MAP3K14

Abstract: The noncanonical nuclear factor-κB (NF-κB) signaling pathway mediates activation of the p52/RelB NF-κB complex and, thereby, regulates specific immunological processes. This NF-κB pathway relies on the inducible processing of NF-κB2 precursor protein, p100, as opposed to the degradation of IκBα in the canonical NF-κB pathway. A central signaling component of the noncanonical NF-κB pathway is NF-κB-inducing kinase (NIK), which functions together with a downstream kinase, IKKα (inhibitor of NF-κB kinase α), to induce phosphorylation-dependent ubiquitination and processing of p100. Under normal conditions, NIK is targeted for continuous degradation by a tumor necrosis factor (TNF) receptor-associated factor-3 (TRAF3)-dependent E3 ubiquitin ligase. In response to signals mediated by a subset of TNF receptor superfamily members, NIK becomes stabilized as a result of TRAF3 degradation, leading to the activation of noncanonical NF-κB. This review discusses both the historical perspectives and the recent progress in the regulation and biological function of the noncanonical NF-κB pathway.

Abstract: Activation of the transcription factor NF-κB by inflammatory cytokines involves the successive action of NF-κB-inducing kinase (NIK) and two IκB kinases, IKK-α and IKK-β. Here we show that NIK preferentially phosphorylates IKK-α over IKK-β, leading to the activation of IKK-α kinase activity. This phosphorylation of IKK-α occurs specifically on Ser-176 in the activation loop between kinase subdomains VII and VIII. A mutant form of IKK-α containing alanine at residue 176 cannot be phosphorylated or activated by NIK and acts as a dominant negative inhibitor of interleukin 1- and tumor necrosis factor-induced NF-κB activation. Conversely, a mutant form of IKK-α containing glutamic acid at residue 176 is constitutively active. Thus, the phosphorylation of IKK-α on Ser-176 by NIK may be required for cytokine-mediated NF-κB activation.