Association of Csk to VE-cadherin and inhibition of cell proliferation.
Vascular endothelial cadherin (VE-cadherin) mediates contact inhibition of cell growth in quiescent endothelial cell layers. Searching for proteins that could be involved in VE-cadherin signaling, we found the cytosolic C-terminal Src kinase (Csk), a negative regulator of Src family kinases. We show that Csk binds via its SH2 domain to ... the phosphorylated tyrosine 685 of VE-cadherin. VE-cadherin recruits Csk to cell contacts and both proteins can be co-precipitated from cell lysates of transfected cells and endothelial cells. Association of VE-cadherin and Csk in endothelial cells increased with increasing cell density. CHO cells expressing the tyrosine replacement mutant VE-cadherin-Y685F grow to higher cell densities than cells expressing wild-type VE-cadherin. Overexpression of Csk in these cells under an inducible promoter inhibits cell proliferation in the presence and absence of VE-cadherin, but not in the presence of VE-cadherin-Y685F. Reduction of Csk expression by RNA interference enhances endothelial cell proliferation. Our results suggest that the phosphorylated tyrosine residue 685 of VE-cadherin and probably the binding of Csk to this site are involved in inhibition of cell growth triggered by cell density.
Mesh Terms:
Animals, Antigens, CD, Binding Sites, CHO Cells, COS Cells, Cadherins, Cell Line, Tumor, Cell Proliferation, Cricetinae, Endothelium, Vascular, Gene Library, Glutathione Transferase, Mice, Phosphorylation, Protein Binding, Protein-Tyrosine Kinases, RNA, Small Interfering, Tyrosine
Animals, Antigens, CD, Binding Sites, CHO Cells, COS Cells, Cadherins, Cell Line, Tumor, Cell Proliferation, Cricetinae, Endothelium, Vascular, Gene Library, Glutathione Transferase, Mice, Phosphorylation, Protein Binding, Protein-Tyrosine Kinases, RNA, Small Interfering, Tyrosine
EMBO J.
Date: May. 04, 2005
PubMed ID: 15861137
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