A novel mechanism for regulating transforming growth factor beta (TGF-beta) signaling - Functional modulation of type III TGF-beta receptor expression through interaction with the PDZ domain protein, GIPC

Transforming growth factor beta (TGF-beta) mediates its biological effects through three high-affinity cell surface receptors, the TGF-beta type I, ty pe II, and type III receptors, and the Smad family of transcription factors . Although the functions of the type II and type I receptors are well estab lished, the precise role of the type III receptor in TGF-beta signaling rem ains to be established. While expression cloning signaling molecules downst ream of TGF-beta, we cloned GIPC (GAIP-interacting protein, C terminus), a PDZ domain-containing protein. GIPC binds a Class I PDZ binding motif in th e cytoplasmic domain of the type III receptor resulting in regulation of ex pression of the type III receptor at the cell surface. Increased expression of the type III receptor mediated by GIPC enhanced cellular responsiveness to TGF-beta both in terms of inhibition of proliferation and in plasminoge n-activating inhibitor (PAD-based promoter gene induction assays. In all ca ses, deletion of the Class I PDZ binding motif of the type III receptor pre vented the type III receptor from binding to GIPC and abrogated the effects of GIPC on type III receptor expressing cells. These results establish, fo r the first time, a protein that interacts with the cytoplasmic domain of t he type III receptor, determine that expression of the type III receptor is regulated at the protein level and that increased expression of the type I II receptor is sufficient to enhance TGF-beta signaling. These results furt her support an essential, non-redundant role for the type I receptor in TGF -beta signaling.