SUMOylation of AMPK[alpha]1 by PIAS4 specifically regulates mTORC1 signalling

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-sp...

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Published in:Nature communications 2015-11, Vol.6, p.8979
Main Authors: Yan, Yan, Ollila, Saara, Wong, Iris P L, Vallenius, Tea, Palvimo, Jorma J, Vaahtomeri, Kari, Mäkelä, Tomi P
Format: Article
Language:English
Subjects:
Activation
AMP
AMP-activated protein kinase
Breast cancer
Cancer
Deactivation
Depletion
Fatty acids
Inactivation
Kinases
Phosphates
Protein biosynthesis
Protein synthesis
Proteins
Restoration
Signal transduction
Signaling
Substrate specificity
Substrates
SUMO protein
Ubiquitin-protein ligase
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container_title Nature communications
container_volume 6
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Ollila, Saara
Wong, Iris P L
Vallenius, Tea
Palvimo, Jorma J
Vaahtomeri, Kari
Mäkelä, Tomi P
description 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.
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subjects Activation
AMP
AMP-activated protein kinase
Breast cancer
Cancer
Deactivation
Depletion
Fatty acids
Inactivation
Kinases
Phosphates
Protein biosynthesis
Protein synthesis
Proteins
Restoration
Signal transduction
Signaling
Substrate specificity
Substrates
SUMO protein
Ubiquitin-protein ligase
title SUMOylation of AMPK[alpha]1 by PIAS4 specifically regulates mTORC1 signalling
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