Galectin-3

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=== Biological roles of GBP-ligand interaction ===
=== Biological roles of GBP-ligand interaction ===
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Regulation of cellular responses. <br>
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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 (6, 7)). <br>
 +
 +
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 (8, 9, 10). <br>
 +
 +
Endogenous galectin-3 regulates cellular responses by functioning inside the cells, including pre-mRNA splicing, where galectin-3 functions as a component of spliceosomes (11), 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 (12, 13)). <br>
 +
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Endogenous galectin-3 inhibits apoptosis in various cell types by functioning inside the cells (reviewed in (14, 15)). <br>
 +
 +
Endogenous galectin-3 controls intracellular trafficking of glycoproteins (16, 17), 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 (18, 19). Galecin-3 contributes to maintenance of the barrier function of ocular surface epithelial cells (20).<br><br>
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Immunity and Inflammation. <br>
 +
 +
Functions demonstrated in vitro. T and B cells. Endogenous galectin-3 regulates the differentiation of B cells into plasma cells and memory B cells (21). Endogenous galectin-3 is anti-apoptotic in B cell lines (22).<br>
 +
 +
Galectin-3 induces IL-2 production (23) and calcium influx (24) in Jurkat T cells. Galectin-3 induces apoptosis in human T leukemic cell lines, human peripheral blood mononuclear cells, and mouse activated T cells (25) (26), normal human T cells (27), and a human tumor infiltrating T cell line (28). In some T cell lines, such as MOLT-4 cells, galectin-3 induces only phosphatidylserine exposure, an early event in apoptosis, but not cell death.(27) Galectin-3 induces apoptosis in both Th1 and Th2 cells (29). Galectin-3 also induces apoptosis in CD4-CD8- human thymocytes (26), Galectin-3 attenuates interaction of thymocytes with thymic nurse cells in vitro (30). <br>
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Endogenous galectin-3 has anti-apoptotic activity in the human T cell line Jurkat (31).<br>
 +
 +
Galectin-3 binds to Mgat5-modified T cell receptor (TCR) and suppresses T cell activation induced by TCR engagement, which is associated with a decrease in lateral motility of TCR.(32) In CD8+ tumor-infiltrating lymphocytes, galectin-3 causes separation of CD8 and TCR, thus making these cells anergic (33). Endogenous galectin-3 negatively regulates TCR-mediated CD4+ T-cell activation at the immunological synapse, by functioning inside the cells (34). <br>
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Dendritic cells. Endogenous galectin-3 1) suppresses the production of IL-12 by dendritic cells (35) and thus may suppress the Th1 response; (36) 2) promotes Th2 polarization in the setting of antigen presentation to T cells by dendritic cells (36) (Another study suggests endogenous endogenous galectin-3 suppresses the antigen-presenting function of dendritic cells. (37)); and 3) promotes the migratory pattern of dendritic cells by functioning inside the cells (38). Galectin-3 promotes adhesion of mouse dendritic cells (39). <br>
 +
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Neutrophils. Galectin-3 1) induces oxidative burst (40-42) and L-selectin shedding as well as IL-8 production (43) in neutrophils; and 2) promotes neutrophil adhesion to the extracellular protein laminin (44) and endothelial cells (45). Galectin-3 protects neutrophils from apoptosis in one study (43), but induces phosphatidylserine exposure in the absence of cell death in another (27), and induces apoptosis, in a third study (46).<br>
 +
 +
Macrophages. Galectin-3 triggers human peripheral blood monocytes to produce superoxide anion (47) and potentiates LPS-induced IL-1 production (48). Galectin-3 can function as a chemoattractant for monocytes and macrophages (52). Galectin-3 functions as an opsonin and enhances the macrophage clearance of apoptotic neutrophils (49). It also activates microglia cells (tissue macrophages of the central nervous system) to phagocytose degenerated myelin mediated by complement receptor-3 and scavenger receptor (50).<br>
 +
 +
Endogenous galectin-3 is anti-apoptotic in macrophages treated with LPS and IFN-γ (51). It plays a critical role in the phagocytic function of macrophages in ingesting opsonized sheep red blood cells and apoptotic thymocytes (xx).<br>
 +
 +
Galectin-3 binds to a major xenoantigen, a-Gal [Gala(1,3)Galb(1,4)GlcNAc], expressed on porcine endothelial cells (53) and may mediate adhesion of human monocytes to porcine endothelial cells. Galectin-3 suppresses LPS-induced production of inflammatory cytokines by macrophages, including IL-6, IL-12, and TNF-α (54). Endogenous galectin-3 plays a criticla role in alternative macrophage activation (55).<br>
 +
 +
Mast cells. Galectin-3 induces mediator release from both IgE-sensitized and nonsensitized mast cells (56, 57), but apoptosis following prolonged treatment (18-44 h) (58). Endogenous galectin-3 is a positive regulator of mast cell mediator release and cytokine production (59). <br>
 +
 +
Eosinophils. Galectin-3 suppresses IL-5 production by human eosinophils (60). Galectin-3 mediates rolling and firm adhesion of eosinophils on immobilized VCAM-1 under conditions of flow (61).<br>
 +
 +
Functions demonstrated in vivo.<br>
 +
 +
A large number of biological functions have been identified by using Lgals3-/- mice. In relationship to acute inflammation and allergic inflammation, Galectin-3 1) has a proinflammatory role in acute inflammation, induced by intraperitoneal injection of thioglycollate broth, in terms of the neutrophil response (51) and macrophage response (62); 2) 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 then challenged with the same antigen through the airways (63); 3) promotes allergic skin inflammation and a systemic Th2 response in a model of atopic dermatitis, in which mice are repeatedly sensitized with ovalbumin epicutaneously (36); and 4) promotes allergic contact hypersensitivity, in which mice are sensitized with the hapten oxazalone, and then challenged with the same hapten at another skin site (38). However, rats and mice treated by intranasal delivery of cDNA encoding Galectin-3 showed reduced eosinophil infiltration following airway antigen challenge (64, 65)<br>
 +
 +
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 (66). Galectin-3 suppresses the development of glomerulopathy in mice rendered diabetic with streptozotocin, associated with lower accumulation of advanced glycation end products (AGE) in the kidneys (67). Galectin-3 may serve as an AGE receptor and protects from AGE-induced tissue injury (68) as well as age-dependent changes (69). However, galectin-3 contributes to the development of diabetes induced by multiple low doses of streptozotocin (70); this may be related to its upregulation of TNF-α and nitric oxide production by macrophages. Galectin-3 also contributes to ischemia and neovascularization in retina in a mouse model of oxygen-induced proliferative retinopathy after perfusion of preformed AGEs (71). Galectin-3 is expressed in foam cells and macrophages in atherosclerotic lesions (72) and contributes to the development of atherosclerosis in apolipoprotein (Apo)E-deficient mice (73).<br>
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== CFG resources used in investigations ==
== 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].
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].

