Regulation of TAK–TAB Complex Activation through Ubiquitylation

¹ The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, 250100 Jinan, Shandong, China

² Cardiovascular Disease Research Center, Jinan Central Hospital, Shandong First Medical University, 250102 Jinan, Shandong, China

^*Correspondence: zhangmeng@sdu.edu.cn (Meng Zhang)
^†These authors contributed equally.

Front. Biosci. (Landmark Ed) 2024, 29(5), 169; https://doi.org/10.31083/j.fbl2905169

Submitted: 28 November 2023 | Revised: 7 March 2024 | Accepted: 11 March 2024 | Published: 29 April 2024

This is an open access article under the CC BY 4.0 license.

Abstract

Transforming growth factor- $\beta{}$ (TGF- $\beta{}$ ) activated kinase 1 (TAK1), also named mitogen-activated protein kinase 7 (MAPK7), forms a pivotal signaling complex with TAK1-binding proteins (TAB1, TAB2, and TAB3), orchestrating critical biological processes, including immune responses, cell growth, apoptosis, and stress responses. Activation of TAK1 by stimuli, such as tumor necrosis factor $\alpha{}$ (TNF $\alpha{}$ ), interleukin-1 $\beta{}$ (IL-1 $\beta{}$ ), and Toll-like receptors (TLRs), underscores its central role in cellular signaling. Given the critical role of the TAK1-binding protein (TAK1–TAB) complex in cellular signaling and its impact on various biological processes, this review seeks to understand how ubiquitination thoroughly regulates the TAK1–TAB complex. This understanding is vital for developing targeted therapies for diseases where this signaling pathway is dysregulated. The exploration is significant as it unveils new insights into the activity, stability, and assembly of the complex, underscoring its therapeutic potential in disease modulation.

Keywords

TAK1

TAB1

TAB2

TAB3

ubiquitination

Funding

82270487/National Natural Science Foundation of China

Figures

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Fig. 1.

Schematic illustration of the domain structures of human transforming growth factor- $\beta{}$ (TGF- $\beta{}$ ) activated kinase 1 (TAK1), TAK1-binding proteins (TAB)1, TAB2, and TAB3. TAK1 contains a kinase domain at the N-terminus, followed by a TAB1 binding domain (TAB1 BD) and a TAB2/3 binding domain (TAB2/3 BD). TAB1 is characterized by a pseudo-phosphatase domain and a TAK1 binding domain (TAK1 BD). TAB2 and TAB3 are homologous proteins, and both have a CUE domain at the N-terminus, a TAK1 BD, and an Npl4 zinc-finger (NZF) domain at the C-terminus. CUE, Coupling of Ubiquitin to ER degradation.

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