TRAF3:NIK binds TRAF2:cIAP1/2

Stable Identifier
Reaction [binding]
Homo sapiens
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Mitogen-activated protein kinase kinase kinase 14 (MAP3K14 also named as NIK) is a central signalling component of the non-canonical pathway which integrates signals from TNFR2 and activates IkB kinase-alpha (IkBA) for triggering p100 phosphorylation and processing (Sun 2011). A tight control of NIK stability is essential to achieve controlled activation of the noncanonical NF-kB signalling upon TNFR2 activation. In unstimulated cells the level of NIK protein is extremely low, which is due to constant degradation by a ubiquitination-dependent mechanism (Liao et al. 2004). Proteasomal degradation of NIK occurs on assembly of a regulatory complex through TRAF3 complexed with NIK and TRAF2 which exists in a preassembled complex with cellular Inhibitor of apoptosis 1 (cIAP1) and cIAP2 (cIAP1,2:TRAF2::TRAF3:NIK). The c-IAPs do not directly contact TNFR2, but rather associate with TRAF2 through their N-terminal BIR motif-comprising domain (Rothe et al. 1995, Shu et al. 1996). TRAF3 functions as a bridging factor between cIAP1/2-TRAF2 E3 complex and NIK enabling cIAP to mediate K48 linked ubiquitination of NIK (Zarnegar et al. 2008, Vallabhapurapu et al. 2008, Li et al. 2004).

Literature References
PubMed ID Title Journal Year
18997794 Noncanonical NF-kappaB activation requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2 and TRAF3 and the kinase NIK

Mahoney, DJ, Wang, Y, Shiba, T, Mak, TW, Yeh, WC, Cheng, G, Dempsey, PW, He, J, Cheung, HH, Korneluk, RG, Yang, X, Zarnegar, BJ

Nat. Immunol. 2008
18997792 Nonredundant and complementary functions of TRAF2 and TRAF3 in a ubiquitination cascade that activates NIK-dependent alternative NF-kappaB signaling

Zhang, W, Tseng, PH, Matsuzawa, A, Vignali, DA, Bergsagel, PL, Keats, JJ, Karin, M, Wang, H, Vallabhapurapu, S

Nat. Immunol. 2008
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