SUMOylation of AMPKα1 by PIAS4 specifically regulates mTORC1 signalling

Yan Yan, Saara Ollila, Iris P. L. Wong, Tea Vallenius, Jorma J. Palvimo, Kari Vaahtomeri and Tomi P. Mäkelä ()
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Yan Yan: Research Programs Unit, Faculty of Medicine, University of Helsinki, Biomedicum Helsinki
Saara Ollila: Research Programs Unit, Faculty of Medicine, University of Helsinki, Biomedicum Helsinki
Iris P. L. Wong: Research Programs Unit, Faculty of Medicine, University of Helsinki, Biomedicum Helsinki
Tea Vallenius: Research Programs Unit, Faculty of Medicine, University of Helsinki, Biomedicum Helsinki
Jorma J. Palvimo: Institute of Biomedicine, University of Eastern Finland, Kuopio
Kari Vaahtomeri: Research Programs Unit, Faculty of Medicine, University of Helsinki, Biomedicum Helsinki
Tomi P. Mäkelä: Research Programs Unit, Faculty of Medicine, University of Helsinki, Biomedicum Helsinki

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: 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 AMPKα1 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 AMPKα1 SUMOylation and the inhibition of AMPKα1 activity towards mTORC1 signalling. The activity of a SUMOylation-deficient AMPKα1 mutant is higher than the wild type towards mTORC1 signalling when reconstituted in AMPKα-deficient cells. PIAS4 depletion reduced growth of breast cancer cells, specifically when combined with direct AMPK activator A769662, suggesting that inhibiting AMPKα1 SUMOylation can be explored to modulate AMPK activation and thereby suppress cancer cell growth.

Date: 2015
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DOI: 10.1038/ncomms9979

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