Mechanism of TGF beta receptor inhibition by FKBP12

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