IκB Kinase-β: NF-κB Activation and Complex Formation with IκB Kinase-α and NIK

Abstract

Activation of the transcription factor nuclear factor kappa B (NF-kappaB) by inflammatory cytokines requires the successive action of NF-kappaB-inducing kinase (NIK) and IkappaB kinase-alpha (IKK-alpha). A widely expressed protein kinase was identified that is 52 percent identical to IKK-alpha. IkappaB kinase-beta (IKK-beta) activated NF-kappaB when overexpressed and phosphorylated serine residues 32 and 36 of IkappaB-alpha and serines 19 and 23 of IkappaB-beta. The activity of IKK-beta was stimulated by tumor necrosis factor and interleukin-1 treatment. IKK-alpha and IKK-beta formed heterodimers that interacted with NIK. Overexpression of a catalytically inactive form of IKK-beta blocked cytokine-induced NF-kappaB activation. Thus, an active IkappaB kinase complex may require three distinct protein kinases.

Modulation of the NF-κB pathway by virally encoded Death Effector Domains-containing proteins

“…TRAF2 and its homologs have been recently shown to bind to NIK, which subsequently binds to two recently identi®ed protein kinases termed I-kappa B kinase kinase 1 (IKK1 or IKKa) and 2 (IKK2 or IKKb) (Figure 1) (DiDonato et al, 1997;Mercurio et al, 1997;Regnier et al, 1997;Woronicz et al, 1997;Zandi et al, 1997). As shown in Figure 3c, dominantnegative mutants of NIK and IKK2 could block NFkB activation mediated by the ORF-K13, whereas a similar mutant of IKK1 failed to do so.…”

Inhibitors of NF-κB signaling: 785 and counting

“…Specifically, dominant-negative forms of IKKa and b, which are capable of blocking activation of NF-kB, can be created either by mutations in the ATP-binding site or by mutations in the kinase activation loop (DiDonato et al, 1997;Mercurio et al, 1997;Regnier et al, 1997;Woronicz et al, 1997;Zandi et al, 1997;Ling et al, 1998). Because of their distinct roles in the canonical (IKKb-dependent) and non-canonical (IKKa-dependent) pathways, dominantnegative IKK mutants can show stimulus-dependent inhibition.…”

Transcriptional activation of survivin through the NF‐κB pathway by human T‐cell leukemia virus type I tax

“…36 Previous studies indicated that members of the mitogenactivated protein kinase kinase kinase protein kinase family mediate physiologic activation of IKK. 37 These kinases include NIK 38 and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1. 39 Dominant interfering mutants of IkBa and IkBb and kinase-deficient mutants of IKKa, IKKb and NIK were tested for their ability to inhibit Tax-mediated activation of survivin-driven reporter gene.…”