title: SUMOylation of AMPKα1 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 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.
authors.affiliation: Research Programs Unit, Faculty of Medicine, University of Helsinki, Biomedicum Helsinki, Haartmaninkatu 8, PO Box 63, Helsinki FI-00014, Finland.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Research Programs Unit, Faculty of Medicine, University of Helsinki, Biomedicum Helsinki, Haartmaninkatu 8, PO Box 63, Helsinki FI-00014, Finland.
authors.forename: Saara
authors.initials: S
authors.lastname: Ollila
authors.affiliation: Research Programs Unit, Faculty of Medicine, University of Helsinki, Biomedicum Helsinki, Haartmaninkatu 8, PO Box 63, Helsinki FI-00014, Finland.
authors.forename: Iris P L
authors.initials: IPL
authors.lastname: Wong
authors.affiliation: Research Programs Unit, Faculty of Medicine, University of Helsinki, Biomedicum Helsinki, Haartmaninkatu 8, PO Box 63, Helsinki FI-00014, Finland.
authors.forename: Tea
authors.initials: T
authors.lastname: Vallenius
authors.affiliation: Institute of Biomedicine, University of Eastern Finland, Kuopio, PO Box 1627, FI-70211 Kuopio, Finland.
authors.forename: Jorma J
authors.initials: JJ
authors.lastname: Palvimo
authors.affiliation: Research Programs Unit, Faculty of Medicine, University of Helsinki, Biomedicum Helsinki, Haartmaninkatu 8, PO Box 63, Helsinki FI-00014, Finland.
authors.forename: Kari
authors.initials: K
authors.lastname: Vaahtomeri
authors.affiliation: Research Programs Unit, Faculty of Medicine, University of Helsinki, Biomedicum Helsinki, Haartmaninkatu 8, PO Box 63, Helsinki FI-00014, Finland.
authors.forename: Tomi P
authors.initials: TP
authors.lastname: Mäkelä
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D000075223:Poly-ADP-Ribose Binding Proteins; D050828:Protein Inhibitors of Activated STAT / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D058207:Sumoylation; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; C485891:PIAS4 protein, human; D000075223:Poly-ADP-Ribose Binding Proteins; D050828:Protein Inhibitors of Activated STAT; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C526180:PRKAA1 protein, human