Mechanism of TGFβ receptor inhibition by FKBP12

Ye Guang Chen, Fang Liu, Joan Massagué

Research output: Contribution to journalArticlepeer-review

292 Scopus citations


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

Original languageEnglish (US)
Pages (from-to)3866-3876
Number of pages11
JournalEMBO Journal
Issue number13
StatePublished - Jul 1 1997
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)


  • FKBP12
  • Receptor signaling
  • Transforming growth factor-β


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