FKBP12 functions as an adaptor of the Smad7-Smurf1 complex on activin type I receptor.
The cytoplasmic immunophilin FKBP12, a 12 kDa FK506-binding protein, has been shown to act as an inhibitor for transforming growth factor-beta (TGF-beta) signaling. FKBP12 binds to the glycine- and serine-rich motif (GS motif) of the TGF-beta type I receptor, and functions as a secure switch to prevent the leaky signal. Upon stimulation with ligand, FKBP12 is released from the receptor to fully propagate the signal. We found that activin, a member of TGF-beta superfamily, also induced the dissociation of FKBP12 from the activin type I receptor (ALK4). However, we observed that the released FKBP12 associates again with the receptor a few hours later. FKBP12 also interacted with another inhibitory molecule of activin signal, Smad7, in an activin-dependent manner, and formed a complex with Smad7 on the type I receptor. FK506, a chemical ligand for FKBP12, which dissociates FKBP12 from the receptor, decreased the interaction between Smad7 and Smad ubiquitin regulatory factor 1 (Smurf1). FK506 also inhibited the ubiquitination of the type I receptor by Smurf1. These findings indicate a new inhibitory function of FKBP12 as an adaptor molecule for the Smad7-Smurf1 complex to regulate the duration of the activin signal.
Yamaguchi
T
T
Division of Molecular Cytology, Institute for Enzyme Research, University of Tokushima, 3-18-15, Kuramoto, Tokushima 770-8503, Japan.
Kurisaki
A
A
Yamakawa
N
N
Minakuchi
K
K
Sugino
H
H
D030201:Activin Receptors, Type I / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D005786:Gene Expression Regulation; D006801:Humans; D046912:Multiprotein Complexes; D015398:Signal Transduction / Q000502:physiology; D051906:Smad7 Protein / Q000235:genetics / Q000378:metabolism*; D022061:Tacrolimus Binding Protein 1A / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
D046912:Multiprotein Complexes; C497806:SMAD7 protein, human; D051906:Smad7 Protein; D025801:Ubiquitin; C498342:SMURF1 protein, human; D044767:Ubiquitin-Protein Ligases; C498932:ACVR1B protein, human; D030201:Activin Receptors, Type I; D022061:Tacrolimus Binding Protein 1A