SUMOylation of AMPK?1 by PIAS4 specifically regulates mTORC1 signalling.

ABSTRACT: AMP-activated protein kinase (AMPK) inhibits several anabolic pathways such as fatty acid and protein synthesis, and identification of AMPK substrate specificity would be useful to understand its role in particular cellular processes and develop strategies to modulate AMPK activity in a substrate-specific manner. Here we show that SUMOylation of AMPK?1 attenuates AMPK activation specifically towards mTORC1 signalling. SUMOylation is also important for rapid inactivation of AMPK, to allow prompt restoration of mTORC1 signalling. PIAS4 and its SUMO E3 ligase activity are specifically required for the AMPK?1 SUMOylation and the inhibition of AMPK?1 activity towards mTORC1 signalling. The activity of a SUMOylation-deficient AMPK?1 mutant is higher than the wild type towards mTORC1 signalling when reconstituted in AMPK?-deficient cells. PIAS4 depletion reduced growth of breast cancer cells, specifically when combined with direct AMPK activator A769662, suggesting that inhibiting AMPK?1 SUMOylation can be explored to modulate AMPK activation and thereby suppress cancer cell growth.

SUBMITTER: Yan Y 

PROVIDER: S-EPMC4674823 | biostudies-other | 2015

REPOSITORIES: biostudies-other