VE-cadherin increases the half-life of VEGF receptor 2.
VE-cadherin plays a critical role in cell-cell interactions by forming adherens junctions in endothelial cells. VE-cadherin has increasingly been implicated in the cell signaling cascades initiated by the activation of growth factor receptors. Vascular endothelial growth factor receptor 2 (VEGFR-2) is present in regions of cell-cell contact and coimmunoprecipitates with VE-cadherin. In this study, we report that stable overexpression of VE-cadherin in two different endothelial cells induced an increase in VEGFR-2 protein levels. The increase in VEGFR-2 was also induced by overexpression of other classical cadherins such as E-cadherin or N-cadherin. Removing the extracellular domain of VE-cadherin abolished this effect, and a truncated form of VE-cadherin lacking the intracellular domain decreased VEGFR-2 instead of increasing it. VE-cadherin-induced changes in VEGFR-2 levels were paralleled by a corresponding shift in the VEGF-dependent activation of MAPK signaling, which demonstrated the functional relevance of varying the VEGFR-2 levels. Since VE-cadherin upregulated endogenous VEGFR-2 or exogenously expressed VEGFR-2, we hypothesized that the mechanism may be posttranslational. Indeed, the half-life of VEGFR-2 was 70 min in control cells whereas in cells overexpressing VE-cadherin the half-life was extended to 146 min. These results support the existence of a novel layer of functional regulation of VEGFR-2 by VE-cadherin.
Calera
Mónica R
MR
Schepens Eye Research Institute, Harvard Medical School, Boston, MA 02114, USA.
Venkatakrishnan
Anna
A
Kazlauskas
Andrius
A
D022005:Adherens Junctions / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD; D015820:Cadherins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D002417:Cattle; D002448:Cell Adhesion / Q000502:physiology; D002450:Cell Communication / Q000502:physiology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics; D006207:Half-Life; D020935:MAP Kinase Signaling System / Q000235:genetics; D051379:Mice; D018919:Neovascularization, Physiologic / Q000235:genetics / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary / Q000235:genetics; D034421:Sus scrofa; D015854:Up-Regulation / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*; D000099152:Cadherin 5
D015703:Antigens, CD; D015820:Cadherins; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D000099152:Cadherin 5