The immunophilin FKBP12 functions as a common inhibitor of the TGF beta family type I receptors.
The immunophilin FKBP12 is an evolutionarily conserved abundant protein; however, its physiological roles remain poorly defined. Here we report 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 mediated 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 (G89P, I90K) abolish the inhibitory activity of FKBP12, suggesting that FKBP12 may dock a cytoplasmic protein to the type I receptors to inhibit TGF beta family mediated signaling.
Wang
T
T
Massachusetts General Hospital Department of Surgery Harvard Medical School Boston 02114, USA.
Li
B Y
BY
Danielson
P D
PD
Shah
P C
PC
Rockwell
S
S
Lechleider
R J
RJ
Martin
J
J
Manganaro
T
T
Donahoe
P K
PK
D030201:Activin Receptors, Type I; D000595:Amino Acid Sequence; D000818:Animals; D019703:Calcineurin; D002148:Calmodulin-Binding Proteins / Q000378:metabolism; D002352:Carrier Proteins / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000502:physiology*; D004330:Drosophila; D006360:Heat-Shock Proteins / Q000502:physiology*; D008969:Molecular Sequence Data; D019814:Myristic Acid; D009227:Myristic Acids / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; 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* / Q000378:metabolism; D015398:Signal Transduction; D022021:Tacrolimus Binding Proteins; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D002148:Calmodulin-Binding Proteins; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D009227:Myristic Acids; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D019814:Myristic Acid; 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; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; D022021:Tacrolimus Binding Proteins