Gene interactions and pathways from curated databases and text-mining
Genes Dev 2003, PMID: 12869586

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

Inoki, Ken; Li, Yong; Xu, Tian; Guan, Kun-Liang

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.

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Text Mining Data

TSC1/TSC2 → mTOR: " These functions of TSC1/TSC2 are likely mediated by mTOR "

TSC1/TSC2 → mTOR: " These functions of TSC1/TSC2 are likely mediated by mTOR "

4EBP1 → Rheb: " Rheb stimulates phosphorylation of S6K and 4EBP1 "

mTOR → Rheb: " 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 "

4EBP1 — Rheb: " 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 "

Manually curated Databases

  • IRef Biogrid Interaction: RHEB — TSC2 (direct interaction, enzymatic study)
  • IRef Hprd Interaction: TSC1 — TSC2 (in vitro)
  • IRef Hprd Interaction: TSC1 — TSC2 (in vivo)
  • IRef Hprd Interaction: TSC1 — TSC2 (two hybrid)
  • NCI Pathway Database mTOR signaling pathway: RHEB/GTP complex (RHEB) → RHEB/GTP complex (RHEB) (modification, collaborate)
    Evidence: mutant phenotype, assay
  • NCI Pathway Database mTOR signaling pathway: RHEB/GTP complex (RHEB) → None (modification, collaborate)
    Evidence: mutant phenotype, assay
  • NCI Pathway Database mTOR signaling pathway: RHEB/GTP complex (RHEB) → TSC1/TSC2 complex (TSC1-TSC2) (modification, collaborate)
    Evidence: mutant phenotype, assay
  • NCI Pathway Database mTOR signaling pathway: RHEB/GTP complex (RHEB) → None (modification, collaborate)
    Evidence: mutant phenotype, assay
  • NCI Pathway Database mTOR signaling pathway: TSC1/TSC2 complex (TSC1-TSC2) → None (modification, activates)
    Evidence: mutant phenotype, assay
  • NCI Pathway Database mTOR signaling pathway: mTORC1 complex (MTOR-MLST8-RPTOR) → mTORC1/PRAS40/DEPTOR complex (MTOR-MLST8-AKT1S1-DEPTOR-RPTOR) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database mTOR signaling pathway: mTORC1 complex (MTOR-MLST8-RPTOR) → DEPTOR (DEPTOR) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database mTOR signaling pathway: mTORC1 complex (MTOR-MLST8-RPTOR) → PRAS40 (AKT1S1) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database mTOR signaling pathway: AKT1 (AKT1) → RHEB/GTP complex (RHEB) (modification, activates)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database mTOR signaling pathway: AKT1 (AKT1) → mTORC1/PRAS40/DEPTOR complex (MTOR-MLST8-AKT1S1-DEPTOR-RPTOR) (modification, activates)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database mTOR signaling pathway: AKT1 (AKT1) → DEPTOR (DEPTOR) (modification, activates)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database mTOR signaling pathway: AKT1 (AKT1) → PRAS40 (AKT1S1) (modification, activates)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database mTOR signaling pathway: RHEB/GTP complex (RHEB) → mTORC1/PRAS40/DEPTOR complex (MTOR-MLST8-AKT1S1-DEPTOR-RPTOR) (modification, activates)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database mTOR signaling pathway: RHEB/GTP complex (RHEB) → DEPTOR (DEPTOR) (modification, activates)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database mTOR signaling pathway: RHEB/GTP complex (RHEB) → PRAS40 (AKT1S1) (modification, activates)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database mTOR signaling pathway: mTORC1/PRAS40/DEPTOR complex (MTOR-MLST8-AKT1S1-DEPTOR-RPTOR) → DEPTOR (DEPTOR) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database mTOR signaling pathway: mTORC1/PRAS40/DEPTOR complex (MTOR-MLST8-AKT1S1-DEPTOR-RPTOR) → PRAS40 (AKT1S1) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database mTOR signaling pathway: DEPTOR (DEPTOR) → PRAS40 (AKT1S1) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • Reactome Reaction: RHEB → TSC1 (reaction)
  • Reactome Reaction: RHEB → TSC2 (reaction)
In total, 30 gene pairs are associated to this article in curated databases