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.