Post-Translational Modifications of the TAK1-TAB Complex

Abstract

Transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) is a member of the mitogen-activated protein kinase kinase kinase (MAPKKK) family that is activated by growth factors and cytokines such as TGF-β, IL-1β, and TNF-α, and mediates a wide range of biological processes through activation of the nuclear factor-κB (NF-κB) and the mitogen-activated protein (MAP) kinase signaling pathways. It is well established that activation status of TAK1 is tightly regulated by forming a complex with its binding partners, TAK1-binding proteins (TAB1, TAB2, and TAB3). Interestingly, recent evidence indicates the importance of post-translational modifications (PTMs) of TAK1 and TABs in the regulation of TAK1 activation. To date, a number of PTMs of TAK1 and TABs have been revealed, and these PTMs appear to fine-tune and coordinate TAK1 activities depending on the cellular context. This review therefore focuses on recent advances in the understanding of the PTMs of the TAK1-TAB complex.

The family of the interleukin‐1 receptors

“…It should be emphasized that to this point in signal transduction of the IL‐1Rs, no amplification of the signal has been achieved by the 2 protein kinases, IRAK‐4 and IRAK‐1 This suggests that the initial phosphorylation events in the juxtamembrane signalosome serve regulatory functions rather than amplifying the incoming signal to the first protein kinase in the module that actually does amplifies the incoming signal, the TGFβ1‐activated kinase 1 (TAK1) . TAK1 serves as an integrator of a series of incoming signaling pathways besides of the TIR domain‐containing receptors, such as TNFR and BCR or TCR, and at the same time funnels the signal to the IKKβ complex or MKKs (reviewed in ). The activation mechanism of TAK1 involves a series of proteins.…”

Roles of NF-κB in Cancer and Their Therapeutic Approaches

“…Thus, targeting of deregulated upstream pathways, such as chronic active BCR signaling, which drive constitutive NF-κB activation, potentially offers higher specificity for the malignant cells and represents an attractive alternative in the treatment of lymphoid malignancies. The validity of this concept has first been demonstrated by the therapeutic efficacy of the BTK inhibitor ibrutinib in ABC DLBCL and other lymphoid cancers relying on chronic BCR signaling [67,89,253,254]. Additional therapeutic targets in lymphoid tumors addicted to chronic BCR activation include SYK, LYN, and PKCβ [67,255,256].…”

Role of the transforming growth factor (TGF)-β1 and TGF-β1 signaling pathway on the pathophysiology of respiratory pneumococcal infections

“…In addition to the Smad proteins, phosphorylated TβRs activate MAPK kinase kinases (MAP3Ks) including TGF-β-activated kinase 1 (TAK1) and Raf, which play critical roles in the TGF-β1-induced Smad-independent signaling pathways [19]. Activated TAK1 activates MAPK kinase and the inhibitor of nuclear factor (NF)-κBβ, which results in subsequent activation of MAPKs, such as JNK and p38 MAPKs, and NF-κB.…”

“…IL-1R and TLRs activate the pathways mediated by TNF receptor-associated factor 6 (TRAF6) and TAK1, which are fundamental for the TGF-β1-induced activation of the JNK/p38 MAPK pathways [19,20].…”

“…The activation of TβRs by TGF-β1 triggers the Smad-dependent signaling pathway and many other non-canonical signaling pathways, including ERK1/2, p38 mitogen activated protein kinases (MAPKs) and phosphoinositide 3-kinase (PI3K)-Akt signaling ( Fig. 1) [19,20].…”