TY - JOUR
T1 - TAK1 activation of alpha-TAT1 and microtubule hyperacetylation control AKT signaling and cell growth
AU - Shah, Nirav
AU - Kumar, Sanjay
AU - Zaman, Naveed
AU - Pan, Christopher C.
AU - Bloodworth, Jeffrey C.
AU - Lei, Wei
AU - Streicher, John M.
AU - Hempel, Nadine
AU - Mythreye, Karthikeyan
AU - Lee, Nam Y.
N1 - Funding Information:
We thank Dr. Jianhuan Yang (Baylor College of Medicine) for the TAK1 constructs and Dr. Maxence Nachury (Stanford) for αTAT1–/– MEFs. We acknowledge the Mass Spectrometry and Proteomics Facility at The Ohio State University for their technical assistance. This work was supported in part by NIH CA178443 awarded to N.Y.L., and University of Arizona Cancer Center and University of Arizona Department of Pharmacology, and Department of Chemistry and Biochemistry for internal funding.
Funding Information:
We thank Dr. Jianhuan Yang (Baylor College of Medicine) for the TAK1 constructs and Dr. Maxence Nachury (Stanford) for αTAT1-/- MEFs. We acknowledge the Mass Spectrometry and Proteomics Facility at The Ohio State University for their technical assistance. This work was supported in part by NIH CA178443 awarded to N.Y.L., and University of Arizona Cancer Center and University of Arizona Department of Pharmacology, and Department of Chemistry and Biochemistry for internal funding.
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-018-04121-y
DO - 10.1038/s41467-018-04121-y
M3 - Article
C2 - 29703898
AN - SCOPUS:85046126406
VL - 9
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 1696
ER -