Gene interactions and pathways from curated databases and text-mining
EMBO J 1997, PMID: 9233797

Mechanism of TGFbeta receptor inhibition by FKBP12.

Chen, Y G; Liu, F; Massague, J

Transforming growth factor-beta (TGFbeta) signaling requires phosphorylation of the type I receptor TbetaR-I by TbetaR-II. Although TGFbeta promotes the association of TbetaR-I with TbetaR-II, these receptor components have affinity for each other which can lead to their ligand-independent activation. The immunophilin FKBP12 binds to TbetaR-I and inhibits its signaling function. We investigated the mechanism and functional significance of this effect. FKBP12 binding to TbetaR-I involves the rapamycin/Leu-Pro binding pocket of FKBP12 and a Leu-Pro sequence located next to the activating phosphorylation sites in TbetaR-I. Mutations in the binding sites of FKBP12 or TbetaR-I abolish the interaction between these proteins, leading to receptor activation in the absence of added ligand. FKBP12 does not inhibit TbetaR-I association with TbetaR-II, but inhibits TbetaR-I phosphorylation by TbetaR-II. Rapamycin, which blocks FKBP12 binding to TbetaR-I, reverses the inhibitory effect of FKBP12 on TbetaR-I phosphorylation. By impeding the activation of TGFbeta receptor complexes formed in the absence of ligand, FKBP12 may provide a safeguard against leaky signaling resulting from the innate tendency of TbetaR-I and TbetaR-II to interact with each other.

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Text Mining Data

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Manually curated Databases

  • NCI Pathway Database TGF-beta receptor signaling: TGFB/TGFBR2/betaglycan complex (TGFBR3-TGFBR2) → TGFB/TGFBR2/TGFBR1 complex (TGFBR1-TGFBR2) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction, other species
  • NCI Pathway Database TGF-beta receptor signaling: TGFB/TGFBR2/betaglycan complex (TGFBR3-TGFBR2) → FKBP12/TGFBR1 (dimer) complex (TGFBR1-FKBP1A) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction, other species
  • NCI Pathway Database TGF-beta receptor signaling: TGFB/TGFBR2/betaglycan complex (TGFBR3-TGFBR2) → betaglycan (dimer) complex (TGFBR3) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction, other species
  • NCI Pathway Database TGF-beta receptor signaling: TGFB/TGFBR2/betaglycan complex (TGFBR3-TGFBR2) → BAMBI/TGFBR1 complex (BAMBI-TGFBR1) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction, other species
  • NCI Pathway Database TGF-beta receptor signaling: TGFB/TGFBR2/betaglycan complex (TGFBR3-TGFBR2) → FKBP12 (FKBP1A) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction, other species
  • NCI Pathway Database TGF-beta receptor signaling: TGFB/TGFBR2/TGFBR1 complex (TGFBR1-TGFBR2) → FKBP12/TGFBR1 (dimer) complex (TGFBR1-FKBP1A) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction, other species
  • NCI Pathway Database TGF-beta receptor signaling: TGFB/TGFBR2/TGFBR1 complex (TGFBR1-TGFBR2) → betaglycan (dimer) complex (TGFBR3) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction, other species
  • NCI Pathway Database TGF-beta receptor signaling: TGFB/TGFBR2/TGFBR1 complex (TGFBR1-TGFBR2) → FKBP12 (FKBP1A) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction, other species
  • NCI Pathway Database TGF-beta receptor signaling: FKBP12/TGFBR1 (dimer) complex (TGFBR1-FKBP1A) → betaglycan (dimer) complex (TGFBR3) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction, other species
  • NCI Pathway Database TGF-beta receptor signaling: FKBP12/TGFBR1 (dimer) complex (TGFBR1-FKBP1A) → BAMBI/TGFBR1 complex (BAMBI-TGFBR1) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction, other species
  • NCI Pathway Database TGF-beta receptor signaling: FKBP12/TGFBR1 (dimer) complex (TGFBR1-FKBP1A) → FKBP12 (FKBP1A) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction, other species
  • NCI Pathway Database TGF-beta receptor signaling: betaglycan (dimer) complex (TGFBR3) → FKBP12 (FKBP1A) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction, other species
  • NCI Pathway Database TGF-beta receptor signaling: BAMBI/TGFBR1 complex (BAMBI-TGFBR1) → FKBP12 (FKBP1A) (modification, inhibits)
    Evidence: mutant phenotype, assay, physical interaction, other species
  • Reactome Reaction: TGFB1 → PARD6A (reaction)
  • Reactome Reaction: TGFBR2 → TGFBR2 (reaction)
  • Reactome Reaction: TGFB1 → TGFBR1 (reaction)
  • Reactome Reaction: FKBP1A → TGFBR2 (reaction)
  • Reactome Reaction: FKBP1A → TGFBR1 (reaction)
  • Reactome Reaction: FKBP1A → PARD6A (reaction)
  • Reactome Reaction: TGFB1 → TGFBR1 (indirect_complex)
  • Reactome Reaction: PRKCZ → TGFB1 (reaction)
  • Reactome Reaction: TGFBR2 → PARD3 (reaction)
  • Reactome Reaction: FKBP1A → RHOA (reaction)
  • Reactome Reaction: TGFBR2 → PARD6A (reaction)
  • Reactome Reaction: CGN → TGFB1 (reaction)
  • Reactome Reaction: FKBP1A → ARHGEF18 (reaction)
  • Reactome Reaction: FKBP1A → F11R (reaction)
  • Reactome Reaction: RHOA → TGFB1 (reaction)
  • Reactome Reaction: TGFB1 → PARD3 (reaction)
  • Reactome Reaction: PRKCZ → TGFBR2 (reaction)
  • Reactome Reaction: F11R → TGFBR2 (reaction)
  • Reactome Reaction: TGFBR1 → TGFBR2 (indirect_complex)
  • Reactome Reaction: TGFB1 → TGFBR2 (indirect_complex)
  • Reactome Reaction: F11R → TGFB1 (reaction)
  • Reactome Reaction: CGN → FKBP1A (reaction)
  • Reactome Reaction: TGFB1 → TGFB1 (reaction)
  • Reactome Reaction: FKBP1A → TGFB1 (reaction)
  • Reactome Reaction: RHOA → TGFBR2 (reaction)
  • Reactome Reaction: TGFB1 → ARHGEF18 (reaction)
  • Reactome Reaction: CGN → TGFBR2 (reaction)
  • Reactome Reaction: TGFB1 → TGFBR2 (reaction)
  • Reactome Reaction: TGFBR2 → ARHGEF18 (reaction)
  • Reactome Reaction: TGFBR1 → TGFBR2 (reaction)
  • Reactome Reaction: FKBP1A → PRKCZ (reaction)
  • Reactome Reaction: FKBP1A → PARD3 (reaction)
In total, 39 gene pairs are associated to this article in curated databases