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PMID: 12869586 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling.

Genes & development ·Vol. 17 ·No. 15 ·2003-08-01 ·Pages 1829-34

Inoki K, Li Y, Xu T, Guan KL

Abstract

Tuberous sclerosis complex (TSC) is a genetic disease caused by mutation in either TSC1 or TSC2. The TSC1 and TSC2 gene products form a functional complex and inhibit phosphorylation of S6K and 4EBP1. These functions of TSC1/TSC2 are likely mediated by mTOR. Here we report that TSC2 is a GTPase-activating protein (GAP) toward Rheb, a Ras family GTPase. Rheb stimulates phosphorylation of S6K and 4EBP1. This function of Rheb is blocked by rapamycin and dominant-negative mTOR. Rheb stimulates the phosphorylation of mTOR and plays an essential role in regulation of S6K and 4EBP1 in response to nutrients and cellular energy status. Our data demonstrate that Rheb acts downstream of TSC1/TSC2 and upstream of mTOR to regulate cell growth.

MeSH Terms
Antibiotics, Antineoplastic/pharmacology Cell Division Cell Line Dose-Response Relationship, Drug GTP Phosphohydrolases/metabolism Genes, Dominant Guanosine Triphosphate/metabolism Humans Hydrolysis Models, Biological Monomeric GTP-Binding Proteins/metabolism,physiology Mutation Neuropeptides/metabolism,physiology Phosphorylation Plasmids/metabolism Protein Binding Protein Biosynthesis Protein Kinases/metabolism Protein Structure, Tertiary Proteins/metabolism Ras Homolog Enriched in Brain Protein Repressor Proteins/metabolism Ribosomal Protein S6 Kinases, 70-kDa/metabolism Signal Transduction Sirolimus/pharmacology TOR Serine-Threonine Kinases Time Factors Tuberous Sclerosis Complex 1 Protein Tuberous Sclerosis Complex 2 Protein Tumor Suppressor Proteins
Chemicals
Antibiotics, Antineoplastic Neuropeptides Proteins RHEB protein, human Ras Homolog Enriched in Brain Protein Repressor Proteins TSC1 protein, human TSC2 protein, human Tuberous Sclerosis Complex 1 Protein Tuberous Sclerosis Complex 2 Protein Tumor Suppressor Proteins Guanosine Triphosphate Protein Kinases MTOR protein, human Ribosomal Protein S6 Kinases, 70-kDa TOR Serine-Threonine Kinases ribosomal protein S6 kinase, 70kD, polypeptide 2 GTP Phosphohydrolases Monomeric GTP-Binding Proteins Sirolimus
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Inoki Ken
Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Li Yong
Xu Tian
Guan Kun-Liang
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34 references, click to expand
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Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
0890-9369
DOI
10.1101/gad.1110003
Published
2003-08-01
Epub
2003-00-17
Pages
1829-34
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC196227
Subset
IM
External Links
PubMed source DOI: 10.1101/gad.1110003 PMC Full Text View journal details
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