Role of receptor-interacting protein in tumor necrosis factor-alpha -dependent MEKK1 activation.
Receptor-interacting protein (RIP), a death domain serine/threonine kinase, has been shown to play a critical role in tumor necrosis factor-alpha (TNF-alpha)-induced activation of the nuclear factor-kappaB signaling pathway. We demonstrate here that ectopically expressed RIP induces I-kappaB kinase-beta (IKKbeta) activation in intact cells and that RIP-induced IKKbeta 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 IKKbeta and nuclear factor-kappaB. We also demonstrated that the TNF-alpha-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-alpha-induced MEKK1 activation.
Kim
J W
JW
National Creative Research Initiative Center for Cell Death, Graduate School of Biotechnology, Korea University, Seoul 156-701, Korea.
Joe
C O
CO
Choi
E J
EJ
D002460:Cell Line; D004789:Enzyme Activation; D006801:Humans; D048728:MAP Kinase Kinase Kinase 1; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D012694:Serine; D017346:Protein Serine-Threonine Kinases; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human