Receptor-interacting protein (RIP), a death domain serine/threonine kinase, has been shown to play a critical role in tumor necrosis factor-α (TNF-α)-induced activation of the nuclear factor-κB signaling pathway. We demonstrate here that ectopically expressed RIP induces I-κB kinase-κB kinase-β (IKKβ) activation in intact cells and that RIP-induced IKKβ activation can be blocked by a kinase-inactive form of MEKK1, MEKK1(K1253M). Interestingly, RIP physically associated with MEKK1 both in vitro and in vivo. RIP phosphorylated MEKK1 at Ser-957 and Ser-994. Our data also indicate that RIP induced the stimulation of MEKK1 but not MEKK1(S957A/S994A) in transfected cells. Furthermore, overexpressed MEKK1(S957A/S994A) inhibited the RIP-induced activation of both IKKβ and nuclear factor-κB. We also demonstrated that the TNF-α-induced MEKK1 activation was defective in RIP-deficient Jurkat cells. Taken together, our results suggest that RIP phosphorylates and activates MEKK1 and that RIP is involved in TNF-α-induced MEKK1 activation.
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