Glycolytic Flux Signals to mTOR through Glyceraldehyde-3-Phosphate Dehydrogenase-Mediated Regulation of Rheb
Open Access
- 1 July 2009
- journal article
- research article
- Published by Taylor & Francis Ltd in Molecular and Cellular Biology
- Vol. 29 (14), 3991-4001
- https://doi.org/10.1128/mcb.00165-09
Abstract
The mammalian target of rapamycin (mTOR) interacts with raptor to form the protein complex mTORC1 (mTOR complex 1), which plays a central role in the regulation of cell growth in response to environmental cues. Given that glucose is a primary fuel source and a biosynthetic precursor, how mTORC1 signaling is coordinated with glucose metabolism has been an important question. Here, we found that the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) binds Rheb and inhibits mTORC1 signaling. Under low-glucose conditions, GAPDH prevents Rheb from binding to mTOR and thereby inhibits mTORC1 signaling. High glycolytic flux suppresses the interaction between GAPDH and Rheb and thus allows Rheb to activate mTORC1. Silencing of GAPDH or blocking of the Rheb-GAPDH interaction desensitizes mTORC1 signaling to changes in the level of glucose. The GAPDH-dependent regulation of mTORC1 in response to glucose availability occurred even in TSC1-deficient cells and AMPK-silenced cells, supporting the idea that the GAPDH-Rheb pathway functions independently of the AMPK axis. Furthermore, we show that glyceraldehyde-3-phosphate, a glycolytic intermediate that binds GAPDH, destabilizes the Rheb-GAPDH interaction even under low-glucose conditions, explaining how high-glucose flux suppresses the interaction and activates mTORC1 signaling. Taken together, our results suggest that the glycolytic flux regulates mTOR's access to Rheb by regulating the Rheb-GAPDH interaction, thereby allowing mTORC1 to coordinate cell growth with glucose availability.Keywords
This publication has 50 references indexed in Scilit:
- Reassessment of the role of FKBP38 in the Rheb/mTORC1 pathwayFEBS Letters, 2009
- Re-evaluating the Roles of Proposed Modulators of Mammalian Target of Rapamycin Complex 1 (mTORC1) SignalingOnline Journal of Public Health Informatics, 2008
- Tumorigenic activity and therapeutic inhibition of Rheb GTPaseGenes & Development, 2008
- AMPK Phosphorylation of Raptor Mediates a Metabolic CheckpointMolecular Cell, 2008
- Constitutive mTOR activation in TSC mutants sensitizes cells to energy starvation and genomic damage via p53The EMBO Journal, 2007
- Stress and mTORture signalingOncogene, 2006
- Complexity of the TOR signaling networkTrends in Cell Biology, 2006
- Biochemical and Functional Characterizations of Small GTPase Rheb and TSC2 GAP ActivityMolecular and Cellular Biology, 2004
- Rheb is a direct target of the tuberous sclerosis tumour suppressor proteinsNature, 2003
- TOR signalling in bugs, brain and brawnNature Reviews Molecular Cell Biology, 2003