Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Rheb Activates mTOR by Antagonizing Its Endogenous Inhibitor, FKBP38
Xiaochun Bai,1,3Dongzhu Ma,1Anling Liu,1Xiaoyun Shen,1Qiming J. Wang,1Yongjian Liu,2Yu Jiang1*
The mammalian target of rapamycin, mTOR, is a central regulatorof cell growth. Its activity is regulated by Rheb, a Ras-likesmall guanosine triphosphatase (GTPase), in response to growthfactor stimulation and nutrient availability. We show that Rhebregulates mTOR through FKBP38, a member of the FK506-bindingprotein (FKBP) family that is structurally related to FKBP12.FKBP38 binds to mTOR and inhibits its activity in a manner similarto that of the FKBP12-rapamycin complex. Rheb interacts directlywith FKBP38 and prevents its association with mTOR in a guanosine5'-triphosphate (GTP)–dependent manner. Our findings suggestthat FKBP38 is an endogenous inhibitor of mTOR, whose inhibitoryactivity is antagonized by Rheb in response to growth factorstimulation and nutrient availability.
1 Department of Pharmacology, University of Pittsburgh School of Medicine, E1357 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15213, USA. 2 Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. 3 Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, China.
* To whom correspondence should be addressed. E-mail: jiang{at}server.pharm.pitt.edu
The editors suggest the following Related Resources on Science sites:
In Science Magazine
PERSPECTIVES
Christopher G. Proud (9 November 2007) Science318 (5852), 926.
[DOI: 10.1126/science.1150653] |Summary »|Full Text »|PDF »
In Science Signaling
EDITORS' CHOICE
L. Bryan Ray (13 November 2007) Sci. STKE2007 (412), tw418.
[DOI: 10.1126/stke.4122007tw418] |Abstract »
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Site-Specific mTOR Phosphorylation Promotes mTORC1-Mediated Signaling and Cell Growth.
H. A. Acosta-Jaquez, J. A. Keller, K. G. Foster, B. Ekim, G. A. Soliman, E. P. Feener, B. A. Ballif, and D. C. Fingar (2009)
Mol. Cell. Biol.
29, 4308-4324
|Abstract »|Full Text »|PDF »
Glycolytic Flux Signals to mTOR through Glyceraldehyde-3-Phosphate Dehydrogenase-Mediated Regulation of Rheb.
M. N. Lee, S. H. Ha, J. Kim, A. Koh, C. S. Lee, J. H. Kim, H. Jeon, D.-H. Kim, P.-G. Suh, and S. H. Ryu (2009)
Mol. Cell. Biol.
29, 3991-4001
|Abstract »|Full Text »|PDF »
Upregulation of the Mammalian Target of Rapamycin Complex 1 Pathway by Ras Homolog Enriched in Brain in Pancreatic {beta}-Cells Leads to Increased {beta}-Cell Mass and Prevention of Hyperglycemia.
S. Hamada, K. Hara, T. Hamada, H. Yasuda, H. Moriyama, R. Nakayama, M. Nagata, and K. Yokono (2009)
Diabetes
58, 1321-1332
|Abstract »|Full Text »|PDF »
Specific Activation of mTORC1 by Rheb G-protein in Vitro Involves Enhanced Recruitment of Its Substrate Protein.
T. Sato, A. Nakashima, L. Guo, and F. Tamanoi (2009)
J. Biol. Chem.
284, 12783-12791
|Abstract »|Full Text »|PDF »
Atg5 Regulates Phenethyl Isothiocyanate-Induced Autophagic and Apoptotic Cell Death in Human Prostate Cancer Cells.
A. Bommareddy, E.-R. Hahm, D. Xiao, A. A. Powolny, A. L. Fisher, Y. Jiang, and S. V. Singh (2009)
Cancer Res.
69, 3704-3712
|Abstract »|Full Text »|PDF »
Amino acid regulation of TOR complex 1.
J. Avruch, X. Long, S. Ortiz-Vega, J. Rapley, A. Papageorgiou, and N. Dai (2009)
Am J Physiol Endocrinol Metab
296, E592-E602
|Abstract »|Full Text »|PDF »
The TSC-mTOR Pathway Mediates Translational Activation of TOP mRNAs by Insulin Largely in a Raptor- or Rictor-Independent Manner.
