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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

Serge Ducommun, Maria Deak, Anja Zeigerer, Olga Göransson, Susanne Seitz, Caterina Collodet, Agnete Bjerregaard Madsen, Thomas Elbenhardt Jensen, Benoit Viollet, Marc Foretz, Philipp Gut, David Sumpton, Kei Sakamoto

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 organization. Further characterization 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.

OriginalsprogEngelsk
TidsskriftCellular Signalling
Vol/bind57
Sider (fra-til)45-57
Antal sider13
ISSN0898-6568
DOI
StatusUdgivet - 2019

Bibliografisk note

CURIS 2019 NEXS 073
Copyright © 2019. Published by Elsevier Inc.

ID: 213663914