Vav1 couples the T cell receptor to cAMP response element activation via a PKC-dependent pathway.
The transcription factor cAMP-responsive element binding protein (CREB) is a regulator of the expression of several genes important for lymphocyte activation and proliferation. However, the proximal signaling events leading to activation of CREB in T cells upon antigen receptor stimulation remain unknown. Here we identify a role for Vav1 in the activation of the cAMP response element (CRE), the binding site for CREB. T cell receptor (TCR)/CD28 - induced costimulation of Jurkat T cells expressing Vav1 but not a GEF-deficient mutant showed increased CRE activation (7.2+/-2.4 fold over control), whereas Vav1 downregulation by siRNA reduced activation of CRE by 2.6+/-1.3 fold. Inhibition of PKC and MEK but not p38 could reduce Vav1-mediated CRE activation, suggesting that Vav1 transmits TCR and CD28 signals to activation of CRE via PKC and ERK signaling pathways. As a consequence, downregulation of Vav1 impaired the expression of several CRE-containing genes like cyclin D1, INFgamma and IL-2, whereas overexpression of Vav1 enhanced CRE-dependent gene expression. Furthermore, cAMP-induced CRE-dependent transcription and gene expression was also modulated by Vav1, but did not require activation of PKC and the GEF function of Vav1. Our data provide insights into the signal transduction events regulating CRE-mediated gene expression in T cells, which affects T cell development, proliferation and activation. We identify Vav1 as an essential component of TCR-induced CRE activation and gene expression, which underlines the central role for Vav1 as key player for TCR signal transduction and gene expression.
Novartis Institutes of BioMedical Research, Autoimmunity, Transplantation & Inflammation, 4002 Basel, Switzerland.
Dirk
D
Haubert
Gisbert
G
Weckbecker
D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D020218:Response Elements; D015398:Signal Transduction
D017362:Cyclic AMP Response Element-Binding Protein; D051567:Proto-Oncogene Proteins c-vav; D011948:Receptors, Antigen, T-Cell; D000242:Cyclic AMP; D011493:Protein Kinase C; D020929:Mitogen-Activated Protein Kinase Kinases