title: Mechanism of TGFbeta receptor inhibition by FKBP12.
abstract: 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.
authors.affiliation: Cell Biology Program and Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
authors.forename: Y G
authors.initials: YG
authors.lastname: Chen
authors.forename: F
authors.initials: F
authors.lastname: Liu
authors.forename: J
authors.initials: J
authors.lastname: Massague
mesh_terms: D030201:Activin Receptors, Type I; D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics / Q000494:pharmacology*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression; D006360:Heat-Shock Proteins / Q000235:genetics / Q000494:pharmacology*; D006801:Humans; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D011090:Polyenes / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus; D022021:Tacrolimus Binding Proteins
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D006360:Heat-Shock Proteins; D011090:Polyenes; D018125:Receptors, Transforming Growth Factor beta; D011993:Recombinant Fusion Proteins; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D022021:Tacrolimus Binding Proteins; D020123:Sirolimus