THE IMMUNOPHILIN FKBP12 FUNCTIONS AS A COMMON INHIBITOR OF THE TGF-BETA FAMILY TYPE-I RECEPTORS

The immunophilin FKBP12 is an evolutionarily conserved abundant protei n; however, its physiological roles remain poorly defined. Here we rep ort that FKBP12 is a common cytoplasmic interactor of TGF beta family type I receptors. FKBP12 binds to ligand-free TGF beta type I receptor , from which it is released upon a ligand-induced, type II receptor me diated phosphorylation of the type I receptor. Blocking FKBP12/type I receptor interaction with FK506 nonfunctional derivatives enhances the ligand activity, indicating that FKBP12 binding is inhibitory to the signaling pathways of the TGF beta family ligands. Overexpression of a myristylated FKBP12 in Mv1Lu cell specifically inhibits two separate pathways activated by TGF beta, and two point mutations on FKBP12 (G89 P, 190K) abolish the inhibitory activity of FKBP12, suggesting that FK BP12 may dock a cytoplasmic protein to the type I receptors to inhibit TGF beta family mediated signaling.