scholarly journals Vascular Endothelial Growth Factor Stimulates Tyrosine Phosphorylation and Recruitment to New Focal Adhesions of Focal Adhesion Kinase and Paxillin in Endothelial Cells

1997 ◽  
Vol 272 (24) ◽  
pp. 15442-15451 ◽  
Author(s):  
Husna Abedi ◽  
Ian Zachary
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Focal Adhesion Kinase ◽  
Tyrosine Phosphorylation ◽  
Focal Adhesion ◽  
Focal Adhesions ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor

Src mediates stimulation by vascular endothelial growth factor of the phosphorylation of focal adhesion kinase at tyrosine 861, and migration and anti-apoptosis in endothelial cells

2001 ◽  
Vol 360 (1) ◽  
pp. 255-264 ◽  
Author(s):  
Robin ABU-GHAZALEH ◽  
Jahangir KABIR ◽  
Haiyan JIA ◽  
Mel LOBO ◽  
Ian ZACHARY
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Cell Migration ◽  
Growth Factor ◽  
Focal Adhesion Kinase ◽  
Tyrosine Phosphorylation ◽  
Focal Adhesion ◽  
Endothelial Cell Migration ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor

Vascular endothelial growth factor (VEGF) stimulates the tyrosine phosphorylation of focal adhesion kinase (FAK), increases focal adhesion formation and is chemotactic for human umbilical-vein endothelial cells (HUVECs). In the present study we identified the major sites of VEGF-induced FAK tyrosine phosphorylation and investigated the mechanism mediating this pathway in the action of VEGF. VEGF increased the focal adhesion localization of FAK phosphorylated at Tyr-397 (Y397) and Y861 but stimulated a marked increase in phosphorylation at Y861 without significantly affecting the total level of phospho-Y397 FAK. Inhibition of Src with the specific inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) completely blocked VEGF-induced Y861 phosphorylation without decreasing the level of phospho-Y397 FAK. We also examined the role of Src in mediating endothelial functions of VEGF in which FAK has been implicated as having a role. PP2 markedly inhibited VEGF-induced chemotaxis and wound-healing cell migration. The Src inhibitor also decreased the anti-apoptotic effect of VEGF determined by surface staining of annexin V but did not increase FAK proteolysis or prevent the VEGF-dependent inhibition of FAK proteolysis. In contrast, the specific PtdIns 3-kinase inhibitor LY294002 induced apoptosis and markedly decreased p125FAK expression and increased FAK proteolysis but had little effect on Y861 phosphorylation. These findings identify Src-dependent FAK phosphorylation at Y861 as a novel VEGF-induced signalling pathway in endothelial cells and suggest that this pathway might be involved in the mechanisms mediating VEGF-induced endothelial cell migration and anti-apoptosis.

scholarly journals Src-mediated coupling of focal adhesion kinase to integrin αvβ5 in vascular endothelial growth factor signaling

2002 ◽  
Vol 157 (1) ◽  
pp. 149-160 ◽  
Author(s):  
Brian P. Eliceiri ◽  
Xose S. Puente ◽  
John D. Hood ◽  
Dwayne G. Stupack ◽  
David D. Schlaepfer ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Critical Event ◽  
Growth Factor Signaling ◽  
Vascular Endothelial ◽  
Signaling Complex ◽  
Specific Growth Factor ◽  
Endothelial Growth Factor

Vascular endothelial growth factor (VEGF) promotes vascular permeability (VP) and neovascularization, and is required for development. We find that VEGF-stimulated Src activity in chick embryo blood vessels induces the coupling of focal adhesion kinase (FAK) to integrin αvβ5, a critical event in VEGF-mediated signaling and biological responsiveness. In contrast, FAK is constitutively associated with β1 and β3 integrins in the presence or absence of growth factors. In cultured endothelial cells, VEGF, but not basic fibroblast growth factor, promotes the Src-mediated phosphorylation of FAK on tyrosine 861, which contributes to the formation of a FAK/αvβ5 signaling complex. Moreover, formation of this FAK/αvβ5 complex is significantly reduced in pp60c-src-deficient mice. Supporting these results, mice deficient in either pp60c-src or integrin β5, but not integrin β3, have a reduced VP response to VEGF. This FAK/αvβ5 complex was also detected in epidermal growth factor-stimulated epithelial cells, suggesting a function for this complex outside the endothelium. Our findings indicate that Src can coordinate specific growth factor and extracellular matrix inputs by recruiting integrin αvβ5 into a FAK-containing signaling complex during growth factor–mediated biological responses.

