and Raz, A. Racial disparity in breast cancer and functional germ line mutation in galectin-3 (rs4644): a pilot study, Cancer Res 2008 Dec; (68): p. 10045-10050 Featured paper

Balan, V., Miller, GS., Kaplun, L., Balan, K., Chong, ZZ., Li, F., Kaplun, A., VanBerkum, MF., Arking, R., Freeman, DC., Maiese, K., and Tzivion, G. Lifespan extension and neuronal cell protection by Drosophila nicotinamidase. JBC 2008 Oct; 238 (41): p. 27810-27819

Nangia-Makker, P., Balan, V., Raz, A. Regulation of Tumor Progression by Extracellular Galectin-3. Cancer Microenvironment 2008 Feb; 20 (1875-2284)

Leicht, D. T., Balan, V., Kaplun, A., Singh-Gupta, V., Kaplun, L., Dobson, M., and Tzivion, G. Raf kinases: Function, regulation and role in human cancer, Biochim Biophys Acta 2007 May; 1773 (8): p. 1196-1212

Balan, V., Leicht, D., Zhu, J., Balan, K., Singh, V., Qin, J., and Tzivion, G. Identification of novel in vivo Raf phosphorylation sites mediating positive feedback Raf regulation by ERK-1. Mol Biol Cell 2006 Mar; 17 (3): p. 1141-53

Tzivion, G., Singh, V., Kaplun L., Balan, V. 14-3-3 proteins as potential oncogenes. Semin Cancer Biol. 2006 Jun; 16 (3): p. 203-213

*Zhu, J., *Balan, V., Bronisz, A., Balan, K., Sun, H., Leicht, D., Luo, Z., Qin, J., Avruch, J., Tzivion, G. Identification of Raf-1 S471 as a novel phosphorylation site critical for Raf-1 and B-Raf kinase activities and for MEK binding. Mol Biol Cell 2005 Oct; (16): p. 4733–4744
*These authors contributed equally to this work.

Bar-Ilan, A., Balan, V., Titmann, K., Vyazmensky, M., Hubher, G., Barak, Z., Chipman, D. Binding and activation of thiamin diphosphate in acetohydroxyacid synthase. Biochemistry 2001 Oct 2; 40 (39): p. 11946-54

Book Chapters:

Nangia-Makker, P., Balan, V., Raz, A. Galectin-3 Binding and Metastasis. In: Methods in Molecular Medicine: Metastasis Research Protocols. Dr Brooks S. and Schumacher U. (Ed.), Humana Press, in press

Wang, Y., Balan, V., Raz, A. Galectin-3 and cancer. In: Animal Lectins: A Functional View. Vasta GR. and Ahmed H. (Ed.), CRC Press (Taylor and Francis group), p. 195-206, 2009

Presentations:
• Balan V, Nangia-Makker P, Raz A. The interplay between prostate specific antigen and galectin-3 during prostate cancer progression. Abstract at the Gordon Research Conference on Matrix Metalloproteinases (2011) Smithfield, RI
• Balan V, Nangia-Makker P, Raz A. Tyrosine Phosphorylation of Galectin-3 Regulates its Cleavage by PSA [abstract]. In: Proceedings of the 102th Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; 2011. Abstract nr 1495
• Balan V, Nangia-Makker P, Raz A. The role of tyrosine phosphorylation in galectin-3 regulated cell motility [abstract]. In: Proceedings of the 100th Annual Meeting of the American Association for Cancer Research; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2166
• Balan, V., Nangia-Makker, P., Raz, A., (2008) Galectin-3 nsSNP rs4644 Foretells Human Breast Cancer Risk Associated With Racial Disparity [abstract]. In: Proceedings of the 99th Annual Meeting of the American Association for Cancer Research, San Diego, CA, USA
• Balan, V., Kaplun, A., Tzivion, G., (2007) Alanine mutation scanning of Raf-1 reveals novel residues important for its activation. Abstract at the FASEB Summer Research Conference "Protein Kinases & Protein Phosphorylation", Indian Wells, CA, USA.
• Balan, V., Leicht, D., Tzivion, G., (2006) Raf-1 Regulation by Novel Phosphorylations. Abstract at the Gordon Research Conference, New London, CT, USA
• Balan, V., Balan, K., Leicht, D., Tzivion, G., (2005) Identification of Novel In Vivo Raf-1 Phosphorylation Sites Mediating Positive Feedback Raf-1 Regulation Targeted By ERK. Abstract at the FASEB Research Conference, Snowmass, CO, USA
• Balan, V., Leicht, D., Balan, K., Singh-Gupta, V., Tzivion, G. (2005) Regulation of Raf-1 By Phosphorylation and Protein Interactions. Abstract at the FASEB Research Conference, Snowmass, CO, USA
• Balan, V., Bronisz, A., Sun, H., Godlewski, J., Shen, YH., Zhu, J., Tzivion, G., (2004) 14-3-3 Regulation, An Interplay Of Phosphorylation, Dimerization And Sequestration. Abstract at the Gordon Research Conference, Ventura, CA, USA
• Tzivion, G., Shen, YH., Godlewski, J., Balan, V., Sun, H., Zhu, J. and Bronisz, M. (2004) Role of 14-3-3 Proteins in Tumorigenesis; Use of a Transgenic 14-3-3 Mouse Line as a Model. Presentation at the Gordon Research Conference on "Biology of 14-3-3 Proteins", Ventura, CA, USA.
• Tzivion, G., Zhu, J., Bronisz, A., Balan, V., Cain, J., Godlewski, J., (2003) Identification of Raf phosphorylation site(s) critical for Raf kinase activity and MEK binding provides a new approach for the development of Raf/MEK inhibitors. Abstract at the SALK/EMBL meeting on Oncogenes and Growth Control, La Jolla, CA, USA
• Balan, V., Kaplun, A., Barak, Z., Chipman, D. (2001) Thiamin diphosphate binding and the assembly of acetohydroxyacid synthase. Abstract at the International Conference on Thiamin, its Biochemistry, and Structural Biology, Newark, NJ, USA
• Balan, V., Barak, Z., Chipman, D. (1998) Amino Acids Responsible for Mg2+ Binding in Acetohydroxy Acid Synthase. Abstract at the 25th Silver Jubilee FEBS Meeting, Copenhagen, Denmark
• Balan, V., Bar-Ilan, A., Barak, Z., Chipman, D., Mendel S., and Vyazmensky, M. (1998) Study of the Catalytic site of Acetohydroxy Acid Synthase II by Directed Mutagenesis. Abstract at the 2nd Conferences of Federation of the Israeli Society of Experemental Biology, Eilat, Israel

Invited Seminars:
1. Wayne State University, Karmanos Cancer Institute, August 15, 2006

2. Wayne State University, Department of Pathology, September 15, 2010

3. Wayne State University, Department of Oncology, January 21, 2011

4. Wayne State University, Karmanos Cancer Institute, Molecular Biology&Genetics Program Meeting, March 8, 2011

MEMBERSHIPS
American Association for Cancer Research

RESEARCH PROJECTS ONGOING, PENDING OR COMPLETED

Ongoing Research Support:

IRG #11-053-01-IRG
Title of project: The interplay between prostate specific antigen and galectin-3 during prostate cancer progression.
Funding Source: American Cancer Society
Role: Principal Investigator
Performance Period: 9-01-2011 to 8-31-2012

Instructions

2011-07-25T02:41:19Z

Anna Crie:

Purpose: The purpose of the CFG Wiki Paradigm Pages is to involve Participating Investigators (PIs) in demonstrating how the CFG has made progress against its overall goal to 'define paradigms by which protein-carbohydrate interactions mediate cell communication.' To lay the foundation for this vision, the CFG Steering Committee assembled a team of PIs to identify “Paradigms” that represented exemplary glycan binding proteins (GBPs) for each major family. Ultimately, 30 Paradigms were selected to cover 9 families of GBPs. The Paradigms share two key characteristics: they are representative of many other GBPs in their family, and they have clear biological functions that have become better understood through the use of CFG resources. Combined, the Paradigms cover the majority of the mammalian and microbial GBPs that are within the scope of the CFG, and show how the CFG has driven progress in the field as a whole.
 
Process: The CFG's Paradigm Pages are open to contributions from all CFG Participating Investigators. To obtain editing privileges, you must first [http://www.functionalglycomics.org/CFGparadigms/index.php/Special:UserLogin request an user account]. If you already have one, simply log in.
 
Focus: For consistency between Paradigm Pages, please maintain the 30 selected paradigm glycan-binding proteins that are listed on the paradigm pages and the standard outline and formatting of each individual Paradigm Page. The CFG would be particularly grateful to PIs for filling in the gaps regarding:
 
''Progress toward understanding this GBP paradigm''. This section includes five subheadings that together address the 7 specific aims of the CFG.
<li>Carbohydrate ligands: Describe progress that has been made towards defining the specificity and affinity of this GBP for carbohydrate ligands and identifying the glycan ligand(s) that mediate GBP binding.
<li>Cellular expression of GBP and ligands: Describe progress that has been made towards establishing the cell types involved in cell communication.
<li>Biosynthesis of ligands: Describe progress that has been made towards identifying the glycosyltransferases that synthesize carbohydrate ligands for the GBP and determining whether regulation of glycosylation modulates GBP function.
<li>Structure: Describe progress that has been made towards determining the structure of the GBP.
<li>Biological roles of GBP-ligand interaction: Describe progress that has been made towards determining how GBP-ligand interactions mediate cell communication.
 
''CFG resources used in investigations''. This section documents how investigators have used CFG resources to assess the function of the GBP paradigm.
 
<li>Describe use (or non-use) of CFG resources including glycan profiling, glycogene microarray screening, knockout mouse analysis, and glycan array screening.
<li>Include hyperlinks to relevant datasets in the CFG databases.
 
''Other related GBPs''. List related GBPs believed to have similar functions.
 
''References''. Citations will appear here once references are added to the above sections.

 
'''How to edit the CFG Paradigm Pages:'''
* Click the 'Log in' link in the top right-hand corner.
* Login or request a new account (enter any text in the 'biography' box) and wait for administrative approval. If you forgot your password, click 'E-mail new password'.
* From the [http://www.functionalglycomics.org/CFGparadigms/index.php/Welcome_to_the_CFG_Paradigm_Pages Paradigm Pages], find the paradigm GBP you are interested in. Follow the link to that page.
* Click the 'edit' tab at the top of the page.
* You will see a text box containing all of the text and html tags that make up that Paradigm Page.
* Contribute 2-3 sentences for each of the blank fields (e.g. 'Progress toward understanding this GBP paradigm').
* If you can, contribute to the 'CFG resources used in investigations' section, including links to specific datasets in the [http://www.functionalglycomics.org CFG database].
* For formatting and addition of hyperlinks and references, use common html tags ([http://www.functionalglycomics.org/static/consortium/Paradigms/WikiCodes.pdf see table]). ''Tip: Copy and paste text from the edit box of another Wiki page that contains the formatting style you would like to emulate.''
* Click 'Show preview' below the editing box.
* When finished, click 'Save page'.
* For more help editing Wiki pages, visit the [http://en.wikipedia.org/wiki/Help:Wiki_markup Wikipedia markup help page].

