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

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

  • Ducommun S Nestlé Research, École Polytechnique Fédérale de Lausanne (EPFL) Innovation Park, bâtiment G, 1015 Lausanne, Switzerland; School of Life Sciences, EPFL, 1015 Lausanne, Switzerland.
  • Deak M Nestlé Research, École Polytechnique Fédérale de Lausanne (EPFL) Innovation Park, bâtiment G, 1015 Lausanne, Switzerland.
  • Zeigerer A Institute for Diabetes and Cancer, Helmholtz Center for Environmental Health, 85764 Neuherberg, Germany; Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany.
  • Göransson O Department of Experimental Medical Sciences, Lund University, 221 84 Lund, Sweden.
  • Seitz S Institute for Diabetes and Cancer, Helmholtz Center for Environmental Health, 85764 Neuherberg, Germany; Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany.
  • Collodet C Nestlé Research, École Polytechnique Fédérale de Lausanne (EPFL) Innovation Park, bâtiment G, 1015 Lausanne, Switzerland; School of Life Sciences, EPFL, 1015 Lausanne, Switzerland.
  • Madsen AB Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
  • Jensen TE Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
  • Viollet B Inserm, U1016, Institut Cochin, Paris, France; CNRS, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris cité, Paris, France.
  • Foretz M Inserm, U1016, Institut Cochin, Paris, France; CNRS, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris cité, Paris, France.
  • Gut P Nestlé Research, École Polytechnique Fédérale de Lausanne (EPFL) Innovation Park, bâtiment G, 1015 Lausanne, Switzerland.
  • Sumpton D Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK.
  • Sakamoto K Nestlé Research, École Polytechnique Fédérale de Lausanne (EPFL) Innovation Park, bâtiment G, 1015 Lausanne, Switzerland; School of Life Sciences, EPFL, 1015 Lausanne, Switzerland. Electronic address: Kei.Sakamoto@rd.nestle.com.
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  • 2019-02-18
Published in:
  • Cellular signalling. - 2019
GTPase activating protein and VPS9 domains 1
Shokat
Starch-binding domain 1
AMP-Activated Protein Kinases
Animals
Guanine Nucleotide Exchange Factors
Hepatocytes
Homeostasis
Lipid Metabolism
Liver
Mass Spectrometry
Membrane Proteins
Mice, Knockout
Muscle Proteins
Phosphorylation
Substrate Specificity
English 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.
Language
  • English
Open access status
hybrid
Identifiers
Persistent URL
https://sonar.ch/global/documents/209830
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