Galectins

The galectin family of proteins consists of beta-galactoside binding lectins containing homologous carbohydrate recognition domains (CRDs). To date, 12 mammalian galectin family members have been identified.^1,2 Unlike the selectin family of proteins, the carbohydrate binding specificity of galectins is calcium-independent.² A common function of galectins is to cross-link structures containing N-acetyl-lactosamine located at the cell surface and within the extracellular matrix. They also possess hemagglutination activity, which is attributable to their bivalent carbohydrate binding properties. Assays evaluating galectin activity include: hemagglutination assays,^3,4 eosinophil chemotactic activity assays,^3,5,6 and cell migration assays using purified monocytes.⁷ Galectins are active both intracellularly and extracellularly. Although they are localized primarily in the cytoplasm and lack a classical signal peptide, galectins can also be secreted by one or more unidentified, non-classical, secretory pathways.⁸ They have diverse effects on many cellular functions including adhesion, migration, polarity, chemotaxis, proliferation, apoptosis, and differentiation.⁹ Galectins may therefore play a key role in many pathological states, including autoimmune diseases, allergic reactions, inflammation, tumor cell metastasis, atherosclerosis, and diabetic complications.⁹

Figure 1. Galectins may modulate cell adhesion by inhibiting or enhancing adhesive potential between cells or between cells and the extracellular matrix. A galectin may act monovalently via ligation of glycoproteins of either an integrin or extracellular matrix protein, thus weakening the adhesive interaction by steric hindrance. A functionally bivalent galectin can act synergistically in cell-cell adhesions and cell-matrix adhesions. [Note: this illustration has been adapted from the review by Hughes, R.C. (2001) Biochimie 83:667.]

Galectins possess one or two characteristic CRDs that are highly conserved [i.e. 80-90% at the amino acid (aa) level]. Galectins bind glycoconjugates of the extracellular matrix (ECM) via the CRDs. Each CRD is composed of three exons with the middle exon encoding the aa sequence that demonstrates the highest degree of conservation. This exon represents four contiguous beta-strands and intervening loops, incorporating all of the aa that directly interact with the carbohydrate ligand.¹⁰ Most galectins act by utilizing multiple CRDs on a single molecule or act following dimerization (see table 1).⁹ Galectins-1, -2, -5, -7, -10 and -11 are prototypical galectins, consisting of a single CRD preceded by a short N-terminal sequence. Several prototype galectins can act as dimers, however, thereby broadening the range of structures they are able to cross-link. Galectins-4, -6, -8, -9 and -12 are tandem galectins that are comprised of two different CRDs joined by a linker peptide. Tandem galectins can cross-link glycoproteins due to the presence of more than one CRD, whereas the prototypical galectins must dimerize in order to cross-link target structures. Galectin-3 is a chimeric structure with an extra N-terminal tail consisting of 8-13 copies of a 9 aa-repeat consensus sequence that is rich in proline, tyrosine, and glycine.² Varying degrees of homology exist between human and mouse orthologs (e.g. 65-88% overall aa identity). The aa identity increases to 80-90% when comparing only the CRDs. Within one mammalian species, the aa identity of the CRDs among different galectins ranges from approximately 20-40%.

The galectin family of proteins exhibit a restricted distribution of expression that is tissue specific, as well as developmentally regulated, throughout embryogenesis (see table 1).⁹ Although the expression levels of galectins are distinct, they do overlap.^9,10 The expression level and subcellular localization is modulated by external stimuli such as sodium butyrate, viral infections, tumor suppressor genes, and inflammatory agents.⁹ Secretion levels of many galectins increase in response to stress, such as inflammation or heat shock.¹⁰ The role of galectins in modulating the immune system and regulating cell growth has been well documented. Galectin-1 induces apoptosis of PHA-activated peripheral T cells and thymocytes¹¹ through a signaling pathway involving CD45.¹² This induction appears to be mediated via its sugar-binding moiety since apoptosis can be inhibited by lactose.^9,11,12 Other examples of galectin-induced signaling include: the induction of oxidative burst in neutrophils¹³ and the down-regulation of IL-5 gene expression by galectin-3;¹⁴ eosinophil chemotaxis by galectin-9;¹⁵ and mitogenesis by Galectin-1.¹⁶ Several galectins are capable of both promoting and inhibiting cellular proliferation and growth. This biphasic response seems to be concentration dependent; for example, Galectin-1 is mitogenic at low concentrations yet inhibits cell proliferation and growth at high concentrations.¹⁶ Other signals, cell type, and the receptor expression profile on the cell surface can influence whether a galectin will stimulate or inhibit cell growth.¹⁶

Galectins can also either facilitate or inhibit cellular adhesion by binding one of the interacting partners involved in the adhesion process (see figure 1).² The effect on adhesion is dependent on the concentration and specificity of the galectin as well as the glycosylation state of the receptor to which it binds. Galectins bind to several cell adhesion molecules and glycoproteins containing polylactosamines such as laminin, lysosome-associated membrane proteins 1 and 2 (LAMP-1 and LAMP-2), fibronectin, and CD45. Several integrins also serve as receptors for galectins; Galectin-1 binds alpha7-beta1 in myoblasts, Galectins-3 and -8 bind alpha3-beta1 in several cell types, and the alpha-subunit of the alphaM-beta2 integrin is the major receptor for Galectins-1 and -3.² Galectins have the ability to cross-link glycoproteins of different cells or glycoproteins of the cell and the ECM. At high galectin concentrations, cell surface glycoproteins on individual cells may become cross-linked, which also can result in the loss of adhesive potential.⁹

References

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