Activin receptor type-1B
positive regulation of activin receptor signaling pathway
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.