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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 LU ; Seitz, Susanne; Collodet, Caterina; Madsen, Agnete B.; Jensen, Thomas E.; Viollet, Benoit and Foretz, Marc, et al. (2019) In Cellular Signalling 57. p.45-57
Abstract

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... (More)

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.

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publication status
published
subject
keywords
GTPase activating protein and VPS9 domains 1, Shokat, Starch-binding domain 1
in
Cellular Signalling
volume
57
pages
13 pages
publisher
Elsevier
external identifiers
  • scopus:85061782847
ISSN
0898-6568
DOI
10.1016/j.cellsig.2019.02.001
language
English
LU publication?
yes
id
7338f3d3-1b26-4e49-b7c4-2a6f1953b560
date added to LUP
2019-03-01 11:02:16
date last changed
2019-09-11 04:13:08
@article{7338f3d3-1b26-4e49-b7c4-2a6f1953b560,
  abstract     = {<p>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.</p>},
  author       = {Ducommun, Serge and Deak, Maria and Zeigerer, Anja and Göransson, Olga and Seitz, Susanne and Collodet, Caterina and Madsen, Agnete B. and Jensen, Thomas E. and Viollet, Benoit and Foretz, Marc and Gut, Philipp and Sumpton, David and Sakamoto, Kei},
  issn         = {0898-6568},
  keyword      = {GTPase activating protein and VPS9 domains 1,Shokat,Starch-binding domain 1},
  language     = {eng},
  pages        = {45--57},
  publisher    = {Elsevier},
  series       = {Cellular Signalling},
  title        = {Chemical genetic screen identifies Gapex-5/GAPVD1 and STBD1 as novel AMPK substrates},
  url          = {http://dx.doi.org/10.1016/j.cellsig.2019.02.001},
  volume       = {57},
  year         = {2019},
}