The transforming growth factor beta (TGF-beta) superfamily is comprised of a large number of polypeptide growth factors that regulate growth, differentiation and morphogenesis. The involvement of the TGF-beta signaling pathway in oncogenesis both as tumorsuppressors and as regulators of cellular invasion and metastasis highlights the importance of this pathway in tumor biology. TGF-beta regulates cellular processes by binding to high affinity receptors, the type I, type II, and type III receptors. The role and signaling pathways utilized by the type III receptor are not well understood. In Preliminary Studies, I have determined that the cytoplasmic domain of the type III receptor is essential for enhancing TGF-beta signaling. I have also established specific functions of t he cytoplasmic domain of the type III receptor (binding to and phosphorylation by the type II receptor, and binding the PDZ domain containing protein, GIPC). Based on these preliminary data, I propose the following hypothesis: The type III receptor enhances TGF-beta signaling through specific interactions of its cytoplasmic domain with the type II receptor and the PDZ domain containing protein, GIPC. To test this hypothesis I propose the following specific aims:
Specific Aim 1 : To establish the mechanism by which the cytoplasmic domain of type III receptor interacts with the type II receptor to enhance TGF-beta signaling. Planned objectives: a) to determine the site of action of the cytoplasmic domain of the type III receptor in the TGF-beta signaling pathway, b) to determine the site(s) of phosphorylation of the cytoplasmic domain of the type III receptor by the type II receptor, c) to determine the structural elements of the cytoplasmic domain of the type III receptor required for interaction with the type II receptor and for TGF-beta signaling, and d) to determine the mechanism by which these functions of the cytoplasmic domain of the type III receptor enhance TGF-beta signaling.
Specific Aim 2 : To determine the role of the type III receptor binding protein, GIPC, in regulating the type III receptor, type III receptor function and TGF-beta signaling. Planned objectives: a) to determine the effect of GIPC on the type III receptor and type III receptor functions, b) to determine the effect of GIPC on TGF-beta signaling, and c) to establish the mechanism of action of GIPC on the type III receptor, type III receptor functions and on T G F - beta signaling. These studies will aid in designing specific interventions to manipulate TGF-beta signaling pathway(s) for the prevention and treatment of human cancers.
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