Alpha2,6-sialic acid on platelet endothelial cell adhesion molecule (PECAM) regulates its homophilic interactions and downstream antiapoptotic signaling.
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 alpha2,6-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 alpha2,6-sialic acid. We also found that the absence of alpha2,6-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.
Kitazume
Shinobu
S
Disease Glycomics Team, RIKEN Advanced Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
Imamaki
Rie
R
Ogawa
Kazuko
K
Komi
Yusuke
Y
Futakawa
Satoshi
S
Kojima
Soichi
S
Hashimoto
Yasuhiro
Y
Marth
Jamey D
JD
Paulson
James C
JC
Taniguchi
Naoyuki
N
D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D042783:Endothelial Cells; D004730:Endothelium, Vascular / Q000166:cytology; D006031:Glycosylation; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D019158:N-Acetylneuraminic Acid / Q000502:physiology*; D018919:Neovascularization, Physiologic; D010766:Phosphorylation; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism; D015398:Signal Transduction
D019408:Platelet Endothelial Cell Adhesion Molecule-1; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse; D019158:N-Acetylneuraminic Acid