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 transduces signals by recruiting associating molecules, The TNF-R1 associated death domain protein interacts with the p55 TNF-R1 cytoplasmic domain and recruits the Fas-associated death domain protein (which directly activates the apoptotic proteases), the protein kinase receptor interacting protein, and TNF receptor-associated factor 2 (TRAF2), TRAF2 has previously been demonstrated to activate both transcription factor nuclear factor kappa B (NF kappa B) and the c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) pathway, which in turn stimulates transcription factor activating protein 1 (AP1) mainly via phosphorylation of the c-Jun component. We have investigated the signaling properties of NF kappa B-inducing kinase (NIK), a TRAF2-associated protein kinase that mediates NF kappa B induction, NM was found to be unable to activate JNK/SAPK, mitogen-activated protein kinase, or p38 kinase, Moreover, NIK was not required for JNK/SAPK activation by TNF-R1, thus representing the first TNF-R1 complex component to dissect the NF kappa B and the JNK/SAPK pathways. Despite being unable to activate JNK/SAPK and mitogen-activated protein kinase, NIK strongly activated AP1 and was required for TNF-R1-induced AP1 activation, Therefore, NIK links TNF-R1 to a novel, JNK/SAPK-independent, AP1 activation pathway.