MAP3K-related kinase involved in NF-KB induction by TNF, CD95 and IL-1

Abstract

Several members of the tumour-necrosis/nerve-growth factor (TNF/NGF) receptor family activate the transcription factor NF-kappaB through a common adaptor protein, Traf2 (refs 1-5), whereas the interleukin 1 type-I receptor activates NF-kappaB independently of Traf2 (ref. 4). We have now cloned a new protein kinase, NIK, which binds to Traf2 and stimulates NF-kappaB activity. This kinase shares sequence similarity with several MAPKK kinases. Expression in cells of kinase-deficient NIK mutants fails to stimulate NF-kappaB and blocks its induction by TNF, by either of the two TNF receptors or by the receptor CD95 (Fas/Apo-1), and by TRADD, RIP and MORT1/FADD, which are adaptor proteins that bind to these receptors. It also blocked NF-kappaB induction by interleukin-1. Our findings indicate that NIK participates in an NF-kappaB-inducing signalling cascade common to receptors of the TNF/NGF family and to the interleukin-1 type-I receptor.

Antitumor activity and macrophage nitric oxide producing action of medicinal herb, Crassocephalum crepidioides

“…In the NF-κB activation pathway, IKK complex can induce serine phosphorylation of IκBα and IκBβ [22]. Previous studies suggested the involvement of serine/threonine kinase NIK in phosphorylation and activation of the IKK complex [23]. To determine the roles of NIK, IKKα, IKKβ and IKKγ in C. crepidioides -induced iNOS expression in RAW264.7 cells, plasmids encoding dominant-negative mutants of NIK, IKKα, IKKβ and IKKγ were used.…”

Inhibitors of NF-κB signaling: 785 and counting

“…Overexpression of NIK potently induces NF-kB (Malinin et al, 1997), primarily through the non-canoncial pathway (Scheidereit, 2006). In addition, some studies have demonstrated that MEKK1 is activated by TNFa and IL-1 and can potentiate the stimulatory effect of TNFa on IKK and NF-kB activation (Hirano et al, 1996;Lee et al, 1998).…”

“…More specifically, NIK can directly phosphorylate IKKa for activation of the non-canonical p52/RelB pathway (see Perkins, 2006;Scheidereit, 2006). As such, overexpression of kinasedeficient NIK mutants can block the ability of IL-1 and TNFa to induce NF-kB (Malinin et al, 1997;Song et al, 1997).…”

Modulation of life and death by the TNF receptor superfamily

“…Once free, unbound NF-kB dimerizes and becomes an active transcription factor that translocates to the nucleus and activates transcription of NFkB-responsive genes. IKKs are phosphorylated by NIK (NF-kB-inducing kinase), a MAP kinase that is part of the TNF-RI receptor complex (reviewed in Gilmore et al, 1996;Malinin et al, 1997). According to this model, TNF-RI activation may stimulate RIP kinase activity, which then phosphorylates NIK, which in turn, activates IKKa and IKKb.…”