α2,6-Sialic Acid on Platelet Endothelial Cell Adhesion Molecule (PECAM) Regulates Its Homophilic Interactions and Downstream Antiapoptotic Signaling

Abstract

Antiangiogenesis therapies are now part of the standard repertoire of cancer therapies, but the mechanisms for the proliferation and survival of endothelial cells are not fully understood. Although endothelial cells are covered with a glycocalyx, little is known about how endothelial glycosylation regulates endothelial functions. Here, we show that α2,6-sialic acid is necessary for the cell-surface residency of platelet endothelial cell adhesion molecule (PECAM), a member of the immunoglobulin superfamily that plays multiple roles in cell adhesion, mechanical stress sensing, antiapoptosis, and angiogenesis. As a possible underlying mechanism, we found that the homophilic interactions of PECAM in endothelial cells were dependent on α2,6-sialic acid. We also found that the absence of α2,6-sialic acid down-regulated the tyrosine phosphorylation of PECAM and recruitment of Src homology 2 domain-containing protein-tyrosine phosphatase 2 and rendered the cells more prone to mitochondrion-dependent apoptosis, as evaluated using PECAM- deficient endothelial cells. The present findings open up a new possibility that modulation of glycosylation could be one of the promising strategies for regulating angiogenesis.

NEU1 Sialidase Regulates the Sialylation State of CD31 and Disrupts CD31-driven Capillary-like Tube Formation in Human Lung Microvascular Endothelia

“…NEU1 Impairs EC Capillary-like Tube Formation-Because a number of EC sialoproteins participate in the angiogenic response (17)(18)(19)(20)(21)(22)(23) and the angiogenic phenotype is associated with altered sialylation patterns (3-6), we asked whether NEU1 might influence EC capillary-like tube formation in a Matrigel system as a measure of in vitro angiogenesis (Fig. 1).…”

“…CD31 Is an in Vivo NEU1 Substrate-CD31 participates in both EC migration (52,54) and angiogenesis (52,(55)(56)(57) and in human umbilical vein ECs (HUVECs) is sialylated via ␣2,6-linkage (20). We first asked whether in HPMECs, CD31 is similarly sialylated via ␣2,6-linkages.…”

“…Multiple galectins, endogenous lectins that bind galactose residues and regulate angiogenesis (16), were also up-regulated. Finally, a number of EC sialoproteins directly participate in the angiogenic process, including vascular endothelial cadherin (17), selectins and other adhesion molecules (18,19), CD31 (20), CD44 (21), fibroblast growth factor receptor (22), and ␣ v ␤ 3 integrin (23). Taken together, these combined studies establish a central role for glycan structures (and more specifically, sialylation) as intrinsic to the angiogenic process.…”

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

“…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). It has also been determined that ST6Gal-I levels are up-regulated after radiation treatment in mice (44), and these higher levels confer protection against radiation-induced apoptosis.…”

The Inhibitory Role of α2,6-Sialylation in Adipogenesis

“…5D), suggesting that adipogenesis is abnormally enhanced in these mutant mice. St6gal1 knockout mice have been reported to show multiple phenotypes involving abnormal B cell responses (61), altered T cell development in the thymus (62), and vulnerability of endothelial cells to apoptotic stimuli (63), but the effects of St6gal1 deficiency on adipogenesis have not yet been investigated. It was reported previously that SNPs at the St6gal1 gene are associated with obesity and type 2 diabetes (64,65).…”