title: FKBP12 is not required for the modulation of transforming growth factor beta receptor I signaling activity in embryonic fibroblasts and thymocytes.
abstract: Transforming growth factor beta (TGF-beta) signals through a heteromeric complex of type I and type II transmembrane serine-threonine kinases. Recent evidence suggests that the immunophilin FKBP12 modulates the activity of the type I receptor, based on data that immunosuppressive drugs that disrupt FKBP12 binding to the type I receptor enhance TGF-beta signaling in mink lung epithelial cells, and overexpression of FKBP12 inhibits type I receptor phosphorylation by the type II receptor. To determine the physiological relevance of the FKBP12-TGF-beta receptor I interaction, we investigated whether disruption of this interaction affects TGF-beta-signaling in primary mouse embryo fibroblasts and thymocytes. We found that the addition of excess drugs had no effect on either TGF-beta-mediated transcriptional responses or growth inhibition. Dose-response curves for TGF-beta-mediated signaling in primary fibroblasts and thymocytes isolated from either wild-type or FKBP12-deficient mice were identical. Taken together, our results indicate that FKBP12 does not play a unique physiological role in TGF-beta signaling in primary fibroblasts and thymocytes.
authors.affiliation: Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: C H
authors.initials: CH
authors.lastname: Bassing
authors.forename: W
authors.initials: W
authors.lastname: Shou
authors.forename: S
authors.initials: S
authors.lastname: Muir
authors.forename: J
authors.initials: J
authors.lastname: Heitman
authors.forename: M M
authors.initials: MM
authors.lastname: Matzuk
authors.forename: X F
authors.initials: XF
authors.lastname: Wang
mesh_terms: D030201:Activin Receptors, Type I; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D005347:Fibroblasts / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology; D006360:Heat-Shock Proteins / Q000235:genetics / Q000502:physiology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D016559:Tacrolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D022021:Tacrolimus Binding Proteins; D013950:Thymus Gland / Q000196:embryology / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; C076383:L 685818; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; D022021:Tacrolimus Binding Proteins; D016559:Tacrolimus