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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylation / drug effects
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Acetyltransferases / metabolism*
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Animals
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Benzamides / pharmacology
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COS Cells
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Cell Cycle / drug effects
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Cell Cycle / physiology
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Cell Line
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Cell Proliferation / drug effects
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Cell Proliferation / physiology*
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Chlorocebus aethiops
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Dioxoles / pharmacology
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Gene Knockdown Techniques
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HeLa Cells
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Humans
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MAP Kinase Kinase Kinases / antagonists & inhibitors
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MAP Kinase Kinase Kinases / genetics
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MAP Kinase Kinase Kinases / metabolism*
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Male
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Metabolic Networks and Pathways / drug effects
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Metabolic Networks and Pathways / physiology
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Mice
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Mice, Inbred ICR
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Microtubule Proteins / metabolism*
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Microtubules / drug effects
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Microtubules / metabolism*
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Proto-Oncogene Proteins c-akt / metabolism*
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RNA, Small Interfering / metabolism
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Zearalenone / analogs & derivatives
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Zearalenone / pharmacology
Substances
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4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide
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7-oxozeanol
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Benzamides
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Dioxoles
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Microtubule Proteins
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RNA, Small Interfering
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Zearalenone
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Acetyltransferases
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ATAT1 protein, mouse
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Proto-Oncogene Proteins c-akt
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MAP Kinase Kinase Kinases
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MAP kinase kinase kinase 7