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. 2017 Jan 19;18(1):205.
doi: 10.3390/ijms18010205.

Post-Translational Modifications of the TAK1-TAB Complex

Free PMC article

Post-Translational Modifications of the TAK1-TAB Complex

Yusuke Hirata et al. Int J Mol Sci. .
Free PMC article


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.

Keywords: MAP kinase; NF-κB; TAB1; TAB2; TAB3; TAK1; post-translational modification.

Conflict of interest statement

The authors declare no conflict of interest.


Figure 1
Figure 1
Receptor-mediated TAK1 signaling pathways. Receptor-mediated activation of TAK1 is mainly mediated by the E3 ubiquitin ligase TRAF2 or TRAF6 that promotes formation of the TAK1-TAB complex. On the other hand, the E3 ubiquitin ligase XIAP activates TAK1 through the direct interaction with TAB1 downstream of TGFBR or BMPR activation probably without E3 ubiquitin ligase activity. Moreover, a recent report showed that unanchored K63-linked polyubiquitin chains are sufficient to activate TAK1 [7]. TAK1 activated by these multiple mechanisms upregulates NF-κB- and AP-1-depenedent gene expression through activating the NF-κB and MAP kinase (JNK and p38) pathways. The arrows show positive regulation and “p” indicates phosphorylation.
Figure 2
Figure 2
Schematic representation of the domain structures and PTM sites of human TAK1 and TABs. The amino acid positions of each domain are indicated below the structures. Information of kinase domain of TAK1, pseudophosphatase domain of TAB1, coupling of ubiquitin conjugation to endoplasmic reticulum degradation (CUE), and Npl4 zinc finger (NZF) ubiquitin binding domains of TAB2 and TAB3 was obtained by SMART (simple modular architecture research tool) ( Information of TABs binding domain (BD) in TAK1 [14,18] and TAK1 BD in TABs [9,14,19] was obtained from previous studies analyzing the individual domains. The pseudophosphatase domain of TAB1 has a similar structure to protein phosphatase 2C (PP2C), despite lacking phosphatase activity [20]. The types of PTMs are indicated above the corresponding positions and are color-coded according to the effect on TAK1 activity (positive, red; negative, blue; unknown, black). P, phosphorylation; Ub, ubiquitination; SUMO, SUMOylation; Ac, acetylation; O-GlcNAc, O-GlcNAcylation; Me, Methylation.

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