Instructions

2011-07-25T02:40:19Z

Anna Crie:

Purpose: The purpose of the CFG Wiki Paradigm Pages is to involve Participating Investigators (PIs) in demonstrating how the CFG has made progress against its overall goal to 'define paradigms by which protein-carbohydrate interactions mediate cell communication.' To lay the foundation for this vision, the CFG Steering Committee assembled a team of PIs to identify “Paradigms” that represented exemplary glycan binding proteins (GBPs) for each major family. Ultimately, 30 Paradigms were selected to cover 9 families of GBPs. The Paradigms share two key characteristics: they are representative of many other GBPs in their family, and they have clear biological functions that have become better understood through the use of CFG resources. Combined, the Paradigms cover the majority of the mammalian and microbial GBPs that are within the scope of the CFG, and show how the CFG has driven progress in the field as a whole.
 
Process: The CFG's Paradigm Pages are open to contributions from all CFG Participating Investigators. To obtain editing privileges, you must first [http://www.functionalglycomics.org/CFGparadigms/index.php/Special:UserLogin request an user account]. If you already have one, simply log in.
 
Focus: For consistency between Paradigm Pages, please maintain the 30 selected paradigm glycan-binding proteins that are listed on the paradigm pages and the standard outline and formatting of each individual Paradigm Page. The CFG would be particularly grateful to PIs for filling in the gaps regarding:
 
''Progress toward understanding this GBP paradigm''. This section includes five subheadings that together address the 7 specific aims of the CFG.
<li>Carbohydrate ligands: Describe progress that has been made towards defining the specificity and affinity of this GBP for carbohydrate ligands and identifying the glycan ligand(s) that mediate GBP binding.
<li>Cellular expression of GBP and ligands: Describe progress that has been made towards establishing the cell types involved in cell communication.
<li>Biosynthesis of ligands: Describe progress that has been made towards identifying the glycosyltransferases that synthesize carbohydrate ligands for the GBP and determining whether regulation of glycosylation modulates GBP function.
<li>Structure: Describe progress that has been made towards determining the structure of the GBP.
<li>Biological roles of GBP-ligand interaction: Describe progress that has been made towards determining how GBP-ligand interactions mediate cell communication.
 
''CFG resources used in investigations''. This section documents how investigators have used CFG resources to assess the function of the GBP paradigm.
 
<li>Describe use (or non-use) of CFG resources including glycan profiling, glycogene microarray screening, knockout mouse analysis, and glycan array screening.
<li>Include hyperlinks to relevant datasets in the CFG databases.
 
''Other related GBPs''. List related GBPs believed to have similar functions.
 
''References''. Citations will appear here once references are added to the above sections.

 
'''How to edit the CFG Paradigm Pages:'''
* Click the 'Log in' link in the top right-hand corner.
* Login or request a new account (enter any text in the 'biography' box) and wait for administrative approval. If you forgot your password, click 'E-mail new password'.
* From the [http://www.functionalglycomics.org/CFGparadigms/index.php/Welcome_to_the_CFG_Paradigm_Pages. Paradigm Pages], find the paradigm GBP you are interested in. Follow the link to that page.
* Click the 'edit' tab at the top of the page.
* You will see a text box containing all of the text and html tags that make up that Paradigm Page.
* Contribute 2-3 sentences for each of the blank fields (e.g. 'Progress toward understanding this GBP paradigm').
* If you can, contribute to the 'CFG resources used in investigations' section, including links to specific datasets in the [http://www.functionalglycomics.org CFG database].
* For formatting and addition of hyperlinks and references, use common html tags ([http://www.functionalglycomics.org/static/consortium/Paradigms/WikiCodes.pdf see table]). ''Tip: Copy and paste text from the edit box of another Wiki page that contains the formatting style you would like to emulate.''
* Click 'Show preview' below the editing box.
* When finished, click 'Save page'.
* For more help editing Wiki pages, visit the [http://en.wikipedia.org/wiki/Help:Wiki_markup Wikipedia markup help page].

Instructions

2011-07-25T02:37:03Z

Anna Crie:

Purpose: The purpose of the CFG Wiki Paradigm Pages is to involve Participating Investigators (PIs) in demonstrating how the CFG has made progress against its overall goal to 'define paradigms by which protein-carbohydrate interactions mediate cell communication.' To lay the foundation for this vision, the CFG Steering Committee assembled a team of PIs to identify “Paradigms” that represented exemplary glycan binding proteins (GBPs) for each major family. Ultimately, 30 Paradigms were selected to cover 9 families of GBPs. The Paradigms share two key characteristics: they are representative of many other GBPs in their family, and they have clear biological functions that have become better understood through the use of CFG resources. Combined, the Paradigms cover the majority of the mammalian and microbial GBPs that are within the scope of the CFG, and show how the CFG has driven progress in the field as a whole.
 
Process: The CFG's Paradigm Pages are open to contributions from all CFG Participating Investigators. To obtain editing privileges, you must first [http://www.functionalglycomics.org/CFGparadigms/index.php/Special:UserLogin request an user account]. If you already have one, simply log in.
 
Focus: For consistency between Paradigm Pages, please maintain the 30 selected paradigm glycan-binding proteins that are listed on the paradigm pages and the standard outline and formatting of each individual Paradigm Page. The CFG would be particularly grateful to PIs for filling in the gaps regarding:
 
''Progress toward understanding this GBP paradigm''. This section includes five subheadings that together address the 7 specific aims of the CFG.
<li>Carbohydrate ligands: Describe progress that has been made towards defining the specificity and affinity of this GBP for carbohydrate ligands and identifying the glycan ligand(s) that mediate GBP binding.
<li>Cellular expression of GBP and ligands: Describe progress that has been made towards establishing the cell types involved in cell communication.
<li>Biosynthesis of ligands: Describe progress that has been made towards identifying the glycosyltransferases that synthesize carbohydrate ligands for the GBP and determining whether regulation of glycosylation modulates GBP function.
<li>Structure: Describe progress that has been made towards determining the structure of the GBP.
<li>Biological roles of GBP-ligand interaction: Describe progress that has been made towards determining how GBP-ligand interactions mediate cell communication.
 
''CFG resources used in investigations''. This section documents how investigators have used CFG resources to assess the function of the GBP paradigm.
 
<li>Describe use (or non-use) of CFG resources including glycan profiling, glycogene microarray screening, knockout mouse analysis, and glycan array screening.
<li>Include hyperlinks to relevant datasets in the CFG databases.
 
''Other related GBPs''. List related GBPs believed to have similar functions.
 
''References''. Citations will appear here once references are added to the above sections.

 
'''How to edit the CFG Paradigm Pages:'''
* Click the 'Log in' link in the top right-hand corner.
* Login or request a new account (enter any text in the 'biography' box) and wait for administrative approval. If you forgot your password, click 'E-mail new password'.
* From the [http://www.functionalglycomics.org/CFGparadigms Paradigm Pages], find the paradigm GBP you are interested in. Follow the link to that page.
* Click the 'edit' tab at the top of the page.
* You will see a text box containing all of the text and html tags that make up that Paradigm Page.
* Contribute 2-3 sentences for each of the blank fields (e.g. 'Progress toward understanding this GBP paradigm').
* If you can, contribute to the 'CFG resources used in investigations' section, including links to specific datasets in the [http://www.functionalglycomics.org CFG database].
* For formatting and addition of hyperlinks and references, use common html tags ([http://www.functionalglycomics.org/static/consortium/Paradigms/WikiCodes.pdf see table]). ''Tip: Copy and paste text from the edit box of another Wiki page that contains the formatting style you would like to emulate.''
* Click 'Show preview' below the editing box.
* When finished, click 'Save page'.
* For more help editing Wiki pages, visit the [http://en.wikipedia.org/wiki/Help:Wiki_markup Wikipedia markup help page].

Instructions

2011-07-25T02:36:03Z

Anna Crie:

Purpose: The purpose of the CFG Wiki Paradigm Pages is to involve Participating Investigators (PIs) in demonstrating how the CFG has made progress against its overall goal to 'define paradigms by which protein-carbohydrate interactions mediate cell communication.' To lay the foundation for this vision, the CFG Steering Committee assembled a team of PIs to identify “Paradigms” that represented exemplary glycan binding proteins (GBPs) for each major family. Ultimately, 30 Paradigms were selected to cover 9 families of GBPs. The Paradigms share two key characteristics: they are representative of many other GBPs in their family, and they have clear biological functions that have become better understood through the use of CFG resources. Combined, the Paradigms cover the majority of the mammalian and microbial GBPs that are within the scope of the CFG, and show how the CFG has driven progress in the field as a whole.
 
Process: The CFG's Paradigm Pages are open to contributions from all CFG Participating Investigators. To obtain editing privileges, you must first [http://www.functionalglycomics.org/CFGparadigms/index.php/Special:UserLogin request an user account]. If you already have one, simply log in.
 
Focus: For consistency between Paradigm Pages, please maintain the 30 selected paradigm glycan-binding proteins that are listed on the paradigm pages and the standard outline and formatting of each individual Paradigm Page. The CFG would be particularly grateful to PIs for filling in the gaps regarding:
 
''Progress toward understanding this GBP paradigm''. This section includes five subheadings that together address the 7 specific aims of the CFG.
<li>Carbohydrate ligands: Describe progress that has been made towards defining the specificity and affinity of this GBP for carbohydrate ligands and identifying the glycan ligand(s) that mediate GBP binding.
<li>Cellular expression of GBP and ligands: Describe progress that has been made towards establishing the cell types involved in cell communication.
<li>Biosynthesis of ligands: Describe progress that has been made towards identifying the glycosyltransferases that synthesize carbohydrate ligands for the GBP and determining whether regulation of glycosylation modulates GBP function.
<li>Structure: Describe progress that has been made towards determining the structure of the GBP.
<li>Biological roles of GBP-ligand interaction: Describe progress that has been made towards determining how GBP-ligand interactions mediate cell communication.
 
''CFG resources used in investigations''. This section documents how investigators have used CFG resources to assess the function of the GBP paradigm.
 
<li>Describe use (or non-use) of CFG resources including glycan profiling, glycogene microarray screening, knockout mouse analysis, and glycan array screening.
<li>Include hyperlinks to relevant datasets in the CFG databases.
 
''Other related GBPs''. List related GBPs believed to have similar functions.
 
''References''. Citations will appear here once references are added to the above sections.

