Src-mediated coupling of focal adhesion kinase to integrin alpha(v)beta5 in vascular endothelial growth factor signaling.
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 alpha(v)beta5, a critical event in VEGF-mediated signaling and biological responsiveness. In contrast, FAK is constitutively associated with beta1 and beta3 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/alpha(v)beta5 signaling complex. Moreover, formation of this FAK/alpha(v)beta5 complex is significantly reduced in pp60c-src-deficient mice. Supporting these results, mice deficient in either pp60c-src or integrin beta5, but not integrin beta3, have a reduced VP response to VEGF. This FAK/alpha(v)beta5 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 alpha(v)beta5 into a FAK-containing signaling complex during growth factor-mediated biological responses.
Eliceiri
Brian P
BP
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA. eliceiri@scripps.edu
Puente
Xose S
XS
Hood
John D
JD
Stupack
Dwayne G
DG
Schlaepfer
David D
DD
Huang
Xiaozhu Z
XZ
Sheppard
Dean
D
Cheresh
David A
DA
D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D002642:Chick Embryo; D002823:Chorion / Q000166:cytology / Q000201:enzymology; D016228:Endothelial Growth Factors / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000196:embryology / Q000201:enzymology; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D016023:Integrins / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000166:cytology; D008222:Lymphokines / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D018919:Neovascularization, Physiologic / Q000502:physiology; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism*; D011817:Rabbits; D019030:Receptors, Vitronectin; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014443:Tyrosine / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
D016228:Endothelial Growth Factors; D016023:Integrins; D008222:Lymphokines; D019030:Receptors, Vitronectin; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C064660:integrin alphaVbeta5; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; C496051:Ptk2 protein, mouse; D019061:src-Family Kinases