Revision as of 17:16, 7 July 2010

Galectin-3...

  • is the only member of chimeric subfamily in mammals
  • is a very well-studied glycan-binding protein (GBP)
  • crystal structure is known
  • has unique functions intra- and extra-cellularly, due to unusual N-terminal domain that can participate in protein-protein interactions
  • has a unique mode of multimerization
  • is the only known anti-apoptotic galectin
  • null mice have distinct phenotypes, including alterations in inflammatory and wound-healing responses, and cyst formation in disease[1]
  • 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-16
  • expression is involved in growth modulation[2]
  • has anti-apoptotic activity in its intracellular expression[3]


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 (1-3)). 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 (4)). 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 its serine 6 and serine 12 residues (5).


Contents

CFG Participating Investigators contributing to the understanding of this paradigm

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

Progress toward understanding this GBP paradigm

Carbohydrate ligands


Cellular expression of GBP and ligands


Biosynthesis of ligands


Structure


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 (6, 7)).

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 (8, 9, 10).

Endogenous galectin-3 regulates cellular responses by functioning inside the cells, including pre-mRNA splicing, where galectin-3 functions as a component of spliceosomes (11), 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 (12, 13)).

Endogenous galectin-3 inhibits apoptosis in various cell types by functioning inside the cells (reviewed in (14, 15)).

Endogenous galectin-3 controls intracellular trafficking of glycoproteins (16, 17), 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 (18, 19). Galecin-3 contributes to maintenance of the barrier function of ocular surface epithelial cells (20).

Immunity and Inflammation.

Functions demonstrated in vitro. T and B cells. Endogenous galectin-3 regulates the differentiation of B cells into plasma cells and memory B cells (21). Endogenous galectin-3 is anti-apoptotic in B cell lines (22).

Galectin-3 induces IL-2 production (23) and calcium influx (24) in Jurkat T cells. Galectin-3 induces apoptosis in human T leukemic cell lines, human peripheral blood mononuclear cells, and mouse activated T cells (25) (26), normal human T cells (27), and a human tumor infiltrating T cell line (28). In some T cell lines, such as MOLT-4 cells, galectin-3 induces only phosphatidylserine exposure, an early event in apoptosis, but not cell death.(27) Galectin-3 induces apoptosis in both Th1 and Th2 cells (29). Galectin-3 also induces apoptosis in CD4-CD8- human thymocytes (26), Galectin-3 attenuates interaction of thymocytes with thymic nurse cells in vitro (30).

Endogenous galectin-3 has anti-apoptotic activity in the human T cell line Jurkat (31).

Galectin-3 binds to Mgat5-modified T cell receptor (TCR) and suppresses T cell activation induced by TCR engagement, which is associated with a decrease in lateral motility of TCR.(32) In CD8+ tumor-infiltrating lymphocytes, galectin-3 causes separation of CD8 and TCR, thus making these cells anergic (33). Endogenous galectin-3 negatively regulates TCR-mediated CD4+ T-cell activation at the immunological synapse, by functioning inside the cells (34).

Dendritic cells. Endogenous galectin-3 1) suppresses the production of IL-12 by dendritic cells (35) and thus may suppress the Th1 response; (36) 2) promotes Th2 polarization in the setting of antigen presentation to T cells by dendritic cells (36) (Another study suggests endogenous endogenous galectin-3 suppresses the antigen-presenting function of dendritic cells. (37)); and 3) promotes the migratory pattern of dendritic cells by functioning inside the cells (38). Galectin-3 promotes adhesion of mouse dendritic cells (39).