 
'''How to edit the CFG Paradigm Pages:'''
* Click the 'Log in' link in the top right-hand corner.
* Login or request a new account (enter any text in the 'biography' box) and wait for administrative approval. If you forgot your password, click 'E-mail new password'.
* From the [http://www.functionalglycomics.org/CFGparadigms Main Page], find the paradigm GBP you are interested in. Follow the link to that page.
* Click the 'edit' tab at the top of the page.
* You will see a text box containing all of the text and html tags that make up that Paradigm Page.
* Contribute 2-3 sentences for each of the blank fields (e.g. 'Progress toward understanding this GBP paradigm').
* If you can, contribute to the 'CFG resources used in investigations' section, including links to specific datasets in the [http://www.functionalglycomics.org CFG database].
* For formatting and addition of hyperlinks and references, use common html tags ([http://www.functionalglycomics.org/static/consortium/Paradigms/WikiCodes.pdf see table]). ''Tip: Copy and paste text from the edit box of another Wiki page that contains the formatting style you would like to emulate.''
* Click 'Show preview' below the editing box.
* When finished, click 'Save page'.
* For more help editing Wiki pages, visit the [http://en.wikipedia.org/wiki/Help:Wiki_markup Wikipedia markup help page].

MediaWiki:Sidebar

2011-07-23T16:49:05Z

Anna Crie:

MediaWiki:Sidebar

2011-07-23T16:48:01Z

Anna Crie:

MediaWiki:Sidebar

2011-07-23T16:46:56Z

Anna Crie:

MediaWiki:Sidebar

2011-07-23T12:31:49Z

Anna Crie:

Welcome to the CFG Paradigm Pages

2011-07-23T12:25:27Z

Anna Crie:

The Paradigm Pages were created by the Consortium for Functional Glycomics (CFG) to offer detailed information about 30 exemplary “Paradigm” glycan binding proteins (GBPs) that together encompass nine GBP families studied by the CFG. Each Paradigm GBP is representative of many other GBPs in its family and has clear biological functions that have become better understood through the use of CFG resources. The wiki-based Paradigm Pages are designed to track the progress of the CFG towards our goal to “define paradigms by which protein-carbohydrate interactions mediate cell communication.” CFG investigators are invited to upload and edit information about known progress in understanding each of these Paradigms, with a specific focus on how CFG resources have contributed to progress. To visit the Paradigm Page for each of the selected GBPs, follow the links below.
 
To contribute, please read these [http://www.functionalglycomics.org/static/consortium/CFGParadigm.shtml instructions].
 
 
== C-type Lectins ==
[[Image:C-type lectin.jpg|left|alt text]]

The C-type lectin family consists of proteins with diverse overall organization that contain structurally related carbohydrate-recognition domains. Although they generally share a common mechanism for interacting with sugars through a bound calcium ion, the spectrum of ligands bound by different members of the family is diverse and can include both endogenous mammalian oligosaccharides as well a sugar-containing structures on pathogenic micro-organisms. The biological functions of the C-type lectins are correspondingly diverse, but many of the best understood examples are membrane receptors found on the surface of cells of the immune system, which mediate interactions of these cells with each other and with viruses, bacteria, fungi and parasites, while other members of the family are soluble mediators of innate immunity. Outside the immune system, members of this group participate in clearance of circulating glycoproteins.
<li>Paradigm 1: [[DC-SIGN]]
<li>Paradigm 2: [[Macrophage galactose lectin (MGL)]]
<li>Paradigm 3: [[LSECtin]]
<li>Paradigm 4: [[P-Selectin]]
<li>Paradigm 5: [[Mannose receptor]]
<li>Paradigm 6: [[Ficolins/Mannose-binding protein]]
 

== Galectins ==
[[Image:galectin.jpg|left|alt text]]

Galectins are a family of glycan-binding proteins that are expressed in all multicellular organisms, in virtually every cell and tissue, and that vary considerably in function. There are 15 overall genes encoding galectins in different animals and 11 are expressed in humans. All galectins share a consensus sequence of about 130 amino acids and a homologous carbohydrate recognition domain (CRD) that specifically binds many different types of glycans, including those containing b-galactosides and poly-N-acetyllactosamines, but also including blood group antigens, and sialic acid- or sulfate-containing structures found in O- and N-glycans. The jellyroll-like conformation of the CRD, the hallmark of the galectin family, is composed of two anti-parallel b-sheets that establish a b-sandwich Differences in ligand specificity among this family are determined by specific amino acids in the CRDs, allowing recognition of different modifications of galactose-containing glycans, thus defining the affinity of a particular galectin for specific glycoprotein or glycolipid receptors in a certain tissue or cell type. Galectins are synthesized in the cytoplasm and secreted via a non-classical secretion pathway, so that galectins are found in a variety of intracellular compartments, as well as in the extracellular milieu of almost every cell and tissue type. There are three structural subfamilies of galectins - the prototype, the chimeric, and the tandem repeat. The three paradigmatic galectins described below represent the three structural subfamilies. The prototypical galectin subfamily include galectins-1, -2, -7, -10, -13, and -14; the chimeric galectin subfamily has a single representative galectin-3; and the tandem repeat galectin subfamily includes galectins-4, -8, -9, and -12. Recognition of cell surface glycans by many of the galectins, which is associated with oligomerization and lattice formation of the receptors, induces signaling pathways that are being well defined in leukocytes and epithelial cells. In addition, galectins are important in innate immune responses and can directly recognize glycans on pathogens and provide protection independently of antibodies.
<li>Paradigm 1: [[Galectin-1]]
<li>Paradigm 2: [[Galectin-3]]
<li>Paradigm 3: [[Galectin-9]]
 

== Siglecs ==
[[Image:Siglec.jpg|left|alt text]]

Sialic acid-binding immunoglobulin (Ig)-like lectins, or Siglecs, are a family of type 1 membrane proteins containing an extracellular V-set Ig domain and a variable number of C2-set Ig domains. Siglecs are expressed mainly by cells in the hematopoietic and immune systems, with MAG (Siglec-4) being a major exception due to its exclusive expression by cells of the nervous system. The V-set Ig domain of all siglecs mediates binding to sialylated oligosaccharides via a template centered around a conserved arginine on the F b strand. Extended specificity is mediated by variable residues on interstrand loops, such as the C-C' loop. Many siglecs contain one or more immunoreceptor tyrosine-based inhibitory motifs (ITIMS) that are important for regulating intracellular signaling functions and endocytosis. A recently characterized subset of siglecs can also associate via a basic residue in their transmembrane domains with transmembrane adaptors containing immunoreceptor tyrosine-based activation motifs (ITAMs). Siglecs can be divided into two groups based on sequence similarity. Group 1 contains Siglecs-1, -2, -4 and -15, which are distantly related to one another but well conserved in mammals. The other group includes CD33 and the CD33-related Siglecs which are highly related to each other and whose composition varies considerably amongst mammalian species. The paradigms have been selected on the basis of distinct functions, and include each of the 4 siglecs in group 1 and a representative human/murine pair for the ITIM-containing CD33-related siglecs.
<li>Paradigm 1: [[CD22]]
<li>Paradigm 2: [[Sialoadhesin]]
<li>Paradigm 3: [[Siglec-8]]
<li>Paradigm 4: [[MAG]]
<li>Paradigm 5: [[Siglec-15]]
 

== GBPs Mediating Intracellular Trafficking & Other Mammalian GBPs ==
[[Image:CIMPR.jpg|left|alt text]]

Both calreticulin and the cation-dependent mannose-6-phosphate receptor are glycan-binding proteins recognizing discrete and specific carbohydrates involved in intracellular trafficking of membrane and secretory glycoproteins. In the case of calreticulin, glycan binding is associated with the quality control apparatus ensuring that only properly folded proteins will exit the endoplasmic reticulum. In the case of the cation-dependent mannose-6-phosphate receptor, phosphorylated mannose residues are recognized, allowing lysosomal proteins to be properly targeted. These paradigms are important for understanding diseases of protein misfolding and many lysosomal storage disorders. The ficolins are a class of glycan-binding proteins with affinity for N-acetyl residues that have distinct fold from other known lectins yet mediate pathogen recognition. Polymorphisms in ficoloin genes may also have pathophysiological implications.
<li>Paradigm 1: [[Cation-dependent Mannose-6-phosphate receptor]]
<li>Paradigm 2: [[Calreticulin]]
<li>Paradigm 3: [[Ficolin M (Ficolin 1)]]
 

== Bacterial Adhesins and Lectins ==
[[Image:AdhesinsBacterial.jpg|left|alt text]]

Infection by bacteria is generally initiated by the specific recognition of host epithelial surfaces by adhesins and lectins. These GBPs are therefore virulence factors that play a role in the first step of adhesion and invasion. The GBPs are called adhesins when they are part of organelles, such as fimbriae and flagella. They are referred to as lectins when they are soluble, and lectin-domain when attached to other proteins, which are often hydrolytic enzymes also involved in the infection process. The human targets for bacterial adhesins and lectins are mostly fucosylated human histo-blood group and/or sialylated epitopes. Defining the biological role of bacterial adhesins and lectins together with their structure and specificity is a prerequisite for the development of strategies for inhibiting their binding to human tissues.
<li>Paradigm 1: [[PA-IIL]]
<li>Paradigm 2: [[CBM47]]
<li>Paradigm 3: [[F17G/GafD]]
 

== Bacterial Toxins ==
[[Image:ToxinBacteria.jpg|left|alt text]]

Toxigenic bacteria, which include some species of ''Escherichia'', ''Shigella'', ''Vibrio'', and ''Clostridium'', release protein toxins that alter essential host processes, including endocytic pathways, cell signaling and cytoskeletal reorganization. These toxins are key virulence factors that damage host tissues, and aid the spread of bacteria and evasion of immune clearance. Many bacterial toxins have been shown to bind host glycans. Glycan receptor specificity is critical for the pathogenic process, as it determines host susceptibility, tissue tropism, and the nature and spectrum of the resultant pathology. With contributions from the CFG, knowledge of the molecular and structural bases for toxin-glycan interactions is providing a rational framework for design of specific toxin inhibitors with considerable potential as anti-infective therapeutic agents.
<li>Paradigm 1: AB5 Toxin: [[Subtilase cytotoxin (SubAB)]]
<li>Paradigm 2: Clostridial Neurotoxin: [[Botulinum toxin serotype A (BoNT/A)]]
<li>Paradigm 3: Large Clostridial Cytotoxin: [[C. difficile toxin A (TcdA)| ''C. difficile'' toxin A (TcdA)]]
 

== Capsid Virus GBPs==
[[Image:polyomavirus.gif|left|alt text]]

A significant number of non-enveloped capsid viruses use glycans as cell attachment receptors. In some cases, viruses exclusively engage glycan structures at the cell surface, while in other cases glycans serve as co-receptors, and viruses also bind to proteins. The carbohydrate structures recognized by capsid viruses are diverse, ranging from gangliosides and other glycolipids to protein-bound glycans. Changes in carbohydrate binding specificity among family members of the same virus can often lead to altered tropism and pathogenicity. Thus, the elucidation of parameters that guide the specificity of interactions with glycans are of critical importance for understanding the complex biology of capsid viruses. The three paradigms listed below represent virus families whose glycan binding properties have been successfully studied by CFG investigators.
<li>Paradigm 1: [[Polyomavirus capsid protein (VP1)]]
<li>Paradigm 2: [[Reovirus hemagglutinin (sigma 1)]]
<li>Paradigm 3: [[Parvovirus Minute Virus of Mice (MVM)]]
 

