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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.

Publication ,  Journal Article
Blobe, GC; Liu, X; Fang, SJ; How, T; Lodish, HF
Published in: J Biol Chem
October 26, 2001

Transforming growth factor beta (TGF-beta) mediates its biological effects through three high-affinity cell surface receptors, the TGF-beta type I, type 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 established, the precise role of the type III receptor in TGF-beta signaling remains to be established. While expression cloning signaling molecules downstream 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 the cytoplasmic domain of the type III receptor resulting in regulation of expression 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 plasminogen-activating inhibitor (PAI)-based promoter gene induction assays. In all cases, deletion of the Class I PDZ binding motif of the type III receptor prevented the type III receptor from binding to GIPC and abrogated the effects of GIPC on type III receptor expressing cells. These results establish, for the first time, a protein that interacts with the cytoplasmic domain of the type III receptor, determine that expression of the type III receptor is regulated at the protein level and that increased expression of the type III receptor is sufficient to enhance TGF-beta signaling. These results further support an essential, non-redundant role for the type III receptor in TGF-beta signaling.

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Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

October 26, 2001

Volume

276

Issue

43

Start / End Page

39608 / 39617

Location

United States

Related Subject Headings

  • Two-Hybrid System Techniques
  • Transforming Growth Factor beta
  • Transcriptional Activation
  • Tissue Distribution
  • Stem Cells
  • Signal Transduction
  • Receptors, Transforming Growth Factor beta
  • Receptors, Cell Surface
  • Proteoglycans
  • Protein Structure, Tertiary
 

Citation

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Blobe, G. C., Liu, X., Fang, S. J., How, T., & Lodish, H. F. (2001). 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. J Biol Chem, 276(43), 39608–39617. https://doi.org/10.1074/jbc.M106831200
Blobe, G. C., X. Liu, S. J. Fang, T. How, and H. F. Lodish. “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.J Biol Chem 276, no. 43 (October 26, 2001): 39608–17. https://doi.org/10.1074/jbc.M106831200.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

October 26, 2001

Volume

276

Issue

43

Start / End Page

39608 / 39617

Location

United States

Related Subject Headings

  • Two-Hybrid System Techniques
  • Transforming Growth Factor beta
  • Transcriptional Activation
  • Tissue Distribution
  • Stem Cells
  • Signal Transduction
  • Receptors, Transforming Growth Factor beta
  • Receptors, Cell Surface
  • Proteoglycans
  • Protein Structure, Tertiary