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A modelling-experimental approach reveals insulin receptor substrate (IRS)-dependent regulation of adenosine monosphosphate-dependent kinase (AMPK) by insulin

Lookup NU author(s): Dr Daryl Shanley


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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.

Publication metadata

Author(s): Sonntag AG, Pezze PD, Shanley DP, Thedieck K

Publication type: Article

Publication status: Published

Journal: FEBS Journal

Year: 2012

Volume: 279

Issue: 18

Pages: 3314-3328

Print publication date: 03/05/2012

ISSN (print): 1742-464X

ISSN (electronic): 1742-4658

Publisher: Wiley-Blackwell


DOI: 10.1111/j.1742-4658.2012.08582.x


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Funder referenceFunder name
031 5896ABMBF Gerontosys II - NephAge
EXC 294Excellence Initiative of the German State Government
EXC 294Excellence Initiative of the German Federal Government
LSHG-CT-2007-036894EC 6th FP NoE LifeSpan