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.
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Biochemistry, Genetics and Molecular Biology(all)
- Immunology and Microbiology(all)
- Receptor signaling
- Transforming growth factor-β