Metformin, Independent of AMPK, Inhibits mTORC1 In a Rag GTPase-Dependent Manner
By Adem Kalender, A. Selvaraj, S. Kim, P. Gulati, Sophie Br lé, B. Viollet, Bruce E. Kemp, N. Bardeesy, P. Dennis, John J. Schlager and 3 more. Cell Metabolism, 2010
894 citations recorded by the source corpus.
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 anti-diabetic 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 pre-clinical models of cancer and diabetes, metformin acts to suppress mTORC1 signaling in an AMPK-independent manner. We found that the ability of biguanides to inhibit mTORC1 activation and signaling is, instead, dependent on the Rag GTPases.
Subfields: Molecular Biology, Surgery
View Paper: https://www.semanticscholar.org/paper/4ba4f419f2bb0a7276afd0c645d5247669a4d238
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Citations in the corpus
- mTOR Signaling in Growth, Metabolism, and Disease. (2017, background): “Interestingly, glucose deprivation also inhibits mTORC1 in cells lacking AMPK, through inhibition of the Rag GTPases, suggesting that mTORC1 senses glucose through more than one mechanism (Efeyan et al., 2013; Kalender et al., 2010).”
- Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease (2023, background): “43,44 Hypoxia or oxygen deprivation stress was reported to produce an inhibitory effect on the mTORC1 through activation of AMPK, and induction of REDD1 that resulted in the activation of TSC.”
- Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress (2010, background): “Directly downstream of mTORC1 are numerous proteins that are required for the execution of the autophagic program, including the serine/threonine kinase Atg1/ULK, which plays a key role in the formation of the preautophagosome (Kamada et al., 2000).”