Integrin-dependent tyrosine phosphorylation and growth regulation by Vav.
The proto-oncogene product p95Vav (Vav) undergoes rapid phosphorylation on tyrosine following stimulation of the T or B cell antigen receptor, and in response to a variety of other cell surface stimuli. Vav contains, among other, a guanine nucleotide exchange factor domain with homology to the Rho/Rac/CDC42 exchange protein Db1. It has been recently shown that Vav is functionally linked to small GTPases of the Rho family, suggesting that it is an activator of Rho GTPases and may participate in regulation of cytoskeletal organization. The present study shows that cell adhesion to fibronectin triggers rapid phosphorylation of Vav on tyrosine in Vav-transfected CHO cells and in Jurkat T cells. Vav phosphorylation is strongly dependent on adhesion and is mediated by beta 1 integrins. Furthermore, Vav overexpression enhances the adhesion-dependent increase in the rate and extent of phosphorylation on focal adhesion kinase and paxillin, and the formation of stress fibers and lamellipodia. In addition, there is a marked increase in the amount of Vav localized to the triton-insoluble fraction following 1 h of incubation on FN. Finally, Vav increases the growth rate of the cells in an adhesion-dependent manner. Our results strongly implicate Vav as a mediator of integrin signal transduction.
Yron
I
I
Division of Cell Biology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121, USA. ilanayr@post.tau.ac.il
Deckert
M
M
Reff
M E
ME
Munshi
A
A
Schwartz
M A
MA
Altman
A
A
D000199:Actins / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects*; D006224:Cricetinae; D003598:Cytoskeletal Proteins / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D019012:Integrin beta1 / Q000502:physiology*; D019169:Jurkat Cells; D007700:Kinetics; D015513:Oncogene Proteins / Q000494:pharmacology*; D051419:Paxillin; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011233:Precipitin Tests; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D051567:Proto-Oncogene Proteins c-vav; D013997:Time Factors; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism*
D000199:Actins; D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; D005353:Fibronectins; D019012:Integrin beta1; C000715470:MAS1 protein, human; D015513:Oncogene Proteins; C496061:PXN protein, human; D051419:Paxillin; D010750:Phosphoproteins; D000090063:Proto-Oncogene Mas; D051567:Proto-Oncogene Proteins c-vav; C496618:VAV1 protein, human; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human