Vascular endothelial growth factor induces VE-cadherin tyrosine phosphorylation in endothelial cells

1998 ◽  
Vol 111 (13) ◽  
pp. 1853-1865 ◽  
Author(s):  
S. Esser ◽  
M.G. Lampugnani ◽  
M. Corada ◽  
E. Dejana ◽  
W. Risau
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Vascular Permeability ◽  
Tyrosine Phosphorylation ◽  
Adherens Junction ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor ◽  
Cell Cell

Interendothelial junctions play an important role in the regulation of endothelial functions, such as vasculogenesis, angiogenesis, and vascular permeability. In this paper we show that vascular endothelial growth factor (VEGF), a potent inducer of new blood vessels and vascular permeability in vivo, stimulated the migration of endothelial cells after artificial monolayer wounding and induced an increase in paracellular permeability of human umbilical vein endothelial cells (HUVECs). Furthermore, VEGF increased phosphotyrosine labeling at cell-cell contacts. Biochemical analyses revealed a strong induction of VEGF-receptor-2 (flk-1/KDR) tyrosine-autophosphorylation by VEGF which was maximal after 5 minutes and was followed by receptor downregulation. 15 minutes to 1 hour after VEGF stimulation the endothelial adherens junction components VE-cadherin, beta-catenin, plakoglobin, and p120 were maximally phosphorylated on tyrosine, while alpha-catenin was not modified. PECAM-1/CD31, another cell-cell junctional adhesive molecule, was tyrosine phosphorylated with similar kinetics in response to VEGF. In contrast, activation of VEGF-receptor-1 (Flt-1) by its specific ligand placenta growth factor (PlGF) had no effect on the tyrosine phosphorylation of cadherins and catenins. Despite the rapid and transient receptor activation and the subsequent tyrosine phosphorylation of adherens junction proteins the cadherin complex remained stable and associated with junctions. Our results demonstrate that the endothelial adherens junction is a downstream target of VEGFR-2 signaling and suggest that tyrosine phosphorylation of its components may be involved in the the loosening of cell-cell contacts in established vessels to modulate transendothelial permeability and to allow sprouting and cell migration during angiogenesis.

scholarly journals Src-mediated Phosphorylation of Hsp90 in Response to Vascular Endothelial Growth Factor (VEGF) Is Required for VEGF Receptor-2 Signaling to Endothelial NO Synthase

2007 ◽  
Vol 18 (11) ◽  
pp. 4659-4668 ◽  
Author(s):  
Martine Duval ◽  
Fabrice Le Bœuf ◽  
Jacques Huot ◽  
Jean-Philippe Gratton
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Tyrosine Phosphorylation ◽  
No Synthase ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Endothelial No Synthase ◽  
No Release ◽  
Endothelial Growth Factor

Nitric oxide (NO) release from endothelial cells, via endothelial NO synthase (eNOS) activation, is central to the proangiogenic actions of vascular endothelial growth factor (VEGF). VEGF signaling to eNOS is principally mediated by an Akt-dependent phosphorylation of eNOS and by increased association of eNOS to the molecular chaperone, heat-shock protein 90 kDa (Hsp90). Herein, we report that VEGFR-2 activation induces tyrosine phosphorylation of VEGF receptor 2 (VEGFR-2)-associated Hsp90β. Tyrosine phosphorylation of Hsp90β in response to VEGF is dependent on internalization of the VEGFR-2 and on Src kinase activation. Furthermore, we demonstrate that c-Src directly phosphorylates Hsp90 on tyrosine 300 residue and that this event is essential for VEGF-stimulated eNOS association to Hsp90 and thus NO release from endothelial cells. Our work identifies Y300 phosphorylation of Hsp90 as a novel regulated posttranslational modification of the chaperone and demonstrates its importance in the proangiogenic actions of VEGF, namely by regulating NO release from endothelial cells.

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