I. Patursky-Polischuk, M. Stolovich-Rain, M. Hausner-Hanochi, J. Kasir, N. Cybulski, J. Avruch, M. A. Ruegg, M. N. Hall, and O. Meyuhas (2009)
Mol. Cell. Biol.
29, 640-649
|Abstract »|Full Text »|PDF »
The Rheb-mTOR Pathway Is Upregulated in Reactive Astrocytes of the Injured Spinal Cord.
S. Codeluppi, C. I. Svensson, M. P. Hefferan, F. Valencia, M. D. Silldorff, M. Oshiro, M. Marsala, and E. B. Pasquale (2009)
J. Neurosci.
29, 1093-1104
|Abstract »|Full Text »|PDF »
Making synaptic plasticity and memory last: mechanisms of translational regulation.
RalA Functions as an Indispensable Signal Mediator for the Nutrient-sensing System.
T. Maehama, M. Tanaka, H. Nishina, M. Murakami, Y. Kanaho, and K. Hanada (2008)
J. Biol. Chem.
283, 35053-35059
|Abstract »|Full Text »|PDF »
Characterization of TCTP, the Translationally Controlled Tumor Protein, from Arabidopsis thaliana.
O. Berkowitz, R. Jost, S. Pollmann, and J. Masle (2008)
PLANT CELL
20, 3430-3447
|Abstract »|Full Text »|PDF »
Isolation of Hyperactive Mutants of Mammalian Target of Rapamycin.
Y. Ohne, T. Takahara, R. Hatakeyama, T. Matsuzaki, M. Noda, N. Mizushima, and T. Maeda (2008)
J. Biol. Chem.
283, 31861-31870
|Abstract »|Full Text »|PDF »
Re-evaluating the Roles of Proposed Modulators of Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling.
X. Wang, B. D. Fonseca, H. Tang, R. Liu, A. Elia, M. J. Clemens, U.-A. Bommer, and C. G. Proud (2008)
J. Biol. Chem.
283, 30482-30492
|Abstract »|Full Text »|PDF »
AMP-activated Protein Kinase Contributes to UV- and H2O2-induced Apoptosis in Human Skin Keratinocytes.
C. Cao, S. Lu, R. Kivlin, B. Wallin, E. Card, A. Bagdasarian, T. Tamakloe, W.-m. Chu, K.-l. Guan, and Y. Wan (2008)
J. Biol. Chem.
283, 28897-28908
|Abstract »|Full Text »|PDF »
Cytoplasmic and nuclear distribution of the protein complexes mTORC1 and mTORC2: rapamycin triggers dephosphorylation and delocalization of the mTORC2 components rictor and sin1.
The Switch I Region of Rheb Is Critical for Its Interaction with FKBP38.
D. Ma, X. Bai, S. Guo, and Y. Jiang (2008)
J. Biol. Chem.
283, 25963-25970
|Abstract »|Full Text »|PDF »
Aberrant Rheb-mediated mTORC1 activation and Pten haploinsufficiency are cooperative oncogenic events.
C. Nardella, Z. Chen, L. Salmena, A. Carracedo, A. Alimonti, A. Egia, B. Carver, W. Gerald, C. Cordon-Cardo, and P. P. Pandolfi (2008)
Genes & Dev.
22, 2172-2177
|Abstract »|Full Text »|PDF »
HER3 Is a Determinant for Poor Prognosis in Melanoma.
M. Reschke, D. Mihic-Probst, E. H. van der Horst, P. Knyazev, P. J. Wild, M. Hutterer, S. Meyer, R. Dummer, H. Moch, and A. Ullrich (2008)
Clin. Cancer Res.
14, 5188-5197
|Abstract »|Full Text »|PDF »
Phospholipase D1 is an effector of Rheb in the mTOR pathway.
Y. Sun, Y. Fang, M.-S. Yoon, C. Zhang, M. Roccio, F. J. Zwartkruis, M. Armstrong, H. A. Brown, and J. Chen (2008)
PNAS
105, 8286-8291
|Abstract »|Full Text »|PDF »
Regulation of apoptosis and neurite extension by FKBP38 is required for neural tube formation in the mouse..
M. Shirane, M. Ogawa, J. Motoyama, and K. I. Nakayama (2008)
Genes Cells
13, 635-651
|Abstract »|Full Text »|PDF »
Mammalian target of rapamycin inhibition as a therapeutic strategy in the management of urologic malignancies.