Functional Interactions of Transforming Growth Factor β-activated Kinase 1 with IκB Kinases to Stimulate NF-κB Activation

Abstract

Several mitogen-activated protein kinase kinase kinases play critical roles in nuclear factor-B (NF-B) activation. We recently reported that the overexpression of transforming growth factor-␤-activated kinase 1 (TAK1), a member of the mitogen-activated protein kinase kinase kinase family, together with its activator TAK1-binding protein 1 (TAB1) stimulates NF-B activation. Here we investigated the molecular mechanism of TAK1-induced NF-B activation. Dominant negative mutants of IB kinase (IKK) ␣ and IKK␤ inhibited TAK1-induced NF-B activation. TAK1 activated IKK␣ and IKK␤ in the presence of TAB1. IKK␣ and IKK␤ were coimmunoprecipitated with TAK1 in the absence of TAB1. TAB1-induced TAK1 activation promoted the dissociation of active forms of IKK␣ and IKK␤ from active TAK1, whereas the IKK mutants remained to interact with active TAK1. Furthermore, tumor necrosis factor-␣ activated endogenous TAK1, and the kinase-negative TAK1 acted as a dominant negative inhibitor against tumor necrosis factor-␣-induced NF-B activation. These results demonstrated a novel signaling pathway to NF-B activation through TAK1 in which TAK1 may act as a regulatory kinase of IKKs. Transcription factor nuclear factor B (NF-B)1 is composed of homodimers and heterodimers of Rel family proteins and plays a pivotal role in the gene expression involved in inflammatory and immune responses (1-3). NF-B is sequestered in the cytoplasm by inhibitory proteins such as IB␣, IB␤, and IB⑀, which mask the nuclear localization signal of NF-B (4 -8). The phosphorylation of two Ser residues at an N-terminal regulatory domain of IB proteins triggers polyubiquitination of IB proteins, which targets them for rapid degradation through a proteasome-dependent pathway, thereby releasing NF-B to enter the nucleus (9 -15). Diverse extracellular stimuli such as tumor necrosis factor (TNF)-␣ and interleukin-1␤, phorbol esters, and environmental stresses lead to NF-B activation utilizing the common mechanism for the IB degradation, suggesting the diversity of the upstream signaling pathways for phosphorylation of IB proteins.Several regulatory kinases involved in the signal-induced phosphorylation of IB proteins have recently been reported. Two closely related kinases designated IB kinase (IKK) ␣ and IKK␤ have been identified as components of the multiprotein IKK complex (500 -900 kDa) that directly phosphorylates the critical Ser residues of IB proteins (16 -20). Together, IKK␣ and IKK␤ form a heterodimer through their C-terminal leucine zipper motifs, and the functional IKK complex contains both IKK subunits. NF-B-inducing kinase (NIK) is a member of the mitogen-activated protein kinase kinase kinase (MAPKKK) family, which was first identified as a TNF-␣ receptor-associated factor (TRAF) 2-interacting protein (21). The ligand-mediated trimerization of the TNF-␣ receptor triggers the recruitment of NIK to TRAF2, and this association results in the activation of NIK, which in turn phosphorylates and activates IKKs. NIK also interacts with TRAF6, another member of the...

Pinitol targets nuclear factor-κB activation pathway leading to inhibition of gene products associated with proliferation, apoptosis, invasion, and angiogenesis

“…It is possible that this inhibition is the result of inhibition of an upstream kinase. Recent studies have shown that TAK1 is a major kinase directly responsible for activation of IKK pathway (44,45). We also found that pinitol suppresses NF-nB-dependent reporter gene expression.…”

Combined inhibition of PAK7, MAP3K7 and CK2α kinases inhibits the growth of MiaPaCa2 pancreatic cancer cell xenografts

“…17 MAP3K7 with its activator TAB1 (TAK1-binding protein 1) can activate NF-kB by an NIK (NF-kBinducing kinase)-independent mechanism, 18 but with a functional interaction with IKK (IkB kinase) a and IKKb. 19 This activation of NF-kB has been implicated in liver tumor formation. 20 However, several members of the IAP (inhibitors of apoptosis) family, such as XIAP, NAIP and ML-IAP, activate JNK1 survival pathway through interaction with MAP3K7 and its activator TAB1.…”

Simvastatin Potentiates TNF-α-Induced Apoptosis through the Down-Regulation of NF-κB-Dependent Antiapoptotic Gene Products: Role of IκBα Kinase and TGF-β-Activated Kinase-1

“…Recent studies, however, indicate that TAK1 plays a major role in TNF-␣-induced NF-B activation through its interaction with TAB1 and TAB2. For example, TAK1 can bind and activate IKK␤ leading to NF-B activation (74). TAK1 also has been shown to be recruited by the TNFR1 through TRADD, TRAF2, and RIP (21).…”