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, 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.
Blobe
G C
GC
Department of Medicine and Pharmacology, Duke University Medical Center, Durham, NC 27710, USA. blobe001@mc.duke.edu
Liu
X
X
Fang
S J
SJ
How
T
T
Lodish
H F
HF
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001665:Binding Sites; D002352:Carrier Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic; D003001:Cloning, Molecular; D003546:Cysteine Endopeptidases / Q000378:metabolism; D005786:Gene Expression Regulation; D015723:Gene Library; D051379:Mice; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D009132:Muscles / Q000166:cytology; D009479:Neuropeptides / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011509:Proteoglycans / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology; D014018:Tissue Distribution; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C115271:Gipc1 protein, mouse; D009097:Multienzyme Complexes; D009479:Neuropeptides; D017395:Plasminogen Activator Inhibitor 1; D011509:Proteoglycans; D011956:Receptors, Cell Surface; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; C071736:betaglycan; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex