Vav cooperates with CD28 to induce NF-kappaB activation via a pathway involving Rac-1 and mitogen-activated kinase kinase 1

CD28-delivered costimulatory signals are required to induce NF-κB activation in response to TCR stimulation. We have recently demonstrated that the mitogen-activated kinase kinase 1 (MEKK1), a kinase known to regulate the c-jun N-terminal kinase (JNK) pathway, is also involved in the CD28- and TCR-induced inhibitor of κB factor (IκB) kinases (IKK) and NF-κB activation. Searching for molecules that couple TCR and CD28 to MEKK1, we found that the guanine nucleotide exchange factor Vav synergized with CD28 stimulation in Jurkat cells to induce NF-κB transcriptional activity through the activation of IKKα and IKKβ. Dominant negative mutants of Vav inhibited TCR- and CD28-NF-κB-dependent transcription by interfering with the activation of the IKK complex. Blocking Rac signaling downstream of Vav by dominant negative RacN17 exerts similar effects on IKK and NF-κB activation after TCR/CD28 stimulation. Finally, Vav-induced NF-κB activation in CD28 costimulated cells was inhibited by dominant negative MEKK(KM). These results identify Vav, Rac-1 and MEKK1 as components of a common pathway regulating both NF-κB and AP-1 that contributes to full activation of the CD28 response element (CD28RE).