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
  • Jensen, Thomas Elbenhardt
  • Benoit Viollet
  • Marc Foretz
  • Philipp Gut
  • David Sumpton
  • Sakamoto, Kei

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