== Enveloped Virus GBPs==
[[Image:VirusEnvelope.jpg|left|alt text]]

Enveloped viruses initiate infection by using their surface glycoproteins to attach to receptors on the cell surface. These receptors may be proteins, lipids or glycans. Protein receptors may be cell specific, to direct the virus into only its target tissue (e.g. CD4 for HIV). Glycan receptors may provide broader cell specificity, or be just as specific as protein receptors, but historically the lack of glycan reagents has precluded definitive studies. The CFG, and especially the CFG glycan microarray, has allowed definition of glycan receptor specificity. The influenza viruses and parainfluenza viruses are the two main families of enveloped viruses that use glycan binding proteins for their attachment to host cells.
<li>Paradigm 1: [[Influenza hemagglutinin H3]]
<li>Paradigm 2: [[Parainfluenza virus type 3 hemagglutinin-neuraminidase]]
 

== Eukaryotic Microbial GBPs ==
[[Image:EukaryoticMicrobial.gif|left|alt text]]

Eukaryotic microbes present a tremendous diversity of GBPs, many of which are crucial for microbial interactions within their own species or with other cell types. These relatively under-studied GBPs, both soluble and surface-displayed, include a variety of lectins and adhesins that are crucial for developmental processes, establishment of microbial communities, and interactions with the external environment. In the case of pathogenic organisms these GBPs can be key in host interactions, as in the case of the fungal adhesin paradigm below. The cyanovirin family provides another fascinating case with potential impact on human health.
<li>Paradigm 1: [[Candida glabrata EPA7| ''Candida glabrata'' EPA7]]
<li>Paradigm 2: [[Cyanovirin-N (CVN)]]

[[Category:Main Page]]

Main Page

2011-07-23T12:20:34Z

Anna Crie: moved Main Page to Welcome to the CFG Paradigm Pages

#REDIRECT [[Welcome to the CFG Paradigm Pages]]

Welcome to the CFG Paradigm Pages

2011-07-23T12:20:34Z

Anna Crie: moved Main Page to Welcome to the CFG Paradigm Pages

'''Welcome to the CFG Paradigm Pages!''' 
The Paradigm Pages were created by the Consortium for Functional Glycomics (CFG) to offer detailed information about 30 exemplary “Paradigm” glycan binding proteins (GBPs) that together encompass nine GBP families studied by the CFG. Each Paradigm GBP is representative of many other GBPs in its family and has clear biological functions that have become better understood through the use of CFG resources. The wiki-based Paradigm Pages are designed to track the progress of the CFG towards our goal to “define paradigms by which protein-carbohydrate interactions mediate cell communication.” CFG investigators are invited to upload and edit information about known progress in understanding each of these Paradigms, with a specific focus on how CFG resources have contributed to progress. To visit the Paradigm Page for each of the selected GBPs, follow the links below.
 
To contribute, please read these [http://www.functionalglycomics.org/static/consortium/CFGParadigm.shtml instructions].
 
 
== C-type Lectins ==
[[Image:C-type lectin.jpg|left|alt text]]

The C-type lectin family consists of proteins with diverse overall organization that contain structurally related carbohydrate-recognition domains. Although they generally share a common mechanism for interacting with sugars through a bound calcium ion, the spectrum of ligands bound by different members of the family is diverse and can include both endogenous mammalian oligosaccharides as well a sugar-containing structures on pathogenic micro-organisms. The biological functions of the C-type lectins are correspondingly diverse, but many of the best understood examples are membrane receptors found on the surface of cells of the immune system, which mediate interactions of these cells with each other and with viruses, bacteria, fungi and parasites, while other members of the family are soluble mediators of innate immunity. Outside the immune system, members of this group participate in clearance of circulating glycoproteins.
<li>Paradigm 1: [[DC-SIGN]]
<li>Paradigm 2: [[Macrophage galactose lectin (MGL)]]
<li>Paradigm 3: [[LSECtin]]
<li>Paradigm 4: [[P-Selectin]]
<li>Paradigm 5: [[Mannose receptor]]
<li>Paradigm 6: [[Ficolins/Mannose-binding protein]]
 

== Galectins ==
[[Image:galectin.jpg|left|alt text]]

Galectins are a family of glycan-binding proteins that are expressed in all multicellular organisms, in virtually every cell and tissue, and that vary considerably in function. There are 15 overall genes encoding galectins in different animals and 11 are expressed in humans. All galectins share a consensus sequence of about 130 amino acids and a homologous carbohydrate recognition domain (CRD) that specifically binds many different types of glycans, including those containing b-galactosides and poly-N-acetyllactosamines, but also including blood group antigens, and sialic acid- or sulfate-containing structures found in O- and N-glycans. The jellyroll-like conformation of the CRD, the hallmark of the galectin family, is composed of two anti-parallel b-sheets that establish a b-sandwich Differences in ligand specificity among this family are determined by specific amino acids in the CRDs, allowing recognition of different modifications of galactose-containing glycans, thus defining the affinity of a particular galectin for specific glycoprotein or glycolipid receptors in a certain tissue or cell type. Galectins are synthesized in the cytoplasm and secreted via a non-classical secretion pathway, so that galectins are found in a variety of intracellular compartments, as well as in the extracellular milieu of almost every cell and tissue type. There are three structural subfamilies of galectins - the prototype, the chimeric, and the tandem repeat. The three paradigmatic galectins described below represent the three structural subfamilies. The prototypical galectin subfamily include galectins-1, -2, -7, -10, -13, and -14; the chimeric galectin subfamily has a single representative galectin-3; and the tandem repeat galectin subfamily includes galectins-4, -8, -9, and -12. Recognition of cell surface glycans by many of the galectins, which is associated with oligomerization and lattice formation of the receptors, induces signaling pathways that are being well defined in leukocytes and epithelial cells. In addition, galectins are important in innate immune responses and can directly recognize glycans on pathogens and provide protection independently of antibodies.
<li>Paradigm 1: [[Galectin-1]]
<li>Paradigm 2: [[Galectin-3]]
<li>Paradigm 3: [[Galectin-9]]
 

== Siglecs ==
[[Image:Siglec.jpg|left|alt text]]

Sialic acid-binding immunoglobulin (Ig)-like lectins, or Siglecs, are a family of type 1 membrane proteins containing an extracellular V-set Ig domain and a variable number of C2-set Ig domains. Siglecs are expressed mainly by cells in the hematopoietic and immune systems, with MAG (Siglec-4) being a major exception due to its exclusive expression by cells of the nervous system. The V-set Ig domain of all siglecs mediates binding to sialylated oligosaccharides via a template centered around a conserved arginine on the F b strand. Extended specificity is mediated by variable residues on interstrand loops, such as the C-C' loop. Many siglecs contain one or more immunoreceptor tyrosine-based inhibitory motifs (ITIMS) that are important for regulating intracellular signaling functions and endocytosis. A recently characterized subset of siglecs can also associate via a basic residue in their transmembrane domains with transmembrane adaptors containing immunoreceptor tyrosine-based activation motifs (ITAMs). Siglecs can be divided into two groups based on sequence similarity. Group 1 contains Siglecs-1, -2, -4 and -15, which are distantly related to one another but well conserved in mammals. The other group includes CD33 and the CD33-related Siglecs which are highly related to each other and whose composition varies considerably amongst mammalian species. The paradigms have been selected on the basis of distinct functions, and include each of the 4 siglecs in group 1 and a representative human/murine pair for the ITIM-containing CD33-related siglecs.
<li>Paradigm 1: [[CD22]]
<li>Paradigm 2: [[Sialoadhesin]]
<li>Paradigm 3: [[Siglec-8]]
<li>Paradigm 4: [[MAG]]
<li>Paradigm 5: [[Siglec-15]]
 

== GBPs Mediating Intracellular Trafficking & Other Mammalian GBPs ==
[[Image:CIMPR.jpg|left|alt text]]

Both calreticulin and the cation-dependent mannose-6-phosphate receptor are glycan-binding proteins recognizing discrete and specific carbohydrates involved in intracellular trafficking of membrane and secretory glycoproteins. In the case of calreticulin, glycan binding is associated with the quality control apparatus ensuring that only properly folded proteins will exit the endoplasmic reticulum. In the case of the cation-dependent mannose-6-phosphate receptor, phosphorylated mannose residues are recognized, allowing lysosomal proteins to be properly targeted. These paradigms are important for understanding diseases of protein misfolding and many lysosomal storage disorders. The ficolins are a class of glycan-binding proteins with affinity for N-acetyl residues that have distinct fold from other known lectins yet mediate pathogen recognition. Polymorphisms in ficoloin genes may also have pathophysiological implications.
<li>Paradigm 1: [[Cation-dependent Mannose-6-phosphate receptor]]
<li>Paradigm 2: [[Calreticulin]]
<li>Paradigm 3: [[Ficolin M (Ficolin 1)]]
 

== Bacterial Adhesins and Lectins ==
[[Image:AdhesinsBacterial.jpg|left|alt text]]

Infection by bacteria is generally initiated by the specific recognition of host epithelial surfaces by adhesins and lectins. These GBPs are therefore virulence factors that play a role in the first step of adhesion and invasion. The GBPs are called adhesins when they are part of organelles, such as fimbriae and flagella. They are referred to as lectins when they are soluble, and lectin-domain when attached to other proteins, which are often hydrolytic enzymes also involved in the infection process. The human targets for bacterial adhesins and lectins are mostly fucosylated human histo-blood group and/or sialylated epitopes. Defining the biological role of bacterial adhesins and lectins together with their structure and specificity is a prerequisite for the development of strategies for inhibiting their binding to human tissues.
<li>Paradigm 1: [[PA-IIL]]
<li>Paradigm 2: [[CBM47]]
<li>Paradigm 3: [[F17G/GafD]]
 

== Bacterial Toxins ==
[[Image:ToxinBacteria.jpg|left|alt text]]

Toxigenic bacteria, which include some species of ''Escherichia'', ''Shigella'', ''Vibrio'', and ''Clostridium'', release protein toxins that alter essential host processes, including endocytic pathways, cell signaling and cytoskeletal reorganization. These toxins are key virulence factors that damage host tissues, and aid the spread of bacteria and evasion of immune clearance. Many bacterial toxins have been shown to bind host glycans. Glycan receptor specificity is critical for the pathogenic process, as it determines host susceptibility, tissue tropism, and the nature and spectrum of the resultant pathology. With contributions from the CFG, knowledge of the molecular and structural bases for toxin-glycan interactions is providing a rational framework for design of specific toxin inhibitors with considerable potential as anti-infective therapeutic agents.
<li>Paradigm 1: AB5 Toxin: [[Subtilase cytotoxin (SubAB)]]
<li>Paradigm 2: Clostridial Neurotoxin: [[Botulinum toxin serotype A (BoNT/A)]]
<li>Paradigm 3: Large Clostridial Cytotoxin: [[C. difficile toxin A (TcdA)| ''C. difficile'' toxin A (TcdA)]]
 

