title: Rheb activates mTOR by antagonizing its endogenous inhibitor, FKBP38.
abstract: 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.
authors.affiliation: Department of Pharmacology, University of Pittsburgh School of Medicine, E1357 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15213, USA.
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Bai
authors.forename: Dongzhu
authors.initials: D
authors.lastname: Ma
authors.forename: Anling
authors.initials: A
authors.lastname: Liu
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Shen
authors.forename: Qiming J
authors.initials: QJ
authors.lastname: Wang
authors.forename: Yongjian
authors.initials: Y
authors.lastname: Liu
authors.forename: Yu
authors.initials: Y
authors.lastname: Jiang
mesh_terms: 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
chemical_list: 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