Emerging Role of α2,6-Sialic Acid as a Negative Regulator of Galectin Binding and Function

Abstract

Galectins are ␤-galactoside-binding lectins that regulate diverse cell behaviors, including adhesion, migration, proliferation, and apoptosis. Galectins can be expressed both intracellularly and extracellularly, and extracellular galectins mediate their effects by associating with cell-surface oligosaccharides. Despite intensive current interest in galectins, strikingly few studies have focused on a key enzyme that acts to inhibit galectin signaling, namely ␤-galactoside ␣2,6-sialyltransferase (ST6Gal-I). ST6Gal-I adds an ␣2,6-linked sialic acid to the terminal galactose of N-linked glycans, and this modification blocks galectin binding to ␤-galactosides. This minireview summarizes the evidence suggesting that ST6Gal-I activity serves as an "off switch" for galectin function.Sialic acids comprise a family of nine-carbon sugars added to the termini of oligosaccharides found on secreted or cellsurface glycoproteins and glycolipids (1). Because of their negative charge and relatively large size, sialic acids can mask important functional domains on surface glycoproteins and also serve more generally to protect the cell from various types of assault (2). However, evidence is emerging that sialic acids mediate specific cellular and molecular recognition by regulating association with glycan-binding proteins such as lectins. For example, sialic acids bind specifically to the siglec 2 family of lectins (3), whereas other types of glycan/lectin interactions are conversely inhibited by sialylation. Thus, sialic acids are positioned to play a pivotal role in regulating lectindependent cell/cell and cell/matrix interactions. Sialic acids are added to glycans via ␣2,3-, ␣2,6-, or ␣2,8-linkages, and these linkages are directed by distinct sialyltransferases. ␤-Galactoside ␣2,6-sialyltransferase (ST6Gal-I) is one of the principal enzymes responsible for the addition of ␣2,6-linked sialic acids to the Gal␤1,4GlcNAc disaccharide (4), which is found mainly on N-glycans and, to a lesser extent, on O-glycans. In this minireview, we summarize the evidence suggesting that ST6Gal-I-mediated ␣2,6-sialylation inhibits binding of N-glycans to galectin-type lectins, thereby serving as a negative regulator of galectin-dependent cell responses (of note, ␣2,6-sialic acid/siglec interactions, although of equal biologic importance, will be not be discussed herein due to the availability of other reviews on this topic (3, 5)). GalectinsGalectins are animal lectins that bind ␤-galactosides through their conserved carbohydrate recognition domains (CRDs) (6, 7). At least 15 mammalian galectins have been identified, and these are subdivided into three different groups based on their biochemical structure (Fig. 1). The prototype group (galectin (Gal)-1, -2, -5, -7, -10, -11, -13, -14, and -15) contains one CRD and a short N-terminal sequence. Members of this group typically assemble into noncovalent homodimers. The chimeric group, of which Gal-3 is the only member, contains one CRD and an extended N-terminal domain with a repeated collagen-like seq...

Sialylation of the Fas Death Receptor by ST6Gal-I Provides Protection against Fas-mediated Apoptosis in Colon Carcinoma Cells

“…This sialylation-dependent survival benefit is likely mediated through multiple molecular pathways. Studies by our group and others have shown that ST6Gal-I-directed ␣2-6 sialylation of selected receptors serves as a key negative regulator of galectin-induced apoptosis (39,42,43). Additionally, the diminished internalization of PECAM due to ␣2-6 sialylation allows anti-apoptotic signaling from PECAM for a longer time interval (40).…”

Effect of sialylation on EGFR phosphorylation and resistance to tyrosine kinase inhibition

“…For example, GM3, the ganglioside containing the sialyllactose epitope, has been reported to interact with EGFR and inhibit its kinase activity in a model supplemented with the GM3 glycolipid, and treatment with neuraminidase can rescue the autophosphorylation of EGFR (37). In addition, galectin-3 also can regulate the cellular trafficking and the level of surface EGFR through binding to the glycans on EGFR, and the binding can be blocked by sialylation on EGFR (38,39).…”

Expression of N-Acetylglucosaminyltransferase III Suppresses α2,3-Sialylation, and Its Distinctive Functions in Cell Migration Are Attributed to α2,6-Sialylation Levels

“…Overexpression of GnT-V in either HepG2 parent cells or its ST6GAL1 knock-out cells promoted the cell migration, although GnT-V-overexpressing cells exhibited higher metastatic ability than the GnT-V-overexpressing ST6GAL1 knock-out cells (data not shown). Further, it has been shown that GnT-V plays a pro-metastatic role, at least partially, via interacting with galectin-3 (62), whereas the ␣2,6-sialylation but not ␣2,3-sialylation of N-glycan is able to inhibit its binding to galectin-3 (60,63). Therefore, it is reasonable to consider that ST6GAL1 and GnT-V contributes to the malignant progression by different mechanisms.…”