== Capsid Virus GBPs==
[[Image:polyomavirus.gif|left|alt text]]

A significant number of non-enveloped capsid viruses use glycans as cell attachment receptors. In some cases, viruses exclusively engage glycan structures at the cell surface, while in other cases glycans serve as co-receptors, and viruses also bind to proteins. The carbohydrate structures recognized by capsid viruses are diverse, ranging from gangliosides and other glycolipids to protein-bound glycans. Changes in carbohydrate binding specificity among family members of the same virus can often lead to altered tropism and pathogenicity. Thus, the elucidation of parameters that guide the specificity of interactions with glycans are of critical importance for understanding the complex biology of capsid viruses. The three paradigms listed below represent virus families whose glycan binding properties have been successfully studied by CFG investigators.
<li>Paradigm 1: [[Polyomavirus capsid protein (VP1)]]
<li>Paradigm 2: [[Reovirus hemagglutinin (sigma 1)]]
<li>Paradigm 3: [[Parvovirus Minute Virus of Mice (MVM)]]
 

== Enveloped Virus GBPs==
[[Image:VirusEnvelope.jpg|left|alt text]]

Enveloped viruses initiate infection by using their surface glycoproteins to attach to receptors on the cell surface. These receptors may be proteins, lipids or glycans. Protein receptors may be cell specific, to direct the virus into only its target tissue (e.g. CD4 for HIV). Glycan receptors may provide broader cell specificity, or be just as specific as protein receptors, but historically the lack of glycan reagents has precluded definitive studies. The CFG, and especially the CFG glycan microarray, has allowed definition of glycan receptor specificity. The influenza viruses and parainfluenza viruses are the two main families of enveloped viruses that use glycan binding proteins for their attachment to host cells.
<li>Paradigm 1: [[Influenza hemagglutinin H3]]
<li>Paradigm 2: [[Parainfluenza virus type 3 hemagglutinin-neuraminidase]]
 

== Eukaryotic Microbial GBPs ==
[[Image:EukaryoticMicrobial.gif|left|alt text]]

Eukaryotic microbes present a tremendous diversity of GBPs, many of which are crucial for microbial interactions within their own species or with other cell types. These relatively under-studied GBPs, both soluble and surface-displayed, include a variety of lectins and adhesins that are crucial for developmental processes, establishment of microbial communities, and interactions with the external environment. In the case of pathogenic organisms these GBPs can be key in host interactions, as in the case of the fungal adhesin paradigm below. The cyanovirin family provides another fascinating case with potential impact on human health.
<li>Paradigm 1: [[Candida glabrata EPA7| ''Candida glabrata'' EPA7]]
<li>Paradigm 2: [[Cyanovirin-N (CVN)]]

[[Category:Main Page]]

MediaWiki:Sidebar

2011-07-23T12:15:53Z

Anna Crie:

MediaWiki:Sidebar

2011-07-23T12:08:26Z

Anna Crie:

User talk:Joy Burchell

2011-03-25T15:32:18Z

Anna Crie: Welcome!

User:Joy Burchell

2011-03-25T15:32:18Z

Anna Crie: Creating user page with biography of new user.

Galectin-1

2011-03-13T19:06:19Z

Anna Crie: /* Structure */

Galectin-1 is the best-studied of the prototypic galectins. The crystal structure of Galectin-1 is known, and was the first crystal structure identified for a prototypic galectin.
 
In addition, Galectin-1...
* was the first prototypic galectin for which a function was identified.
* binds novel N- and O-glycan determinants that are involved in cell signaling<ref name="Leppanen 2005" /><ref>Earl LA, Bi S, Baum LG. N- and O-glycans modulate galectin-1 binding, CD45 signaling, and T cell death. ''J Biol Chem'' 285, 2232-2244 (2010).</ref><ref>Song X, ''et al''. Novel fluorescent glycan microarray strategy reveals ligands for galectins. ''Chem Biol'' 16, 36-47 (2009).</ref><ref name="Cooper 2008">Cooper D, Norling LV, Perretti M. Novel insights into the inhibitory effects of Galectin-1 on neutrophil recruitment under flow. ''J Leukoc Biol'' 83, 1459-1466 (2008).</ref><ref>Stillman BN, ''et al''. Galectin-3 and galectin-1 bind distinct cell surface glycoprotein receptors to induce T cell death.'' J Immunol'' 176, 778-789 (2006).</ref>.
* was the first prototypic galectin that was genetically ablated in mice; galectin-1 knockout mice have distinct phenotypes, including aberrant T lymphocyte expansion and increased susceptibility to autoimmune disease <ref>Rabinovich GA, Toscano MA. Turning "sweet" on immunity: galectin-glycan interactions in immune tolerance and inflammation. ''Nat Rev Immunol'' 9, 338-352 (2009). </ref>.
* is the only prototypic galectin that has been administered in animal models of disease to assess therapeutic potential <ref>Rabinovich GA, Daly G, Dreja H, Tailor H, Riera CM, Hirabayashi J, Chernajovsky Y. Recombinant galectin-1 and its genetic delivery suppress collagen-induced arthritis via T cell apoptosis. ''J Exp Med'' 190, 385-398 (1999)</ref>
* selectively regulates Th1, Th2 and Th17 cell survival<ref>Toscano MA, Bianco GA, Ilarregui JM, Croci DO, Correale J, Hernandez JD, Zwirner NW, Poirier F, Riley EM, Baum LG, Rabinovich GA. Differential glycosylation of Th1, Th2 and Th17 effector cells selectively regulates susceptibility to cell death. ''Nat Immunol'' 8, 825-834 (2007).</ref>
* has novel dynamics and functions regarding it oxidized versus reduced status, as well as its dimerization status<ref>Stowell SR, ''et al''. Ligand reduces galectin-1 sensitivity to oxidative inactivation by enhancing dimer formation. ''J Biol Chem'' 284, 4989-4999 (2009).</ref><ref name="Leppanen 2005">Leppanen A, Stowell S, Blixt O, Cummings RD. Dimeric galectin-1 binds with high affinity to alpha2,3-sialylated and non-sialylated terminal N-acetyllactosamine units on surface-bound extended glycans. ''J Biol Chem'' 280, 5549-5562 (2005). </ref>.
* is involved in lymphocyte trafficking and leukocyte recruitment<ref name="Cooper 2008" /><ref>Norling LV, Sampaio AL, Cooper D, Perretti M. Inhibitory control of endothelial galectin-1 on in vitro and in vivo lymphocyte trafficking. ''Faseb J'' 22, 682-690 (2008). </ref>.
* promotes the differentiation of tolerogenic dendritic cells and plays a pivotal role in fetomaternal tolerance <ref>Ilarregui JM, Croci DO, Bianco GA, Toscano MA, Salatino M, Vermeulen ME, Geffner JR, Rabinovich GA.''Nat Immunol'' 10, 981-991 (2009).</ref><ref>Blois SM, ''et al''. A pivotal role for galectin-1 in fetomaternal tolerance. ''Nat Med'' 13,1450-1457 (2007).</ref>
* contributes to tumor cell evasion of immune responses.<ref>Rubinstein N, Alvarez M, Zwirner NW, Toscano MA, Ilarregui JM, Bravo A, Mordoh J, Fainboim L, Podhajcer OL, Rabinovich GA. ''Cancer Cell'' 5, 241-251 (2004).</ref>
* demonstrates novel distributions in muscle cells versus non-muscle cells<ref>Dias-Baruffi M, ''et al''. Differential expression of immunomodulatory galectin-1 in peripheral leukocytes and adult tissues and its cytosolic organization in striated muscle. ''Glycobiology'' '''In Press'''. (2010).</ref>.
* has ligands that are modulated by their differential sialylation, which is also associated with glycoprotein positioning in membranes<ref>Cha SK, ''et al''. Removal of sialic acid involving Klotho causes cell-surface retention of TRPV5 channel via binding to galectin-1. ''Proc Natl Acad Sci U S A'' 105, 9805-9810 (2008).</ref>.

 
== CFG Participating Investigators contributing to the understanding of this paradigm ==

CFG Participating Investigators (PIs) contributing to the understanding of Galectin-1 include: Linda Baum, C. Fred Brewer, Richard Cummings, Anne Dell, Ten Feizi, M.G. Finn, Thomas Gerken, Benhur Lee, J. Michael Pierce, Mauro Perretti, Gabriel Rabinovich, James Rini, Sachiko Sato, Gerald Schwarting, Pamela Stanley, Victor Thijssen, Gerardo Vasta, John Wang

== Progress toward understanding this GBP paradigm ==
This section documents what is currently known about Galectin-1, its carbohydrate ligand(s), and how they interact to mediate cell communication. Further information can be found in the GBP Molecule Pages for [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_hum_Stlect_00116&sideMenu=no human] and [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_1304&sideMenu=no mouse] Galectin-1 in the CFG database.
=== Carbohydrate ligands ===

The ligand of galectin-1 has been shown to be Galβ1-4GlcNAc (or LacNAc).

=== Cellular expression of GBP and ligands ===

Galectin-1 is expressed in many cell types including muscle, epithelial and endothelial cells. Within the immune system this GBP is considerably up-regulated in activated T lymphocytes, macrophages, uterine NK cells and regulatory T cells.

=== Biosynthesis of ligands ===
 
=== Structure ===

Galectin-1 can be found as a monomer as well as a non-covalent homodimer composed of subunits of 14.5 kDa, each containing an identical CRD.
 Crosslinking of galectin-1 and complex biantennary N-glycans. Infinite chains of lectin dimers (cyan) are cross-linked through N-acetyllactosamine units located at the ends antennae (green/yellow) biantennary N-glycans.<ref>Bourne et al. Crosslinking of mammalian lectin (galectin-1) by complex biantennary saccharides. Nat Struct Biol. 12:863-70 (1994).</ref>
 [[File:Galect1Bourne1994.jpg]]

=== Biological roles of GBP-ligand interaction ===

Galectin-1 is involved in immunoregulation, cytokine secretion, host-pathogen interactions, cell adhesion and migration and tumor-immune escape.

== CFG resources used in investigations ==
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=galectin-1&maxresults=20 CFG database search results for Galectin-1].

=== Glycan profiling ===

Glycan profiling of cells known to express Galectin-1 has been done by the CFG analytical core (e.g. [http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=t-lymphocytes&cat=corec T-lymphocytes]).

=== Glycogene microarray ===

 
=== Knockout mouse lines ===
CFG-generated [http://www.functionalglycomics.org/static/consortium/resources/resourcecoref6.shtml Galectin-1 knockout mice] have been used to study the biological functions of this paradigm GBP. The [http://www.functionalglycomics.org/glycomics/publicdata/phenotyping.jsp phenotype] of Galectin-1 knockout mice was analyzed by the CFG.

