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Division of Molecular Cytology, Institute for Enzyme Research, University of Tokushima, 3-18-15, Kuramoto, Tokushima, 770-8503, Japan
¹ Harima Institute at Spring-8, RIKEN, Mikazuki, Sayo, Hyogo, 679-5148, Japan
² Division of Pharmacy, Tokushima University Hospital, 2-50-1, Kuramoto, Tokushima, 770-8503, Japan

(Requests for offprints should be addressed to A Kurisaki; Email: akikuri{at}hotmail.com)

(T Yamaguchi is now at Division of Pharmacy, Ehime University Hospital, Shitsukawa, Toon, 791-0295, Ehime, Japan)

The cytoplasmic immunophilin FKBP12, a 12 kDa FK506-binding protein, has been shown to act as an inhibitor for transforming growth factor-ß (TGF-ß) signaling. FKBP12 binds to the glycine- and serine-rich motif (GS motif) of the TGF-ß 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-ß 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.

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