Neutrophils. Galectin-3 1) induces oxidative burst (40-42) and L-selectin shedding as well as IL-8 production (43) in neutrophils; and 2) promotes neutrophil adhesion to the extracellular protein laminin (44) and endothelial cells (45). Galectin-3 protects neutrophils from apoptosis in one study (43), but induces phosphatidylserine exposure in the absence of cell death in another (27), and induces apoptosis, in a third study (46).

Macrophages. Galectin-3 triggers human peripheral blood monocytes to produce superoxide anion (47) and potentiates LPS-induced IL-1 production (48). Galectin-3 can function as a chemoattractant for monocytes and macrophages (52). Galectin-3 functions as an opsonin and enhances the macrophage clearance of apoptotic neutrophils (49). It also activates microglia cells (tissue macrophages of the central nervous system) to phagocytose degenerated myelin mediated by complement receptor-3 and scavenger receptor (50).

Endogenous galectin-3 is anti-apoptotic in macrophages treated with LPS and IFN-γ (51). It plays a critical role in the phagocytic function of macrophages in ingesting opsonized sheep red blood cells and apoptotic thymocytes (xx).

Galectin-3 binds to a major xenoantigen, a-Gal [Gala(1,3)Galb(1,4)GlcNAc], expressed on porcine endothelial cells (53) and may mediate adhesion of human monocytes to porcine endothelial cells. Galectin-3 suppresses LPS-induced production of inflammatory cytokines by macrophages, including IL-6, IL-12, and TNF-α (54). Endogenous galectin-3 plays a criticla role in alternative macrophage activation (55).

Mast cells. Galectin-3 induces mediator release from both IgE-sensitized and nonsensitized mast cells (56, 57), but apoptosis following prolonged treatment (18-44 h) (58). Endogenous galectin-3 is a positive regulator of mast cell mediator release and cytokine production (59).

Eosinophils. Galectin-3 suppresses IL-5 production by human eosinophils (60). Galectin-3 mediates rolling and firm adhesion of eosinophils on immobilized VCAM-1 under conditions of flow (61).

Functions demonstrated in vivo.

A large number of biological functions have been identified by using Lgals3-/- mice. In relationship to acute inflammation and allergic inflammation, Galectin-3 1) has a proinflammatory role in acute inflammation, induced by intraperitoneal injection of thioglycollate broth, in terms of the neutrophil response (51) and macrophage response (62); 2) 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 then challenged with the same antigen through the airways (63); 3) promotes allergic skin inflammation and a systemic Th2 response in a model of atopic dermatitis, in which mice are repeatedly sensitized with ovalbumin epicutaneously (36); and 4) promotes allergic contact hypersensitivity, in which mice are sensitized with the hapten oxazalone, and then challenged with the same hapten at another skin site (38). However, rats and mice treated by intranasal delivery of cDNA encoding Galectin-3 showed reduced eosinophil infiltration following airway antigen challenge (64, 65)

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 (66). Galectin-3 suppresses the development of glomerulopathy in mice rendered diabetic with streptozotocin, associated with lower accumulation of advanced glycation end products (AGE) in the kidneys (67). Galectin-3 may serve as an AGE receptor and protects from AGE-induced tissue injury (68) as well as age-dependent changes (69). However, galectin-3 contributes to the development of diabetes induced by multiple low doses of streptozotocin (70); this may be related to its upregulation of TNF-α and nitric oxide production by macrophages. Galectin-3 also contributes to ischemia and neovascularization in retina in a mouse model of oxygen-induced proliferative retinopathy after perfusion of preformed AGEs (71). Galectin-3 is expressed in foam cells and macrophages in atherosclerotic lesions (72) and contributes to the development of atherosclerosis in apolipoprotein (Apo)E-deficient mice (73).


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 CFG database search results for Galectin-3.

Glycan profiling


Glycogene microarray


Knockout mouse lines

Galectin-3 knockout mice were phenotyped by 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 here). To see all glycan array results for Galectin-3, click here.

Related GBPs

None in mammals, homologues in invertebrates.

References

  1. Chiu, M.G. et al. Galectin-3 associates with the primary cilium and modulates cyst growth in congenital polycystic kidney disease. Am J Pathol 169, 1925-1938 (2006).
  2. Baptiste, T.A., James, A., Saria, M. & Ochieng, J. Mechano-transduction mediated secretion and uptake of Galectin-3 in breast carcinoma cells: implications in the extracellular functions of the lectin. Exp Cell Res 313, 652-664 (2007).
  3. Saegusa, J. et al. Galectin-3 protects keratinocytes from UVB-induced apoptosis by enhancing AKT activation and suppressing ERK activation. J Invest Dermatol 128, 2403-2411 (2008).

Acknowledgements

The CFG is grateful to the following PIs for their contributions to this wiki page: Linda Baum, Richard Cummings, Michael Demetriou, Fu-Tong Liu

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