Journal article

Metformin, Independent of AMPK, Inhibits mTORC1 in a Rag GTPase-Dependent Manner

Adem Kalender, Anand Selvaraj, So Young Kim, Pawan Gulati, Sophie Brule, Benoit Viollet, Bruce E Kemp, Nabeel Bardeesy, Patrick Dennis, John J Schlager, Andre Marette, Sara C Kozma, George Thomas

CELL METABOLISM | CELL PRESS | Published : 2010

Abstract

Dysfunctional mTORC1 signaling is associated with a number of human pathologies owing to its central role in controlling cell growth, proliferation, and metabolism. Regulation of mTORC1 is achieved by the integration of multiple inputs, including those of mitogens, nutrients, and energy. It is thought that agents that increase the cellular AMP/ATP ratio, such as the antidiabetic biguanides metformin and phenformin, inhibit mTORC1 through AMPK activation of TSC1/2-dependent or -independent mechanisms. Unexpectedly, we found that biguanides inhibit mTORC1 signaling, not only in the absence of TSC1/2 but also in the absence of AMPK. Consistent with these observations, in two distinct preclinica..

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University of Melbourne Researchers

Grants

Awarded by Association Nationale de la Recherche


Awarded by European Commission


Awarded by National Institutes of Health (NIH)


Awarded by NIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)


Awarded by NATIONAL CANCER INSTITUTE


Awarded by NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES


Funding Acknowledgements

We are indebted to all members of the Kozma/Thomas laboratory for discussions and critical reading of the manuscript. We also thank M. Daston and G. Doerman for editing the manuscript and computer graphics, respectively. We thank Birgit Ehmer for assistance in microscopy, D. Pan for the Drosophila TSC1 antibody, and the D. Sabatini laboratory for RagB constructs and useful discussions. A.K. was supported by the Krebsliga, Basel. A.K. and A.S/are supported by appointments to the Research Participation Program at the Air Force Research Laboratory, Human Effectiveness Directorate, Bioscience and Protection, Wright Patterson Air Force Base administered by the Oak Ridge Institute for Science and Education. B.V. is supported by funding from the Association Nationale de la Recherche (Muscle bioenergetics R06428KS), Association de Langue Francaise pour l'Etude du Diabete et des Maladies Metaboliques and by the EXGENESIS Integrated Project (LSHM-CT-2004-005272) funded by the European Commission. B.E.K. is supported by the National Health and Medical Research Council (NHMRC) of Australia and the Australian Research Council (ARC). A.M. is supported by a grant from the Canadian Institutes of Health Research (CIHR). G.T. and S.C.K. are supported by the National Institutes of Health (NIH) Mouse Models for Human Cancer Consortium, U01 CA141464, and NIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grants DK73802 and DK078019. G.T. is supported by the Strauss Chair in Cancer Research.