Chemical genetic screen identifies Gapex-5/GAPVD1 and STBD1 as novel AMPK substrates

AMP-activated protein kinase (AMPK) is a key regulator of cellular energy homeostasis, acting as a sensor of energy and nutrient status. As such, AMPK is considered a promising drug target for treatment of medical conditions particularly associated with metabolic dysfunctions. To better understand the downstream effectors and physiological consequences of AMPK activation, we have employed a chemical genetic screen in mouse primary hepatocytes in an attempt to identify novel AMPK targets. Treatment of hepatocytes with a potent and specific AMPK activator 991 resulted in identification of 65 proteins phosphorylated upon AMPK activation, which are involved in a variety of cellular processes such as lipid/glycogen metabolism, vesicle trafficking, and cytoskeleton organisation. Further characterisation and validation using mass spectrometry followed by immunoblotting analysis with phosphorylation site-specific antibodies identified AMPK-dependent phosphorylation of Gapex-5 (also known as GTPase-activating protein and VPS9 domain-containing protein 1 (GAPVD1)) on Ser902 in hepatocytes and starch-binding domain 1 (STBD1) on Ser175 in multiple cells/tissues. As new promising roles of AMPK as a key metabolic regulator continue to emerge, the substrates we identified could provide new mechanistic and therapeutic insights into AMPK-activating drugs in the liver.

Deak, MariaSwiss Federal Institute of Technology (författare)
Zeigerer, AnjaHelmholtz Zentrum München,University Hospital Heidelberg,German Center for Diabetes Research (författare)
Göransson, OlgaLund University,Lunds universitet,Proteinfosforylering,Forskargrupper vid Lunds universitet,Protein Phosphorylation,Lund University Research Groups(Swepub:lu)medk-ogo (författare)
Seitz, SusanneGerman Center for Diabetes Research,University Hospital Heidelberg,Helmholtz Zentrum München (författare)
Collodet, CaterinaSwiss Federal Institute of Technology (författare)
Madsen, Agnete B.University of Copenhagen (författare)
Jensen, Thomas E.University of Copenhagen (författare)
Viollet, BenoitParis Descartes University,Institut Cochin (författare)
Foretz, MarcInstitut Cochin,Paris Descartes University (författare)
Gut, PhilippSwiss Federal Institute of Technology (författare)
Sumpton, DavidBeatson Institute for Cancer Research (författare)
Sakamoto, KeiSwiss Federal Institute of Technology (författare)
Swiss Federal Institute of TechnologyHelmholtz Zentrum München (creator_code:org_t)

Av författaren/redakt...: Ducommun, Serge; Deak, Maria; Zeigerer, Anja; Göransson, Olga; Seitz, Susanne; Collodet, Cateri ...; visa fler...; Madsen, Agnete B ...; Jensen, Thomas E ...; Viollet, Benoit; Foretz, Marc; Gut, Philipp; Sumpton, David; Sakamoto, Kei; visa färre...

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