Vav1 couples T cell receptor to serum response factor-dependent transcription via a MEK-dependent pathway.
The Vav family of guanine nucleotide exchange factors for Rho family GTPases plays a critical role in lymphocyte proliferation, gene transcription, and cytoskeleton reorganization following immunoreceptor stimulation. However, its role in immediate early gene activation is unclear. In this study, we have investigated the mechanisms by which Vav1 can regulate c-fos serum response element transcriptional activity. We show that T cell antigen receptor (TCR) stimulation induces the phosphorylation of serum response factor (SRF) on serine 103 and increases the binding of SRF complexes on serum response element in a MEK- and p38-dependent pathway. The physiological relevance of our findings is supported by the inhibition of the interleukin-2 gene transcriptional activity by a dominant negative SRF mutant. Overexpression of Vav1, which partially mimics TCR stimulation, promotes SRF-dependent transcription, and dominant negative Vav1 mutants block SRF activation by TCR. SRF activation by Vav1 occurs through a signaling cascade consisting of Rac1/Cdc42 and the serine/threonine kinases Pak1 and MEK, but independently of the phosphatidylinositol 3-kinase pathway. Interestingly, Vav2 also enhances SRF through Rho GTPases, suggesting that Vav proteins are general regulators of SRF activation in lymphocytes. This report establishes Vav proteins as a direct link between antigen receptors and SRF-dependent early gene expression.
Charvet
Celine
C
INSERM U343, IFR50, Hôpital de l'Archet, 06202 Nice Cedex 3, France.
Auberger
Patrick
P
Tartare-Deckert
Sophie
S
Bernard
Alain
A
Deckert
Marcel
M
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017252:CD3 Complex / Q000276:immunology; D018797:Cell Cycle Proteins; D005786:Gene Expression Regulation / Q000276:immunology; D016762:Genes, fos; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics; D019169:Jurkat Cells; D008156:Luciferases / Q000235:genetics; D008213:Lymphocyte Activation; D048728:MAP Kinase Kinase Kinase 1; D020935:MAP Kinase Signaling System / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051567:Proto-Oncogene Proteins c-vav; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D026362:Serum Response Factor / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D014158:Transcription, Genetic / Q000276:immunology; D015533:Transcriptional Activation; D014162:Transfection; D054462:p21-Activated Kinases; D048051:p38 Mitogen-Activated Protein Kinases
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D018797:Cell Cycle Proteins; D007376:Interleukin-2; D008156:Luciferases; D048728:MAP Kinase Kinase Kinase 1; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D010768:Phosphoserine; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D026362:Serum Response Factor; D054462:p21-Activated Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C496618:VAV1 protein, human; C515903:PAK1 protein, human; C482576:MAP3K1 protein, human