=== Glycan array ===
Investigators have made extensive use of carbohydrate compounds and glycan microarrays to study ligand binding specificity of galectin-1 ([http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2745 example]). See all glycan array results for galectin-1 [http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=galectin-1&cat=coreh here].

== Related GBPs ==
Galectins-2, -5, -7, -10, -11, -13, and -14

== References ==
<references/>

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: Linda Baum, Yves Bourne, Richard Cummings, Ten Feizi, Gabriel Rabinovich

Galectin-1

2011-03-13T19:05:56Z

Anna Crie: /* Structure */

Galectin-1 is the best-studied of the prototypic galectins. The crystal structure of Galectin-1 is known, and was the first crystal structure identified for a prototypic galectin.
 
In addition, Galectin-1...
* was the first prototypic galectin for which a function was identified.
* binds novel N- and O-glycan determinants that are involved in cell signaling<ref name="Leppanen 2005" /><ref>Earl LA, Bi S, Baum LG. N- and O-glycans modulate galectin-1 binding, CD45 signaling, and T cell death. ''J Biol Chem'' 285, 2232-2244 (2010).</ref><ref>Song X, ''et al''. Novel fluorescent glycan microarray strategy reveals ligands for galectins. ''Chem Biol'' 16, 36-47 (2009).</ref><ref name="Cooper 2008">Cooper D, Norling LV, Perretti M. Novel insights into the inhibitory effects of Galectin-1 on neutrophil recruitment under flow. ''J Leukoc Biol'' 83, 1459-1466 (2008).</ref><ref>Stillman BN, ''et al''. Galectin-3 and galectin-1 bind distinct cell surface glycoprotein receptors to induce T cell death.'' J Immunol'' 176, 778-789 (2006).</ref>.
* was the first prototypic galectin that was genetically ablated in mice; galectin-1 knockout mice have distinct phenotypes, including aberrant T lymphocyte expansion and increased susceptibility to autoimmune disease <ref>Rabinovich GA, Toscano MA. Turning "sweet" on immunity: galectin-glycan interactions in immune tolerance and inflammation. ''Nat Rev Immunol'' 9, 338-352 (2009). </ref>.
* is the only prototypic galectin that has been administered in animal models of disease to assess therapeutic potential <ref>Rabinovich GA, Daly G, Dreja H, Tailor H, Riera CM, Hirabayashi J, Chernajovsky Y. Recombinant galectin-1 and its genetic delivery suppress collagen-induced arthritis via T cell apoptosis. ''J Exp Med'' 190, 385-398 (1999)</ref>
* selectively regulates Th1, Th2 and Th17 cell survival<ref>Toscano MA, Bianco GA, Ilarregui JM, Croci DO, Correale J, Hernandez JD, Zwirner NW, Poirier F, Riley EM, Baum LG, Rabinovich GA. Differential glycosylation of Th1, Th2 and Th17 effector cells selectively regulates susceptibility to cell death. ''Nat Immunol'' 8, 825-834 (2007).</ref>
* has novel dynamics and functions regarding it oxidized versus reduced status, as well as its dimerization status<ref>Stowell SR, ''et al''. Ligand reduces galectin-1 sensitivity to oxidative inactivation by enhancing dimer formation. ''J Biol Chem'' 284, 4989-4999 (2009).</ref><ref name="Leppanen 2005">Leppanen A, Stowell S, Blixt O, Cummings RD. Dimeric galectin-1 binds with high affinity to alpha2,3-sialylated and non-sialylated terminal N-acetyllactosamine units on surface-bound extended glycans. ''J Biol Chem'' 280, 5549-5562 (2005). </ref>.
* is involved in lymphocyte trafficking and leukocyte recruitment<ref name="Cooper 2008" /><ref>Norling LV, Sampaio AL, Cooper D, Perretti M. Inhibitory control of endothelial galectin-1 on in vitro and in vivo lymphocyte trafficking. ''Faseb J'' 22, 682-690 (2008). </ref>.
* promotes the differentiation of tolerogenic dendritic cells and plays a pivotal role in fetomaternal tolerance <ref>Ilarregui JM, Croci DO, Bianco GA, Toscano MA, Salatino M, Vermeulen ME, Geffner JR, Rabinovich GA.''Nat Immunol'' 10, 981-991 (2009).</ref><ref>Blois SM, ''et al''. A pivotal role for galectin-1 in fetomaternal tolerance. ''Nat Med'' 13,1450-1457 (2007).</ref>
* contributes to tumor cell evasion of immune responses.<ref>Rubinstein N, Alvarez M, Zwirner NW, Toscano MA, Ilarregui JM, Bravo A, Mordoh J, Fainboim L, Podhajcer OL, Rabinovich GA. ''Cancer Cell'' 5, 241-251 (2004).</ref>
* demonstrates novel distributions in muscle cells versus non-muscle cells<ref>Dias-Baruffi M, ''et al''. Differential expression of immunomodulatory galectin-1 in peripheral leukocytes and adult tissues and its cytosolic organization in striated muscle. ''Glycobiology'' '''In Press'''. (2010).</ref>.
* has ligands that are modulated by their differential sialylation, which is also associated with glycoprotein positioning in membranes<ref>Cha SK, ''et al''. Removal of sialic acid involving Klotho causes cell-surface retention of TRPV5 channel via binding to galectin-1. ''Proc Natl Acad Sci U S A'' 105, 9805-9810 (2008).</ref>.

 
== CFG Participating Investigators contributing to the understanding of this paradigm ==

CFG Participating Investigators (PIs) contributing to the understanding of Galectin-1 include: Linda Baum, C. Fred Brewer, Richard Cummings, Anne Dell, Ten Feizi, M.G. Finn, Thomas Gerken, Benhur Lee, J. Michael Pierce, Mauro Perretti, Gabriel Rabinovich, James Rini, Sachiko Sato, Gerald Schwarting, Pamela Stanley, Victor Thijssen, Gerardo Vasta, John Wang

== Progress toward understanding this GBP paradigm ==
This section documents what is currently known about Galectin-1, its carbohydrate ligand(s), and how they interact to mediate cell communication. Further information can be found in the GBP Molecule Pages for [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_hum_Stlect_00116&sideMenu=no human] and [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_1304&sideMenu=no mouse] Galectin-1 in the CFG database.
=== Carbohydrate ligands ===

The ligand of galectin-1 has been shown to be Galβ1-4GlcNAc (or LacNAc).

=== Cellular expression of GBP and ligands ===

Galectin-1 is expressed in many cell types including muscle, epithelial and endothelial cells. Within the immune system this GBP is considerably up-regulated in activated T lymphocytes, macrophages, uterine NK cells and regulatory T cells.

=== Biosynthesis of ligands ===
 
=== Structure ===

Galectin-1 can be found as a monomer as well as a non-covalent homodimer composed of subunits of 14.5 kDa, each containing an identical CRD.
 Crosslinking of galectin-1 and complex biantennary N-glycans. Infinite chains of lectin dimers (cyan) are cross-linked through N-acetyllactosamine units located at the ends antennae (green/yellow) biantennary N-glycans.<ref>Bourne et al. Crosslinking of mammalian lectin (galectin-1) by complex biantennary saccharides. Nat Struct Biol. 12:863-70 (1994).</ref>
[[File:Galect1Bourne1994.jpg]]

=== Biological roles of GBP-ligand interaction ===

Galectin-1 is involved in immunoregulation, cytokine secretion, host-pathogen interactions, cell adhesion and migration and tumor-immune escape.

== CFG resources used in investigations ==
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=galectin-1&maxresults=20 CFG database search results for Galectin-1].

=== Glycan profiling ===

Glycan profiling of cells known to express Galectin-1 has been done by the CFG analytical core (e.g. [http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=t-lymphocytes&cat=corec T-lymphocytes]).

=== Glycogene microarray ===

 
=== Knockout mouse lines ===
CFG-generated [http://www.functionalglycomics.org/static/consortium/resources/resourcecoref6.shtml Galectin-1 knockout mice] have been used to study the biological functions of this paradigm GBP. The [http://www.functionalglycomics.org/glycomics/publicdata/phenotyping.jsp phenotype] of Galectin-1 knockout mice was analyzed by the CFG.

=== Glycan array ===
Investigators have made extensive use of carbohydrate compounds and glycan microarrays to study ligand binding specificity of galectin-1 ([http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2745 example]). See all glycan array results for galectin-1 [http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=galectin-1&cat=coreh here].

== Related GBPs ==
Galectins-2, -5, -7, -10, -11, -13, and -14

== References ==
<references/>

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: Linda Baum, Yves Bourne, Richard Cummings, Ten Feizi, Gabriel Rabinovich

Galectin-1

2011-03-13T18:44:35Z

Anna Crie: /* Structure */

Galectin-1 is the best-studied of the prototypic galectins. The crystal structure of Galectin-1 is known, and was the first crystal structure identified for a prototypic galectin.
 
