PMID- 22452783
OWN - NLM
STAT- MEDLINE
DCOM- 20121119
LR  - 20211203
IS  - 1742-4658 (Electronic)
IS  - 1742-464X (Linking)
VI  - 279
IP  - 18
DP  - 2012 Sep
TI  - A modelling-experimental approach reveals insulin receptor substrate 
      (IRS)-dependent regulation of adenosine monosphosphate-dependent kinase (AMPK) by 
      insulin.
PG  - 3314-28
LID - 10.1111/j.1742-4658.2012.08582.x [doi]
AB  - Mammalian target of rapamycin (mTOR) kinase responds to growth factors, nutrients 
      and cellular energy status and is a central controller of cellular growth. mTOR 
      exists in two multiprotein complexes that are embedded into a complex signalling 
      network. Adenosine monophosphate-dependent kinase (AMPK) is activated by energy 
      deprivation and shuts off adenosine 5'-triphosphate (ATP)-consuming anabolic 
      processes, in part via the inactivation of mTORC1. Surprisingly, we observed that 
      AMPK not only responds to energy deprivation but can also be activated by 
      insulin, and is further induced in mTORC1-deficient cells. We have recently 
      modelled the mTOR network, covering both mTOR complexes and their insulin and 
      nutrient inputs. In the present study we extended the network by an AMPK module 
      to generate the to date most comprehensive data-driven dynamic AMPK-mTOR network 
      model. In order to define the intersection via which AMPK is activated by the 
      insulin network, we compared simulations for six different hypothetical model 
      structures to our observed AMPK dynamics. Hypotheses ranking suggested that the 
      most probable intersection between insulin and AMPK was the insulin receptor 
      substrate (IRS) and that the effects of canonical IRS downstream cues on AMPK 
      would be mediated via an mTORC1-driven negative-feedback loop. We tested these 
      predictions experimentally in multiple set-ups, where we inhibited or induced 
      players along the insulin-mTORC1 signalling axis and observed AMPK induction or 
      inhibition. We confirmed the identified model and therefore report a novel 
      connection within the insulin-mTOR-AMPK network: we conclude that AMPK is 
      positively regulated by IRS and can be inhibited via the negative-feedback loop.
CI  - (c) 2012 The Authors Journal compilation (c) 2012 FEBS.
FAU - Sonntag, Annika G
AU  - Sonntag AG
AD  - Bioinformatics and Molecular Genetics (Faculty of Biology), Institute for Biology 
      3, Albert-Ludwigs-Universitat Freiburg, Germany.
FAU - Dalle Pezze, Piero
AU  - Dalle Pezze P
FAU - Shanley, Daryl P
AU  - Shanley DP
FAU - Thedieck, Kathrin
AU  - Thedieck K
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120503
PL  - England
TA  - FEBS J
JT  - The FEBS journal
JID - 101229646
RN  - 0 (Amino Acids)
RN  - 0 (Insulin)
RN  - 0 (Insulin Receptor Substrate Proteins)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Proteins)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
SB  - IM
MH  - AMP-Activated Protein Kinases/*metabolism
MH  - Amino Acids/pharmacology
MH  - Computer Simulation
MH  - HeLa Cells
MH  - Humans
MH  - Insulin/pharmacology/*physiology
MH  - Insulin Receptor Substrate Proteins/*metabolism
MH  - Kinetics
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Models, Biological
MH  - Multiprotein Complexes
MH  - Proteins
MH  - TOR Serine-Threonine Kinases
EDAT- 2012/03/29 06:00
MHDA- 2012/12/10 06:00
CRDT- 2012/03/29 06:00
PHST- 2012/03/29 06:00 [entrez]
PHST- 2012/03/29 06:00 [pubmed]
PHST- 2012/12/10 06:00 [medline]
AID - 10.1111/j.1742-4658.2012.08582.x [doi]
PST - ppublish
SO  - FEBS J. 2012 Sep;279(18):3314-28. doi: 10.1111/j.1742-4658.2012.08582.x. Epub 
      2012 May 3.