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Nat Commun. 2018 Apr 27;9(1):1696. doi: 10.1038/s41467-018-04121-y.

TAK1 activation of alpha-TAT1 and microtubule hyperacetylation control AKT signaling and cell growth.

Author information

1
Division of Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA.
2
Deparment of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA.
3
Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA.
4
Department of Biochemistry and Molecular Biology, Loyola University Chicago, Chicago, IL, USA.
5
Department of Pharmacology, Penn State University, State College, PA, USA.
6
Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC, USA.
7
Deparment of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA. namlee@email.arizona.edu.
8
Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ, USA. namlee@email.arizona.edu.
9
The University of Arizona Cancer Center, Tucson, AZ, USA. namlee@email.arizona.edu.

Abstract

Acetylation of microtubules (MT) confers mechanical stability necessary for numerous functions including cell cycle and intracellular transport. Although αTAT1 is a major MT acetyltransferase, how this enzyme is regulated remains much less clear. Here we report TGF-β-activated kinase 1 (TAK1) as a key activator of αTAT1. TAK1 directly interacts with and phosphorylates αTAT1 at Ser237 to critically enhance its catalytic activity, as mutating this site to alanine abrogates, whereas a phosphomimetic induces MT hyperacetylation across cell types. Using a custom phospho-αTAT1-Ser237 antibody, we screen various mouse tissues to discover that brain contains some of the highest TAK1-dependent αTAT1 activity, which, accordingly, is diminished rapidly upon intra-cerebral injection of a TAK1 inhibitor. Lastly, we show that TAK1 selectively inhibits AKT to suppress mitogenic and metabolism-related pathways through MT-based mechanisms in culture and in vivo. Collectively, our findings support a fundamental new role for TGF-β signaling in MT-related functions and disease.

PMID:
29703898
PMCID:
PMC5923212
DOI:
10.1038/s41467-018-04121-y
[Indexed for MEDLINE]
Free PMC Article

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