Vav-1 and the IKKα Subunit of IκB Kinase Functionally Associate to Induce NF-κB Activation in Response to CD28 Engagement

Abstract

We have recently observed that CD28 engagement initiates a signaling pathway leading to the activation of IκB kinase (IKK) complex and, consequently, to NF-κB 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 IKKα in both Jurkat and primary CD4+ T cells. Vav-1/IKKα association is mediated by their helix-loop-helix domains, does not involve IKKβ, and is functionally relevant in that Vav-1-associated IKKα kinase activity is increased following CD28 engagement by B7. Moreover, we demonstrate that CD28-induced NF-κB activation is augmented by both IKKα and Vav-1, but not IKKβ. Confocal microscopy showed that endogenous Vav-1 and IKKα, but not IKKβ, 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-κB pathway by targeting IKKα in the T cell membrane and favoring its activation in response to CD28 stimulation.