Synergistic activation of NF-kappa B by functional cooperation between vav and PKCtheta in T lymphocytes

Here we identified PKCtheta as an activator of transcription factor NF-kappaB in T cells. PKCtheta-induced NF-kappaB activation was synergistically augmented by Vav. Several experimental approaches revealed that PKCtheta is located downstream from Vav in the control of the pathway leading to synergistic NF-kappaB activation. In addition to the synergistic activation cascade, Vav also triggered NF-kappaB activity on a separate route. CD3/CD28-induced activation of NF-kappaB was inhibited by dominant negative forms of Vav or PKCtheta, revealing their essential role in this activation pathway. The Vav/PKCtheta-mediated signals preferentially activated IkappaB kinase beta. Vav and PKCtheta were found to be constitutively associated in unstimulated T cells. Only the ligation of the costimulatory CD28 receptor, but not of the T cell receptor, resulted in the transient dissociation of the Vav-PKCtheta complex. In contrast, T cell receptor/CD28 costimulation resulted in faster dissociation and slower reassociation kinetics.