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

ABSTRACT: Acetylation of microtubules (MT) confers mechanical stability necessary for numerous functions including cell cycle and intracellular transport. Although ?TAT1 is a major MT acetyltransferase, how this enzyme is regulated remains much less clear. Here we report TGF-?-activated kinase 1 (TAK1) as a key activator of ?TAT1. TAK1 directly interacts with and phosphorylates ?TAT1 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-?TAT1-Ser237 antibody, we screen various mouse tissues to discover that brain contains some of the highest TAK1-dependent ?TAT1 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-? signaling in MT-related functions and disease.

SUBMITTER: Shah N 

PROVIDER: S-EPMC5923212 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature