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Scientific article
English

Autoactivation of Transforming Growth Factor β-activated Kinase 1 Is a Sequential Bimolecular Process

Contributors

Scholz, R.; Sidler, C. L.; Thali, R. F.; Winssinger, Nicolas; Cheung, P. C. F.; Neumann, D.

Published in

The Journal of biological chemistry, vol. 285, no. 33, p. 25753-25766

Publication date

2010

Abstract

Transforming growth factor-β-activated kinase 1 (TAK1), an MAP3K, is a key player in processing a multitude of inflammatory stimuli. TAK1 autoactivation involves the interplay with TAK1-binding proteins (TAB), e.g. TAB1 and TAB2, and phosphorylation of several activation segment residues. However, the TAK1 autoactivation is not yet fully understood on the molecular level due to the static nature of available x-ray structural data and the complexity of cellular systems applied for investigation. Here, we established a bacterial expression system to generate recombinant mammalian TAK1 complexes. Co-expression of TAK1 and TAB1, but not TAB2, resulted in a functional and active TAK1-TAB1 complex capable of directly activating full-length heterotrimeric mammalian AMP-activated protein kinase (AMPK) in vitro. TAK1-dependent AMPK activation was mediated via hydrophobic residues of the AMPK kinase domain αG-helix as observed in vitro and in transfected cell culture. Co-immunoprecipitation of differently epitope-tagged TAK1 from transfected cells and mutation of hydrophobic αG-helix residues in TAK1 point to an intermolecular mechanism of TAB1-induced TAK1 autoactivation, as TAK1 autophosphorylation of the activation segment was impaired in these mutants. TAB1 phosphorylation was enhanced in a subset of these mutants, indicating a critical role of αG-helix residues in this process. Analyses of phosphorylation site mutants of the activation segment indicate that autophosphorylation of Ser-192 precedes TAB1 phosphorylation and is followed by sequential phosphorylation of Thr-178, Thr-187, and finally Thr-184. Finally, we present a model for the chronological order of events governing TAB1-induced TAK1 autoactivation.

UNIGE affiliation entities

Not a UNIGE publication

Citation (ISO format)

SCHOLZ, R. et al. Autoactivation of Transforming Growth Factor β-activated Kinase 1 Is a Sequential Bimolecular Process. In: The Journal of biological chemistry, 2010, vol. 285, n° 33, p. 25753–25766. doi: 10.1074/jbc.M109.093468

Main files (1)

Article (Published version)

Identifiers

Journal ISSN

0021-9258
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Technical informations

Creation

12/12/2012 10:08:00

First validation

12/12/2012 10:08:00

Update

13/10/2025 23:52:49

Status update

14/03/2023 17:47:43

Last indexation

01/07/2026 06:09:44
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