Guanine exchange-dependent and -independent effects of Vav1 on integrin-induced T cell spreading.
Vav1 is a 95-kDa member of the Dbl family of guanine exchange factors and a prominent hemopoietic cell-specific protein tyrosine kinase substrate, the involvement of which in cytoskeletal rearrangements has been linked to its ability to activate Rho family small GTPases. Beta1 integrin ligation by fibronectin induced Vav1 phosphorylation in peripheral blood lymphocytes and in two different T cell lines. Vav1 overexpression led to massive T cell spreading on beta1 integrin ligands, and, conversely, two dominant negative mutants blocked integrin-induced spreading. Vav1 and beta1 integrin ligation synergistically activated Pak, but not Rac, Cdc42, or c-Jun N-terminal kinase. In addition, Vav1 cooperated with constitutively active V12Rac mutant, but not with V12Cdc42, to induce T cell spreading after integrin occupancy. More importantly, a Vav1 mutant that lacked guanine exchange factor activity still cooperated with V12Rac. In contrast, a point mutation in the SH2 domain of Vav1 abolished this synergistic effect. Therefore, our results suggest a new regulatory effect of Vav1 in T cell spreading, which is independent of its guanine exchange factor activity.
del Pozo
Miguel Angel
MA
Division of Cell Biology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121, USA. mdelpozo@scripps.edu
Schwartz
Martin A
MA
Hu
Junru
J
Kiosses
William B
WB
Altman
Amnon
A
Villalba
Martin
M
D000818:Animals; D018797:Cell Cycle Proteins; D048429:Cell Size / Q000502:physiology; D002478:Cells, Cultured; D004357:Drug Synergism; D004789:Enzyme Activation / Q000502:physiology; D005353:Fibronectins / Q000502:physiology; D020662:Guanine Nucleotide Exchange Factors / Q000502:physiology*; D006801:Humans; D006825:Hybridomas; D016023:Integrins / Q000378:metabolism / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases; D019169:Jurkat Cells; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D051567:Proto-Oncogene Proteins c-vav; D013601:T-Lymphocytes / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D054462:p21-Activated Kinases; D020744:rac GTP-Binding Proteins / Q000378:metabolism
D018797:Cell Cycle Proteins; D005353:Fibronectins; D020662:Guanine Nucleotide Exchange Factors; D016023:Integrins; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; C496618:VAV1 protein, human; C496619:Vav1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins