Gene interactions and pathways from curated databases and text-mining
Mol Cell 2003, PMID: 12820960

Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2.

Garami, Attila; Zwartkruis, Fried J T; Nobukuni, Takahiro; Joaquin, Manel; Roccio, Marta; Stocker, Hugo; Kozma, Sara C; Hafen, Ernst; Bos, Johannes L; Thomas, George

Tumor suppressor genes evolved as negative effectors of mitogen and nutrient signaling pathways, such that mutations in these genes can lead to pathological states of growth. Tuberous sclerosis (TSC) is a potentially devastating disease associated with mutations in two tumor suppressor genes, TSC1 and 2, that function as a complex to suppress signaling in the mTOR/S6K/4E-BP pathway. However, the inhibitory target of TSC1/2 and the mechanism by which it acts are unknown. Here we provide evidence that TSC1/2 is a GAP for the small GTPase Rheb and that insulin-mediated Rheb activation is PI3K dependent. Moreover, Rheb overexpression induces S6K1 phosphorylation and inhibits PKB phosphorylation, as do loss-of-function mutations in TSC1/2, but contrary to earlier reports Rheb has no effect on MAPK phosphorylation. Finally, coexpression of a human TSC2 cDNA harboring a disease-associated point mutation in the GAP domain, failed to stimulate Rheb GTPase activity or block Rheb activation of S6K1.

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Text Mining Data

Rheb ⊣ TSC1: " Insulin activation of Rheb , a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2 "

Insulin ⊣ TSC1: " Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2 "

Insulin → Rheb: " Insulin activation of Rheb , a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2 "

Rheb → insulin: " Here we provide evidence that TSC1/2 is a GAP for the small GTPase Rheb and that insulin mediated Rheb activation is PI3K dependent "

Rheb — PI3K: " Here we provide evidence that TSC1/2 is a GAP for the small GTPase Rheb and that insulin mediated Rheb activation is PI3K dependent "

TSC1/2 — PI3K: " Here we provide evidence that TSC1/2 is a GAP for the small GTPase Rheb and that insulin mediated Rheb activation is PI3K dependent "

S6K1 ⊣ PKB: " Moreover, Rheb overexpression induces S6K1 phosphorylation and inhibits PKB phosphorylation, as do loss-of-function mutations in TSC1/2, but contrary to earlier reports Rheb has no effect on MAPK phosphorylation "

PKB ⊣ Rheb: " Moreover, Rheb overexpression induces S6K1 phosphorylation and inhibits PKB phosphorylation, as do loss-of-function mutations in TSC1/2, but contrary to earlier reports Rheb has no effect on MAPK phosphorylation "

Rheb → S6K1: " Moreover, Rheb overexpression induces S6K1 phosphorylation and inhibits PKB phosphorylation, as do loss-of-function mutations in TSC1/2, but contrary to earlier reports Rheb has no effect on MAPK phosphorylation "

MAPK → PKB: " Moreover, Rheb overexpression induces S6K1 phosphorylation and inhibits PKB phosphorylation, as do loss-of-function mutations in TSC1/2, but contrary to earlier reports Rheb has no effect on MAPK phosphorylation "

Rheb → S6K1: " Finally, coexpression of a human TSC2 cDNA harboring a disease associated point mutation in the GAP domain, failed to stimulate Rheb GTPase activity or block Rheb activation of S6K1 "

Manually curated Databases

  • OpenBEL Selventa BEL large corpus: RHEB (increases, Activity, RHEB Activity)
    Evidence: insulin-mediated Rheb activation is PI3K dependent
  • IRef Biogrid Interaction: RHEB — TSC2 (direct interaction, enzymatic study)
  • IRef Biogrid Interaction: RHEB — TSC1 (direct interaction, enzymatic study)
  • NCI Pathway Database mTOR signaling pathway: TSC1 (TSC1) → TSC2 (TSC2) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database mTOR signaling pathway: TSC1 (TSC1) → TSC1/TSC2 complex (TSC1-TSC2) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database mTOR signaling pathway: TSC2 (TSC2) → TSC1/TSC2 complex (TSC1-TSC2) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database mTOR signaling pathway: AKT1 (AKT1) → TSC1/TSC2 complex (TSC1-TSC2) (modification, activates)
    Evidence: mutant phenotype, assay, physical interaction
  • 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
In total, 34 gene pairs are associated to this article in curated databases