This proposal describes biochemical studies designed to delineate specific intracellular signaling pathways involved in the regulation of cell proliferation via TGF-a /EGF-receptor binding interactions. These pathways include TGF-a-induced EGF-R phosphorylation, the association of receptor binding proteins including phospholipase C (PLC-gamma), 3'- phosphotidyl inositol protein kinase (PI 3K ) and src-family tyrosine kinase with non-catalytic regions of EGF-R. Additionally the applicant proposes that c-Ha-ras activation may be required for the mitogenic response of breast cancer cells to TGF-a or EGF and this will be evaluated. The objectives of this proposal are 1) to define differences in ligand-dependent cell proliferation induced by EGF-R phosphorylation in normal and malignant breast cells, 2) to inactivate EGF-R by introducing mutations in the tyrosine kinase binding domain and to study biochemical events occurring before and after binding of TGF-a or EGF to normal and mutant EGF-R expressing cells and 3) to elucidate the role of c-Ha-ras activation and signaling molecules such as ras GAP (GTP ase- activating protein) in TGF-a/EGF-mediated signal transduction in normal and mutant ras transfected cells. The long range goal of the proposed studies is to identify molecular events underlying tumor progression which may be potential targets for the development of rational therapeutic agents.
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