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Subunit of I
B Kinase Functionally Associate to Induce NF-B Activation in Response to CD28 Engagement1
* Department of Cellular and Developmental Biology, University of Rome La Sapienza, Rome, Italy;
Laboratories of Cell Biology, Istituto Superiore di Sanità, Rome, Italy;
Fondazione Andrea Cesalpino, Policlinico Umberto I, University of Rome La Sapienza, Rome, Italy; and
Program in Signal Transduction Research, The Burnham Institute, La Jolla, CA 92037
We have recently observed that CD28 engagement initiates a signaling pathway leading to the activation of I
B kinase (IKK) complex and, consequently, to NF-B 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 IKK
in both Jurkat and primary CD4+ T cells. Vav-1/IKK association is mediated by their helix-loop-helix domains, does not involve IKK
, and is functionally relevant in that Vav-1-associated IKK kinase activity is increased following CD28 engagement by B7. Moreover, we demonstrate that CD28-induced NF-B activation is augmented by both IKK and Vav-1, but not IKK. Confocal microscopy showed that endogenous Vav-1 and IKK, but not IKK, 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-B pathway by targeting IKK in the T cell membrane and favoring its activation in response to CD28 stimulation.
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