Journal of Biological Chemistry
Volume 272, Issue 42, 17 October 1997, Pages 26079-26082
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Tumor Necrosis Factor (TNF) Receptor 1 Signaling Downstream of TNF Receptor-associated Factor 2: NUCLEAR FACTOR κB (NFκB)-INDUCING KINASE REQUIREMENT FOR ACTIVATION OF ACTIVATING PROTEIN 1 AND NFκB BUT NOT OF c-Jun N-TERMINAL KINASE/STRESS-ACTIVATED PROTEIN KINASE*

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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 κB (NFκB) 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 NFκB-inducing kinase (NIK), a TRAF2-associated protein kinase that mediates NFκB induction. NIK 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 NFκB 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.

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This work was supported by the Applicazioni Cliniche Ricerca Oncologica Project of the Associazione Italiana Ricerca sul Cancro, the II Research Project on Multiple Sclerosis of the Istituto Superiore di Sanità, and the Fondazione Andrea Cesalpino.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.