Mechanism of TGFβ receptor inhibition by FKBP12 Journal Article
| Authors: | Chen, Y. G.; Liu, F.; Massagué, J. |
| Article Title: | Mechanism of TGFβ receptor inhibition by FKBP12 |
| Abstract: | 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. |
| Keywords: | signal transduction; controlled study; protein phosphorylation; carrier protein; dna binding protein; genetics; dna-binding proteins; nonhuman; animal cell; animal; metabolism; animals; gene expression; cell growth; transforming growth factor beta; cell line; enzyme inhibitor; protein serine threonine kinase; cos cells; phosphorylation; physiology; drug antagonism; hybrid protein; recombinant fusion proteins; enzyme inhibitors; protein-serine-threonine kinases; carrier proteins; cell strain cos1; transforming growth factor beta receptor; receptors, transforming growth factor beta; binding site; mutagenesis, site-directed; receptor blocking; site directed mutagenesis; rapamycin; sirolimus; immunophilin; transforming growth factor-β; mammal cell; heat-shock proteins; heat shock protein; fk 506 binding protein; activin receptors, type i; tacrolimus binding proteins; humans; human; priority journal; article; activin receptor 1; tgf beta type i receptor; tgf-beta type i receptor; polyene; receptor signaling; fkbp12; polyenes; transforming growth factor beta type ii receptor; transforming growth factor-beta type ii receptor |
| Journal Title: | EMBO Journal |
| Volume: | 16 |
| Issue: | 13 |
| ISSN: | 0261-4189 |
| Publisher: | Wiley Blackwell |
| Date Published: | 1997-07-01 |
| Start Page: | 3866 |
| End Page: | 3876 |
| Language: | English |
| DOI: | 10.1093/emboj/16.13.3866 |
| PUBMED: | 9233797 |
| PROVIDER: | scopus |
| PMCID: | PMC1170011 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 17 March 2017 -- Source: Scopus |
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