In addition, Galectin-1...
* was the first prototypic galectin for which a function was identified.
* binds novel N- and O-glycan determinants that are involved in cell signaling<ref name="Leppanen 2005" /><ref>Earl LA, Bi S, Baum LG. N- and O-glycans modulate galectin-1 binding, CD45 signaling, and T cell death. ''J Biol Chem'' 285, 2232-2244 (2010).</ref><ref>Song X, ''et al''. Novel fluorescent glycan microarray strategy reveals ligands for galectins. ''Chem Biol'' 16, 36-47 (2009).</ref><ref name="Cooper 2008">Cooper D, Norling LV, Perretti M. Novel insights into the inhibitory effects of Galectin-1 on neutrophil recruitment under flow. ''J Leukoc Biol'' 83, 1459-1466 (2008).</ref><ref>Stillman BN, ''et al''. Galectin-3 and galectin-1 bind distinct cell surface glycoprotein receptors to induce T cell death.'' J Immunol'' 176, 778-789 (2006).</ref>.
* was the first prototypic galectin that was genetically ablated in mice; galectin-1 knockout mice have distinct phenotypes, including aberrant T lymphocyte expansion and increased susceptibility to autoimmune disease <ref>Rabinovich GA, Toscano MA. Turning "sweet" on immunity: galectin-glycan interactions in immune tolerance and inflammation. ''Nat Rev Immunol'' 9, 338-352 (2009). </ref>.
* is the only prototypic galectin that has been administered in animal models of disease to assess therapeutic potential <ref>Rabinovich GA, Daly G, Dreja H, Tailor H, Riera CM, Hirabayashi J, Chernajovsky Y. Recombinant galectin-1 and its genetic delivery suppress collagen-induced arthritis via T cell apoptosis. ''J Exp Med'' 190, 385-398 (1999)</ref>
* selectively regulates Th1, Th2 and Th17 cell survival<ref>Toscano MA, Bianco GA, Ilarregui JM, Croci DO, Correale J, Hernandez JD, Zwirner NW, Poirier F, Riley EM, Baum LG, Rabinovich GA. Differential glycosylation of Th1, Th2 and Th17 effector cells selectively regulates susceptibility to cell death. ''Nat Immunol'' 8, 825-834 (2007).</ref>
* has novel dynamics and functions regarding it oxidized versus reduced status, as well as its dimerization status<ref>Stowell SR, ''et al''. Ligand reduces galectin-1 sensitivity to oxidative inactivation by enhancing dimer formation. ''J Biol Chem'' 284, 4989-4999 (2009).</ref><ref name="Leppanen 2005">Leppanen A, Stowell S, Blixt O, Cummings RD. Dimeric galectin-1 binds with high affinity to alpha2,3-sialylated and non-sialylated terminal N-acetyllactosamine units on surface-bound extended glycans. ''J Biol Chem'' 280, 5549-5562 (2005). </ref>.
* is involved in lymphocyte trafficking and leukocyte recruitment<ref name="Cooper 2008" /><ref>Norling LV, Sampaio AL, Cooper D, Perretti M. Inhibitory control of endothelial galectin-1 on in vitro and in vivo lymphocyte trafficking. ''Faseb J'' 22, 682-690 (2008). </ref>.
* promotes the differentiation of tolerogenic dendritic cells and plays a pivotal role in fetomaternal tolerance <ref>Ilarregui JM, Croci DO, Bianco GA, Toscano MA, Salatino M, Vermeulen ME, Geffner JR, Rabinovich GA.''Nat Immunol'' 10, 981-991 (2009).</ref><ref>Blois SM, ''et al''. A pivotal role for galectin-1 in fetomaternal tolerance. ''Nat Med'' 13,1450-1457 (2007).</ref>
* contributes to tumor cell evasion of immune responses.<ref>Rubinstein N, Alvarez M, Zwirner NW, Toscano MA, Ilarregui JM, Bravo A, Mordoh J, Fainboim L, Podhajcer OL, Rabinovich GA. ''Cancer Cell'' 5, 241-251 (2004).</ref>
* demonstrates novel distributions in muscle cells versus non-muscle cells<ref>Dias-Baruffi M, ''et al''. Differential expression of immunomodulatory galectin-1 in peripheral leukocytes and adult tissues and its cytosolic organization in striated muscle. ''Glycobiology'' '''In Press'''. (2010).</ref>.
* has ligands that are modulated by their differential sialylation, which is also associated with glycoprotein positioning in membranes<ref>Cha SK, ''et al''. Removal of sialic acid involving Klotho causes cell-surface retention of TRPV5 channel via binding to galectin-1. ''Proc Natl Acad Sci U S A'' 105, 9805-9810 (2008).</ref>.

 
== CFG Participating Investigators contributing to the understanding of this paradigm ==

CFG Participating Investigators (PIs) contributing to the understanding of Galectin-1 include: Linda Baum, C. Fred Brewer, Richard Cummings, Anne Dell, Ten Feizi, M.G. Finn, Thomas Gerken, Benhur Lee, J. Michael Pierce, Mauro Perretti, Gabriel Rabinovich, James Rini, Sachiko Sato, Gerald Schwarting, Pamela Stanley, Victor Thijssen, Gerardo Vasta, John Wang

== Progress toward understanding this GBP paradigm ==
This section documents what is currently known about Galectin-1, its carbohydrate ligand(s), and how they interact to mediate cell communication. Further information can be found in the GBP Molecule Pages for [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_hum_Stlect_00116&sideMenu=no human] and [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_1304&sideMenu=no mouse] Galectin-1 in the CFG database.
=== Carbohydrate ligands ===

The ligand of galectin-1 has been shown to be Galβ1-4GlcNAc (or LacNAc).

=== Cellular expression of GBP and ligands ===

Galectin-1 is expressed in many cell types including muscle, epithelial and endothelial cells. Within the immune system this GBP is considerably up-regulated in activated T lymphocytes, macrophages, uterine NK cells and regulatory T cells.

=== Biosynthesis of ligands ===
 
=== Structure ===

Galectin-1 can be found as a monomer as well as a non-covalent homodimer composed of subunits of 14.5 kDa, each containing an identical CRD.
 
[[File:Galect1Bourne1994.jpg]]

 Crosslinking of galectin-1 and complex biantennary N-glycans. Infinite chains of lectin dimers (cyan) are cross-linked through N-acetyllactosamine units located at the ends antennae (green/yellow) biantennary N-glycans.<ref>Bourne et al. Crosslinking of mammalian lectin (galectin-1) by complex biantennary saccharides. Nat Struct Biol. 12:863-70 (1994).</ref>

=== Biological roles of GBP-ligand interaction ===

Galectin-1 is involved in immunoregulation, cytokine secretion, host-pathogen interactions, cell adhesion and migration and tumor-immune escape.

== CFG resources used in investigations ==
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=galectin-1&maxresults=20 CFG database search results for Galectin-1].

=== Glycan profiling ===

Glycan profiling of cells known to express Galectin-1 has been done by the CFG analytical core (e.g. [http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=t-lymphocytes&cat=corec T-lymphocytes]).

=== Glycogene microarray ===

 
=== Knockout mouse lines ===
CFG-generated [http://www.functionalglycomics.org/static/consortium/resources/resourcecoref6.shtml Galectin-1 knockout mice] have been used to study the biological functions of this paradigm GBP. The [http://www.functionalglycomics.org/glycomics/publicdata/phenotyping.jsp phenotype] of Galectin-1 knockout mice was analyzed by the CFG.

=== Glycan array ===
Investigators have made extensive use of carbohydrate compounds and glycan microarrays to study ligand binding specificity of galectin-1 ([http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2745 example]). See all glycan array results for galectin-1 [http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=galectin-1&cat=coreh here].

== Related GBPs ==
Galectins-2, -5, -7, -10, -11, -13, and -14

== References ==
<references/>

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: Linda Baum, Yves Bourne, Richard Cummings, Ten Feizi, Gabriel Rabinovich

Galectin-1

2011-03-13T18:42:34Z

Anna Crie: /* Structure */

Galectin-1 is the best-studied of the prototypic galectins. The crystal structure of Galectin-1 is known, and was the first crystal structure identified for a prototypic galectin.
 
In addition, Galectin-1...
* was the first prototypic galectin for which a function was identified.
* binds novel N- and O-glycan determinants that are involved in cell signaling<ref name="Leppanen 2005" /><ref>Earl LA, Bi S, Baum LG. N- and O-glycans modulate galectin-1 binding, CD45 signaling, and T cell death. ''J Biol Chem'' 285, 2232-2244 (2010).</ref><ref>Song X, ''et al''. Novel fluorescent glycan microarray strategy reveals ligands for galectins. ''Chem Biol'' 16, 36-47 (2009).</ref><ref name="Cooper 2008">Cooper D, Norling LV, Perretti M. Novel insights into the inhibitory effects of Galectin-1 on neutrophil recruitment under flow. ''J Leukoc Biol'' 83, 1459-1466 (2008).</ref><ref>Stillman BN, ''et al''. Galectin-3 and galectin-1 bind distinct cell surface glycoprotein receptors to induce T cell death.'' J Immunol'' 176, 778-789 (2006).</ref>.
* was the first prototypic galectin that was genetically ablated in mice; galectin-1 knockout mice have distinct phenotypes, including aberrant T lymphocyte expansion and increased susceptibility to autoimmune disease <ref>Rabinovich GA, Toscano MA. Turning "sweet" on immunity: galectin-glycan interactions in immune tolerance and inflammation. ''Nat Rev Immunol'' 9, 338-352 (2009). </ref>.
* is the only prototypic galectin that has been administered in animal models of disease to assess therapeutic potential <ref>Rabinovich GA, Daly G, Dreja H, Tailor H, Riera CM, Hirabayashi J, Chernajovsky Y. Recombinant galectin-1 and its genetic delivery suppress collagen-induced arthritis via T cell apoptosis. ''J Exp Med'' 190, 385-398 (1999)</ref>
* selectively regulates Th1, Th2 and Th17 cell survival<ref>Toscano MA, Bianco GA, Ilarregui JM, Croci DO, Correale J, Hernandez JD, Zwirner NW, Poirier F, Riley EM, Baum LG, Rabinovich GA. Differential glycosylation of Th1, Th2 and Th17 effector cells selectively regulates susceptibility to cell death. ''Nat Immunol'' 8, 825-834 (2007).</ref>
* has novel dynamics and functions regarding it oxidized versus reduced status, as well as its dimerization status<ref>Stowell SR, ''et al''. Ligand reduces galectin-1 sensitivity to oxidative inactivation by enhancing dimer formation. ''J Biol Chem'' 284, 4989-4999 (2009).</ref><ref name="Leppanen 2005">Leppanen A, Stowell S, Blixt O, Cummings RD. Dimeric galectin-1 binds with high affinity to alpha2,3-sialylated and non-sialylated terminal N-acetyllactosamine units on surface-bound extended glycans. ''J Biol Chem'' 280, 5549-5562 (2005). </ref>.
* is involved in lymphocyte trafficking and leukocyte recruitment<ref name="Cooper 2008" /><ref>Norling LV, Sampaio AL, Cooper D, Perretti M. Inhibitory control of endothelial galectin-1 on in vitro and in vivo lymphocyte trafficking. ''Faseb J'' 22, 682-690 (2008). </ref>.
* promotes the differentiation of tolerogenic dendritic cells and plays a pivotal role in fetomaternal tolerance <ref>Ilarregui JM, Croci DO, Bianco GA, Toscano MA, Salatino M, Vermeulen ME, Geffner JR, Rabinovich GA.''Nat Immunol'' 10, 981-991 (2009).</ref><ref>Blois SM, ''et al''. A pivotal role for galectin-1 in fetomaternal tolerance. ''Nat Med'' 13,1450-1457 (2007).</ref>
* contributes to tumor cell evasion of immune responses.<ref>Rubinstein N, Alvarez M, Zwirner NW, Toscano MA, Ilarregui JM, Bravo A, Mordoh J, Fainboim L, Podhajcer OL, Rabinovich GA. ''Cancer Cell'' 5, 241-251 (2004).</ref>
* demonstrates novel distributions in muscle cells versus non-muscle cells<ref>Dias-Baruffi M, ''et al''. Differential expression of immunomodulatory galectin-1 in peripheral leukocytes and adult tissues and its cytosolic organization in striated muscle. ''Glycobiology'' '''In Press'''. (2010).</ref>.
* has ligands that are modulated by their differential sialylation, which is also associated with glycoprotein positioning in membranes<ref>Cha SK, ''et al''. Removal of sialic acid involving Klotho causes cell-surface retention of TRPV5 channel via binding to galectin-1. ''Proc Natl Acad Sci U S A'' 105, 9805-9810 (2008).</ref>.

