Gene interactions and pathways from curated databases and text-mining
Mol Cell 2008, PMID: 18439900

AMPK phosphorylation of raptor mediates a metabolic checkpoint.

Gwinn, Dana M; Shackelford, David B; Egan, Daniel F; Mihaylova, Maria M; Mery, Annabelle; Vasquez, Debbie S; Turk, Benjamin E; Shaw, Reuben J

AMPK is a highly conserved sensor of cellular energy status that is activated under conditions of low intracellular ATP. AMPK responds to energy stress by suppressing cell growth and biosynthetic processes, in part through its inhibition of the rapamycin-sensitive mTOR (mTORC1) pathway. AMPK phosphorylation of the TSC2 tumor suppressor contributes to suppression of mTORC1; however, TSC2-deficient cells remain responsive to energy stress. Using a proteomic and bioinformatics approach, we sought to identify additional substrates of AMPK that mediate its effects on growth control. We report here that AMPK directly phosphorylates the mTOR binding partner raptor on two well-conserved serine residues, and this phosphorylation induces 14-3-3 binding to raptor. The phosphorylation of raptor by AMPK is required for the inhibition of mTORC1 and cell-cycle arrest induced by energy stress. These findings uncover a conserved effector of AMPK that mediates its role as a metabolic checkpoint coordinating cell growth with energy status.

Document information provided by NCBI PubMed

Text Mining Data

mTORC1 ⊣ AMPK: " AMPK phosphorylation of the TSC2 tumor suppressor contributes to suppression of mTORC1 ; however, TSC2-deficient cells remain responsive to energy stress "

mTORC1 ⊣ raptor: " The phosphorylation of raptor by AMPK is required for the inhibition of mTORC1 and cell-cycle arrest induced by energy stress "

Manually curated Databases

  • IRef Biogrid Interaction: YWHAQ — RPTOR (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: PRKAA2 — RPTOR (direct interaction, enzymatic study)
  • IRef Biogrid Interaction: PRKAA1 — RPTOR (direct interaction, enzymatic study)
  • NCI Pathway Database LKB1 signaling events: 14-3-3 family (YWHAH/YWHAZ/YWHAQ/SFN/YWHAE/YWHAG/YWHAB) → mTORC1 complex complex (MTOR-MLST8-RPTOR-AKT1S1) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database LKB1 signaling events: 14-3-3 family (YWHAH/YWHAZ/YWHAQ/SFN/YWHAE/YWHAG/YWHAB) → mTORC1 complex/14-3-3 family complex (MTOR-MLST8-RPTOR-AKT1S1-YWHAH_YWHAZ_YWHAQ_SFN_YWHAE_YWHAG_YWHAB) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database LKB1 signaling events: mTORC1 complex complex (MTOR-MLST8-RPTOR-AKT1S1) → mTORC1 complex/14-3-3 family complex (MTOR-MLST8-RPTOR-AKT1S1-YWHAH_YWHAZ_YWHAQ_SFN_YWHAE_YWHAG_YWHAB) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database LKB1 signaling events: AMPKK1-AMPKK2-active () → mTORC1 complex complex (MTOR-MLST8-RPTOR-AKT1S1) (modification, activates)
    Evidence: mutant phenotype, assay
  • NCI Pathway Database mTOR signaling pathway: 14-3-3 family (YWHAH/YWHAZ/YWHAQ/SFN/YWHAE/YWHAG/YWHAB) → mTORC1/PRAS40/DEPTOR complex (MTOR-MLST8-AKT1S1-DEPTOR-RPTOR) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database mTOR signaling pathway: 14-3-3 family (YWHAH/YWHAZ/YWHAQ/SFN/YWHAE/YWHAG/YWHAB) → mTORC1/PRAS40/DEPTOR/14-3-3 family complex (MTOR-MLST8-AKT1S1-DEPTOR-RPTOR-YWHAH_YWHAZ_YWHAQ_SFN_YWHAE_YWHAG_YWHAB) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database mTOR signaling pathway: mTORC1/PRAS40/DEPTOR complex (MTOR-MLST8-AKT1S1-DEPTOR-RPTOR) → mTORC1/PRAS40/DEPTOR/14-3-3 family complex (MTOR-MLST8-AKT1S1-DEPTOR-RPTOR-YWHAH_YWHAZ_YWHAQ_SFN_YWHAE_YWHAG_YWHAB) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • Reactome Reaction: PRKAB1 → RPTOR (reaction)
  • Reactome Reaction: PRKAA1 → RPTOR (reaction)
  • Reactome Reaction: PRKAG1 → RPTOR (reaction)
  • Reactome Reaction: PRKAA2 → RPTOR (reaction)
  • Reactome Reaction: PRKAB2 → RPTOR (reaction)
  • Reactome Reaction: PRKAG2 → RPTOR (reaction)
  • Reactome Reaction: PRKAG3 → RPTOR (reaction)
In total, 85 gene pairs are associated to this article in curated databases