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Cross-talks via mTORC2 can explain enhanced activation in response to insulin in diabetic patients
Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering.
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
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2017 (English)In: Bioscience Reports, ISSN 0144-8463, E-ISSN 1573-4935, Vol. 37, BSR20160514Article in journal (Refereed) Published
Abstract [en]

The molecular mechanisms of insulin resistance in Type 2 diabetes have been extensively studied in primary human adipocytes, and mathematical modelling has clarified the central role of attenuation of mammalian target of rapamycin (mTOR) complex 1 (mTORC1) activity in the diabetic state. Attenuation of mTORC1 in diabetes quells insulin-signalling network-wide, except for the mTOR in complex 2 (mTORC2)-catalysed phosphorylation of protein kinase B (PKB) at Ser(473) (PKB-S473P), which is increased. This unique increase could potentially be explained by feedback and interbranch cross-talk signals. To examine if such mechanisms operate in adipocytes, we herein analysed data from an unbiased phosphoproteomic screen in 3T3-L1 adipocytes. Using a mathematical modelling approach, we showed that a negative signal from mTORC1-p70 S6 kinase (S6K) to rictor-mTORC2 in combination with a positive signal from PKB to SIN1-mTORC2 are compatible with the experimental data. This combined cross-branch signalling predicted an increased PKB-S473P in response to attenuation of mTORC1 - a distinguishing feature of the insulin resistant state in human adipocytes. This aspect of insulin signalling was then verified for our comprehensive model of insulin signalling in human adipocytes. Introduction of the cross-branch signals was compatible with all data for insulin signalling in human adipocytes, and the resulting model can explain all data network-wide, including the increased PKB-S473P in the diabetic state. Our approach was to first identify potential mechanisms in data from a phosphoproteomic screen in a cell line, and then verify such mechanisms in primary human cells, which demonstrates how an unbiased approach can support a direct knowledge-based study.

Place, publisher, year, edition, pages
PORTLAND PRESS LTD , 2017. Vol. 37, BSR20160514
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Cell Biology
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URN: urn:nbn:se:liu:diva-136056DOI: 10.1042/BSR20160514ISI: 000395096100021PubMedID: 27986865OAI: oai:DiVA.org:liu-136056DiVA: diva2:1084842
Note

Funding Agencies|Swedish Research Council [K2014-55X-12157-18-5]; Linkoping Initiative in Life Science Technologies; CENIIT [15.09]

Available from: 2017-03-27 Created: 2017-03-27 Last updated: 2017-04-14

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Magnusson, RasmusGustafsson, MikaCedersund, GunnarStrålfors, PeterNyman, Elin
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