 
== CFG Participating Investigators contributing to the understanding of this paradigm ==

CFG Participating Investigators (PIs) contributing to the understanding of Galectin-1 include: Linda Baum, C. Fred Brewer, Richard Cummings, Anne Dell, Ten Feizi, M.G. Finn, Thomas Gerken, Benhur Lee, J. Michael Pierce, Mauro Perretti, Gabriel Rabinovich, James Rini, Sachiko Sato, Gerald Schwarting, Pamela Stanley, Victor Thijssen, Gerardo Vasta, John Wang

== Progress toward understanding this GBP paradigm ==
This section documents what is currently known about Galectin-1, its carbohydrate ligand(s), and how they interact to mediate cell communication. Further information can be found in the GBP Molecule Pages for [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_hum_Stlect_00116&sideMenu=no human] and [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_1304&sideMenu=no mouse] Galectin-1 in the CFG database.
=== Carbohydrate ligands ===

The ligand of galectin-1 has been shown to be Galβ1-4GlcNAc (or LacNAc).

=== Cellular expression of GBP and ligands ===

Galectin-1 is expressed in many cell types including muscle, epithelial and endothelial cells. Within the immune system this GBP is considerably up-regulated in activated T lymphocytes, macrophages, uterine NK cells and regulatory T cells.

=== Biosynthesis of ligands ===
 
=== Structure ===

Galectin-1 can be found as a monomer as well as a non-covalent homodimer composed of subunits of 14.5 kDa, each containing an identical CRD.
 
[[File:Galect1Bourne1994.jpg]]

 Crosslinking of galectin-1 and complex biantennary N-glycans. Infinite chains of lectin dimers (cyan) are cross-linked through N-acetyllactosamine units located at the ends antennae (green/yellow) biantennary N-glycans.<ref>Bourne et al. Nat Struct Biol. 1994 12:863-70.</ref>

=== Biological roles of GBP-ligand interaction ===

Galectin-1 is involved in immunoregulation, cytokine secretion, host-pathogen interactions, cell adhesion and migration and tumor-immune escape.

== CFG resources used in investigations ==
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=galectin-1&maxresults=20 CFG database search results for Galectin-1].

=== Glycan profiling ===

Glycan profiling of cells known to express Galectin-1 has been done by the CFG analytical core (e.g. [http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=t-lymphocytes&cat=corec T-lymphocytes]).

=== Glycogene microarray ===

 
=== Knockout mouse lines ===
CFG-generated [http://www.functionalglycomics.org/static/consortium/resources/resourcecoref6.shtml Galectin-1 knockout mice] have been used to study the biological functions of this paradigm GBP. The [http://www.functionalglycomics.org/glycomics/publicdata/phenotyping.jsp phenotype] of Galectin-1 knockout mice was analyzed by the CFG.

=== Glycan array ===
Investigators have made extensive use of carbohydrate compounds and glycan microarrays to study ligand binding specificity of galectin-1 ([http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2745 example]). See all glycan array results for galectin-1 [http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=galectin-1&cat=coreh here].

== Related GBPs ==
Galectins-2, -5, -7, -10, -11, -13, and -14

== References ==
<references/>

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: Linda Baum, Yves Bourne, Richard Cummings, Ten Feizi, Gabriel Rabinovich

Galectin-1

2011-03-13T18:39:38Z

Anna Crie: /* Structure */

Galectin-1 is the best-studied of the prototypic galectins. The crystal structure of Galectin-1 is known, and was the first crystal structure identified for a prototypic galectin.
 
In addition, Galectin-1...
* was the first prototypic galectin for which a function was identified.
* binds novel N- and O-glycan determinants that are involved in cell signaling<ref name="Leppanen 2005" /><ref>Earl LA, Bi S, Baum LG. N- and O-glycans modulate galectin-1 binding, CD45 signaling, and T cell death. ''J Biol Chem'' 285, 2232-2244 (2010).</ref><ref>Song X, ''et al''. Novel fluorescent glycan microarray strategy reveals ligands for galectins. ''Chem Biol'' 16, 36-47 (2009).</ref><ref name="Cooper 2008">Cooper D, Norling LV, Perretti M. Novel insights into the inhibitory effects of Galectin-1 on neutrophil recruitment under flow. ''J Leukoc Biol'' 83, 1459-1466 (2008).</ref><ref>Stillman BN, ''et al''. Galectin-3 and galectin-1 bind distinct cell surface glycoprotein receptors to induce T cell death.'' J Immunol'' 176, 778-789 (2006).</ref>.
* was the first prototypic galectin that was genetically ablated in mice; galectin-1 knockout mice have distinct phenotypes, including aberrant T lymphocyte expansion and increased susceptibility to autoimmune disease <ref>Rabinovich GA, Toscano MA. Turning "sweet" on immunity: galectin-glycan interactions in immune tolerance and inflammation. ''Nat Rev Immunol'' 9, 338-352 (2009). </ref>.
* is the only prototypic galectin that has been administered in animal models of disease to assess therapeutic potential <ref>Rabinovich GA, Daly G, Dreja H, Tailor H, Riera CM, Hirabayashi J, Chernajovsky Y. Recombinant galectin-1 and its genetic delivery suppress collagen-induced arthritis via T cell apoptosis. ''J Exp Med'' 190, 385-398 (1999)</ref>
* selectively regulates Th1, Th2 and Th17 cell survival<ref>Toscano MA, Bianco GA, Ilarregui JM, Croci DO, Correale J, Hernandez JD, Zwirner NW, Poirier F, Riley EM, Baum LG, Rabinovich GA. Differential glycosylation of Th1, Th2 and Th17 effector cells selectively regulates susceptibility to cell death. ''Nat Immunol'' 8, 825-834 (2007).</ref>
* has novel dynamics and functions regarding it oxidized versus reduced status, as well as its dimerization status<ref>Stowell SR, ''et al''. Ligand reduces galectin-1 sensitivity to oxidative inactivation by enhancing dimer formation. ''J Biol Chem'' 284, 4989-4999 (2009).</ref><ref name="Leppanen 2005">Leppanen A, Stowell S, Blixt O, Cummings RD. Dimeric galectin-1 binds with high affinity to alpha2,3-sialylated and non-sialylated terminal N-acetyllactosamine units on surface-bound extended glycans. ''J Biol Chem'' 280, 5549-5562 (2005). </ref>.
* is involved in lymphocyte trafficking and leukocyte recruitment<ref name="Cooper 2008" /><ref>Norling LV, Sampaio AL, Cooper D, Perretti M. Inhibitory control of endothelial galectin-1 on in vitro and in vivo lymphocyte trafficking. ''Faseb J'' 22, 682-690 (2008). </ref>.
* promotes the differentiation of tolerogenic dendritic cells and plays a pivotal role in fetomaternal tolerance <ref>Ilarregui JM, Croci DO, Bianco GA, Toscano MA, Salatino M, Vermeulen ME, Geffner JR, Rabinovich GA.''Nat Immunol'' 10, 981-991 (2009).</ref><ref>Blois SM, ''et al''. A pivotal role for galectin-1 in fetomaternal tolerance. ''Nat Med'' 13,1450-1457 (2007).</ref>
* contributes to tumor cell evasion of immune responses.<ref>Rubinstein N, Alvarez M, Zwirner NW, Toscano MA, Ilarregui JM, Bravo A, Mordoh J, Fainboim L, Podhajcer OL, Rabinovich GA. ''Cancer Cell'' 5, 241-251 (2004).</ref>
* demonstrates novel distributions in muscle cells versus non-muscle cells<ref>Dias-Baruffi M, ''et al''. Differential expression of immunomodulatory galectin-1 in peripheral leukocytes and adult tissues and its cytosolic organization in striated muscle. ''Glycobiology'' '''In Press'''. (2010).</ref>.
* has ligands that are modulated by their differential sialylation, which is also associated with glycoprotein positioning in membranes<ref>Cha SK, ''et al''. Removal of sialic acid involving Klotho causes cell-surface retention of TRPV5 channel via binding to galectin-1. ''Proc Natl Acad Sci U S A'' 105, 9805-9810 (2008).</ref>.

 
== CFG Participating Investigators contributing to the understanding of this paradigm ==

CFG Participating Investigators (PIs) contributing to the understanding of Galectin-1 include: Linda Baum, C. Fred Brewer, Richard Cummings, Anne Dell, Ten Feizi, M.G. Finn, Thomas Gerken, Benhur Lee, J. Michael Pierce, Mauro Perretti, Gabriel Rabinovich, James Rini, Sachiko Sato, Gerald Schwarting, Pamela Stanley, Victor Thijssen, Gerardo Vasta, John Wang

== Progress toward understanding this GBP paradigm ==
This section documents what is currently known about Galectin-1, its carbohydrate ligand(s), and how they interact to mediate cell communication. Further information can be found in the GBP Molecule Pages for [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_hum_Stlect_00116&sideMenu=no human] and [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_1304&sideMenu=no mouse] Galectin-1 in the CFG database.
=== Carbohydrate ligands ===

The ligand of galectin-1 has been shown to be Galβ1-4GlcNAc (or LacNAc).

=== Cellular expression of GBP and ligands ===

Galectin-1 is expressed in many cell types including muscle, epithelial and endothelial cells. Within the immune system this GBP is considerably up-regulated in activated T lymphocytes, macrophages, uterine NK cells and regulatory T cells.

=== Biosynthesis of ligands ===
 
=== Structure ===

Galectin-1 can be found as a monomer as well as a non-covalent homodimer composed of subunits of 14.5 kDa, each containing an identical CRD.
 
[[File:Galect1Bourne1994.jpg]]

 Crosslinking of galectin-1 and complex biantennary N-glycans. Infinite chains of lectin dimers (cyan) are cross-linked through N-acetyllactosamine units located at the ends antennae (green/yellow) biantennary N-glycans.

=== Biological roles of GBP-ligand interaction ===

Galectin-1 is involved in immunoregulation, cytokine secretion, host-pathogen interactions, cell adhesion and migration and tumor-immune escape.

== CFG resources used in investigations ==
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=galectin-1&maxresults=20 CFG database search results for Galectin-1].

=== Glycan profiling ===

Glycan profiling of cells known to express Galectin-1 has been done by the CFG analytical core (e.g. [http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=t-lymphocytes&cat=corec T-lymphocytes]).

=== Glycogene microarray ===

 
=== Knockout mouse lines ===
CFG-generated [http://www.functionalglycomics.org/static/consortium/resources/resourcecoref6.shtml Galectin-1 knockout mice] have been used to study the biological functions of this paradigm GBP. The [http://www.functionalglycomics.org/glycomics/publicdata/phenotyping.jsp phenotype] of Galectin-1 knockout mice was analyzed by the CFG.

=== Glycan array ===
Investigators have made extensive use of carbohydrate compounds and glycan microarrays to study ligand binding specificity of galectin-1 ([http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2745 example]). See all glycan array results for galectin-1 [http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=galectin-1&cat=coreh here].

== Related GBPs ==
Galectins-2, -5, -7, -10, -11, -13, and -14

== References ==
<references/>

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: Linda Baum, Yves Bourne, Richard Cummings, Ten Feizi, Gabriel Rabinovich