Chemical genetic screen identifies Gapex-5/GAPVD1 and STBD1 as novel AMPK substrates
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Chemical genetic screen identifies Gapex-5/GAPVD1 and STBD1 as novel AMPK substrates. / Ducommun, Serge; Deak, Maria; Zeigerer, Anja; Göransson, Olga; Seitz, Susanne; Collodet, Caterina; Madsen, Agnete Bjerregaard; Jensen, Thomas Elbenhardt; Viollet, Benoit; Foretz, Marc; Gut, Philipp; Sumpton, David; Sakamoto, Kei.
In: Cellular Signalling, Vol. 57, 2019, p. 45-57.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Chemical genetic screen identifies Gapex-5/GAPVD1 and STBD1 as novel AMPK substrates
AU - Ducommun, Serge
AU - Deak, Maria
AU - Zeigerer, Anja
AU - Göransson, Olga
AU - Seitz, Susanne
AU - Collodet, Caterina
AU - Madsen, Agnete Bjerregaard
AU - Jensen, Thomas Elbenhardt
AU - Viollet, Benoit
AU - Foretz, Marc
AU - Gut, Philipp
AU - Sumpton, David
AU - Sakamoto, Kei
N1 - CURIS 2019 NEXS 073 Copyright © 2019. Published by Elsevier Inc.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
KW - Faculty of Science
KW - GTPase activating protein and VPS9 domains 1
KW - Shokat
KW - Starch-binding domain 1
U2 - 10.1016/j.cellsig.2019.02.001
DO - 10.1016/j.cellsig.2019.02.001
M3 - Journal article
C2 - 30772465
VL - 57
SP - 45
EP - 57
JO - Cellular Signalling
JF - Cellular Signalling
SN - 0898-6568
ER -
ID: 213663914