title: A novel role of vascular endothelial cadherin in modulating c-Src activation and downstream signaling of vascular endothelial growth factor.
abstract: Vascular endothelial growth factor (VEGF) is a potent mediator of angiogenesis and vascular permeability, in which c-Src tyrosine kinase plays an essential role. However, the mechanisms by which VEGF stimulates c-Src activation have remained unclear. Here, we demonstrate that vascular endothelial cadherin (VE-cadherin) plays a critical role in regulating c-Src activation in response to VEGF. In vascular endothelial cells, VE-cadherin was basally associated with c-Src and Csk (C-terminal Src kinase), a negative regulator of Src activation. VEGF stimulated Csk release from VE-cadherin by recruiting the protein tyrosine phosphatase SHP2 to VE-cadherin signaling complex, leading to an increase in c-Src activation. Silencing VE-cadherin with small interference RNA significantly reduced VEGF-stimulated c-Src activation. Disrupting the association of VE-cadherin and Csk through the reconstitution of Csk binding-defective mutant of VE-cadherin also diminished Src activation. Moreover, inhibiting SHP2 by small interference RNA and adenovirus-mediated expression of a catalytically inactive mutant of SHP2 attenuated c-Src activation by blocking the disassociation of Csk from VE-cadherin. Furthermore, VE-cadherin and SHP2 differentially regulates VEGF downstream signaling. The inhibition of c-Src, VE-cadherin, and SHP2 diminished VEGF-mediated activation of Akt and endothelial nitric-oxide synthase. In contrast, inhibiting VE-cadherin and SHP2 enhanced ERK1/2 activation in response to VEGF. These findings reveal a novel role for VE-cadherin in modulating c-Src activation in VEGF signaling, thus providing new insights into the importance of VE-cadherin in VEGF signaling and vascular function.
authors.affiliation: Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, New York 14586, USA.
authors.forename: Chang Hoon
authors.initials: CH
authors.lastname: Ha
authors.forename: Anton M
authors.initials: AM
authors.lastname: Bennett
authors.forename: Zheng-Gen
authors.initials: ZG
authors.lastname: Jin
mesh_terms: D000256:Adenoviridae / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism / Q000502:physiology*; D001665:Binding Sites; D000081247:CSK Tyrosine-Protein Kinase; D015820:Cadherins / Q000378:metabolism / Q000502:physiology*; D042783:Endothelial Cells / Q000166:cytology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D051379:Mice; D008954:Models, Biological; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism*; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D000081247:CSK Tyrosine-Protein Kinase; D015820:Cadherins; D048049:Extracellular Signal-Regulated MAP Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D042461:Vascular Endothelial Growth Factor A; D019061:src-Family Kinases; D000099152:Cadherin 5; C000631346:CSK protein, human