TUMOR-NECROSIS-FACTOR (TNF) RECEPTOR-1 SIGNALING DOWNSTREAM OF TNF RECEPTOR-ASSOCIATED FACTOR-2 - NUCLEAR FACTOR KAPPA-B (NF-KAPPA-B)-INDUCING KINASE REQUIREMENT FOR ACTIVATION OF ACTIVATING PROTEIN-1 AND NF-KAPPA-B BUT NOT OF C-JUN N-TERMINAL KINASE STRESS-ACTIVATED PROTEIN-KINASE/

Like other members of the tumor necrosis factor (TNF) receptor family, p55 TNF receptor 1 (TNF-R1) lacks intrinsic signaling capacity and tr ansduces signals by recruiting associating molecules, The TNF-R1 assoc iated death domain protein interacts with the p55 TNF-R1 cytoplasmic d omain and recruits the Fas-associated death domain protein (which dire ctly activates the apoptotic proteases), the protein kinase receptor i nteracting protein, and TNF receptor-associated factor 2 (TRAF2), TRAF 2 has previously been demonstrated to activate both transcription fact or nuclear factor kappa B (NF kappa B) and the c-Jun N-terminal kinase /stress-activated protein kinase (JNK/SAPK) pathway, which in turn sti mulates transcription factor activating protein 1 (AP1) mainly via pho sphorylation of the c-Jun component. We have investigated the signalin g properties of NF kappa B-inducing kinase (NIK), a TRAF2-associated p rotein kinase that mediates NF kappa B induction, NM was found to be u nable to activate JNK/SAPK, mitogen-activated protein kinase, or p38 k inase, Moreover, NIK was not required for JNK/SAPK activation by TNF-R 1, thus representing the first TNF-R1 complex component to dissect the NF kappa B and the JNK/SAPK pathways. Despite being unable to activat e JNK/SAPK and mitogen-activated protein kinase, NIK strongly activate d AP1 and was required for TNF-R1-induced AP1 activation, Therefore, N IK links TNF-R1 to a novel, JNK/SAPK-independent, AP1 activation pathw ay.