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Molecular and Cellular Biology, July 2009, p. 3991-4001, Vol. 29, No. 14
0270-7306/09/$08.00+0     doi:10.1128/MCB.00165-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Glycolytic Flux Signals to mTOR through Glyceraldehyde-3-Phosphate Dehydrogenase-Mediated Regulation of Rheb{triangledown}

Mi Nam Lee,1 Sang Hoon Ha,1 Jaeyoon Kim,1 Ara Koh,1 Chang Sup Lee,1 Jung Hwan Kim,1 Hyeona Jeon,1 Do-Hyung Kim,2 Pann-Ghill Suh,1 and Sung Ho Ryu1*

Division of Molecular and Life Sciences, POSTECH, Pohang, 790-784, South Korea,1 Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, 6-155 Jackson Hall, 321 Church Street SE, Minneapolis, Minnesota 554552

Received 5 February 2009/ Returned for modification 20 March 2009/ Accepted 6 May 2009

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.

* Corresponding author. Mailing address: Division of Molecular and Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Kyungbook 790-784, South Korea. Phone: 82-54-279-2292. Fax: 82-54-279-0645. E-mail: sungho{at}postech.ac.kr

{triangledown} Published ahead of print on 18 May 2009.

Molecular and Cellular Biology, July 2009, p. 3991-4001, Vol. 29, No. 14
0270-7306/09/$08.00+0     doi:10.1128/MCB.00165-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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