Gene interactions and pathways from curated databases and text-mining
J Biol Chem 2007, PMID: 17510057

PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding.

Wang, Lifu; Harris, Thurl E; Roth, Richard A; Lawrence, John C

Mammalian target of rapamycin (mTOR) functions in two distinct signaling complexes, mTORC1 and mTORC2. In response to insulin and nutrients, mTORC1, consisting of mTOR, raptor (regulatory-associated protein of mTOR), and mLST8, is activated and phosphorylates eukaryotic initiation factor 4E-binding protein (4EBP) and p70 S6 kinase to promote protein synthesis and cell size. Previously we found that activation of mTOR kinase in response to insulin was associated with increased 4EBP1 binding to raptor. Here we identify prolinerich Akt substrate 40 (PRAS40) as a binding partner for mTORC1. A putative TOR signaling motif, FVMDE, is identified in PRAS40 and shown to be required for interaction with raptor. Insulin stimulation markedly decreases the level of PRAS40 bound by mTORC1. Recombinant PRAS40 inhibits mTORC1 kinase activity in vivo and in vitro, and this inhibition depends on PRAS40 association with raptor. Furthermore, decreasing PRAS40 expression by short hairpin RNA enhances 4E-BP1 binding to raptor, and recombinant PRAS40 competes with 4E-BP1 binding to raptor. We, therefore, propose that PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding.

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Text Mining Data

mTORC1 → insulin: " In response to insulin and nutrients, mTORC1 , consisting of mTOR, raptor ( regulatory associated protein of mTOR ), and mLST8, is activated and phosphorylates eukaryotic initiation factor 4E-binding protein ( 4EBP ) and p70 S6 kinase to promote protein synthesis and cell size "

p70 → insulin: " In response to insulin and nutrients, mTORC1, consisting of mTOR, raptor ( regulatory associated protein of mTOR ), and mLST8, is activated and phosphorylates eukaryotic initiation factor 4E-binding protein ( 4EBP ) and p70 S6 kinase to promote protein synthesis and cell size "

Manually curated Databases

  • 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, 26 gene pairs are associated to this article in curated databases