Rheb activates mTOR by antagonizing its endogenous inhibitor, FKBP38.
The mammalian target of rapamycin, mTOR, is a central regulator of cell growth. Its activity is regulated by Rheb, a Ras-like small guanosine triphosphatase (GTPase), in response to growth factor stimulation and nutrient availability. We show that Rheb regulates mTOR through FKBP38, a member of the FK506-binding protein (FKBP) family that is structurally related to FKBP12. FKBP38 binds to mTOR and inhibits its activity in a manner similar to that of the FKBP12-rapamycin complex. Rheb interacts directly with FKBP38 and prevents its association with mTOR in a guanosine 5'-triphosphate (GTP)-dependent manner. Our findings suggest that FKBP38 is an endogenous inhibitor of mTOR, whose inhibitory activity is antagonized by Rheb in response to growth factor stimulation and nutrient availability.
Bai
Xiaochun
X
Department of Pharmacology, University of Pittsburgh School of Medicine, E1357 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15213, USA.
Ma
Dongzhu
D
Liu
Anling
A
Shen
Xiaoyun
X
Wang
Qiming J
QJ
Liu
Yongjian
Y
Jiang
Yu
Y
D000596:Amino Acids / Q000378:metabolism; D002460:Cell Line; D003470:Culture Media; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism*; D046912:Multiprotein Complexes; D050505:Mutant Proteins / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011506:Proteins; D000076205:Ras Homolog Enriched in Brain Protein; D011994:Recombinant Proteins / Q000378:metabolism; D044967:Serum; D015398:Signal Transduction; D020123:Sirolimus / Q000378:metabolism / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D022021:Tacrolimus Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
D000596:Amino Acids; D003470:Culture Media; C471205:FKBP8 protein, human; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D050505:Mutant Proteins; D009479:Neuropeptides; D011506:Proteins; C490211:RHEB protein, human; D000076205:Ras Homolog Enriched in Brain Protein; D011994:Recombinant Proteins; D014157:Transcription Factors; D006160:Guanosine Triphosphate; D011494:Protein Kinases; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020559:Monomeric GTP-Binding Proteins; D022021:Tacrolimus Binding Proteins; D020123:Sirolimus