TRAF2:TRAF1:cIAP1,2:TRAF3:NIK regulatory complex binds LTBR

Stable Identifier
R-HSA-5676593
Type
Reaction [binding]
Species
Homo sapiens
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After clustering or dimerisation lymphotoxin-beta receptor (LTBR) initiates signal transduction by recruiting different TNF receptor-associated factor (TRAF) adaptors to the cytoplasmic domain. LTBR directly binds to several TRAFs, including TRAF2 and TRAF3 through its TRAF-interacting peptide motif (VanArsdale et al. 1997, Nakano et al. 1996, Sanjo et al. 2010).
Mitogen-activated protein kinase kinase kinase 14 (MAP3K14 also named as NIK) is a central signalling component of the non-canonical pathway and a tight control of NIK activation by TRAFs is essential to achieve controlled activation of the noncanonical NF-kB signalling. In unstimulated cells ubiquitin:NIK E3 ligase complex catalyses K48-linked ubiquitination of NIK, leading to constitutive NIK degradation. The ubiquitin:NIK E3 ligase is a multisubunit complex comprised of TRAF3 and TRAF2 in association with cellular inhibitors of apoptosis (cIAP1,2). In the activated state the TRAF2:cIAP1,2:TRAF3:NIK complex is recruited to the receptor upon ligand binding whereupon TRAF2-mediated, K63-linked ubiquitination of cIAP1,2 switches its K48 ubiquitin ligase activity from NIK to TRAF3. The resultant TRAF3 degradation destabilizes the TRAF-cIAP complex, so allowing the accumulation of newly synthesised NIK (Razani et al. 2011, Sun 2011).

Literature References
PubMed ID Title Journal Year
8663299 TRAF5, an activator of NF-kappaB and putative signal transducer for the lymphotoxin-beta receptor

Nakano, H, Oshima, H, Chung, W, Williams-Abbott, L, Ware, CF, Yagita, H, Okumura, K

J. Biol. Chem. 1996
12571250 Endogenous association of TRAF2, TRAF3, cIAP1, and Smac with lymphotoxin beta receptor reveals a novel mechanism of apoptosis

Kuai, J, Nickbarg, E, Wooters, J, Qiu, Y, Wang, J, Lin, LL

J. Biol. Chem. 2003
9122217 Lymphotoxin-beta receptor signaling complex: role of tumor necrosis factor receptor-associated factor 3 recruitment in cell death and activation of nuclear factor kappaB

VanArsdale, TL, VanArsdale, SL, Force, WR, Walter, BN, Mosialos, G, Kieff, E, Reed, JC, Ware, CF

Proc. Natl. Acad. Sci. U.S.A. 1997
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