Vav-1 and the IKKα subunit of IκB kinase functionally associate to induce NF-κB activation in response to CD28 engagement

have recently observed that CD28 engagement initiates a signaling pathway leading to the activation of IkappaB kinase (IKK) complex and, consequently, to NF-kappaB activation, and we identified Vav-1 as an important mediator of this function. Here we report for the first time that Vav-1 constitutively associates with IKKalpha in both Jurkat and primary CD4(+) T cells. Vav-1/IKKalpha association is mediated by their helix-loop-helix domains, does not involve IKKbeta, and is functionally relevant in that Vav-1-associated IKKkappa kinase activity is increased following CD28 engagement by B7. Moreover, we demonstrate that CD28-induced NF-kappaB activation is augmented by both IKKalpha and Vav-1, but not IKKbeta. Confocal microscopy showed that endogenous Vav-1 and IKKalpha, but not IKKbeta, were recruited to the membrane and colocalized in response to CD28 stimulation. Taken together, these data evidence that Vav-1 plays a key role in the control of NF-kappaB pathway by targeting IKKalpha in the T cell membrane and favoring its activation in response to CD28 stimulation.