The overall goal of this research program is to understand the process of signal transduction by the epidermal growth factor (EGF) receptor. A specific focus of this proposal is to define the mechanism and significance of the phosphorylation of the EGF receptor at the negative regulatory site Ser (1046/7). It is anticipated that this research will add significant new information to two different areas of basic research in cell biology: 1)signal transduction by growth factor receptors; and 2) the molecular mechanism of receptor desensitization. Progress in this research will increase the understanding of the mechanisms that account for the increased cellular proliferation caused by growth factors. This information represents a basis for the design of rational therapeutic strategies for the control of proliferative diseases of epithelial tissues such as cancer of the cervix and breast. There are four Specific Aims: 1. To identify growth factor-stimulated protein kinases that cause the phosphorylation of the EGF receptor at Ser-1046/7. The molecular mechanism that accounts for the EGF-stimulated phosphorylation of the EGF receptor at Ser (1046/7) has not been established. The focus of this specific aim is to define the mechanism by which growth factors regulate the phosphorylation state of the EGF receptor at this site. 2. To test the hypothesis that the phosphorylation of the EGF receptor at Ser-1046/7 causes desensitization of EGF receptor signal transduction. Increased phosphorylation of the EGF receptor at Ser (1046/7) has been shown to correlate with EGF receptor desensitization. We will examine whether there is a causal relationship between EGF receptor phosphorylation at Ser (1046/7) and the process of desensitization. 3. To investigate the physiological significance of EGF receptor desensitization during signal transduction. Rapid desensitization of the EGF receptor occurs when cultured cells are incubated with low mitogenic concentrations of EGF. However, the biological significance of receptor desensitization during EGF-stimulated cellular proliferation has not been established. We shall test the hypothesis that receptor desensitization is relevant to the process of signal transduction in EGF-treated cells. 4. To test the hypothesis that the association of signalling molecules with the EGF receptor is regulated by phosphorylation at Ser-1046/7. The phosphorylation site Ser(1046/7) is located within an important effector domain at the COOH terminus of the EGF receptor that: a) binds to signalling molecules; and b) is required for signal transduction. We shall test the hypothesis that Ser(1046/7 phosphorylation regulates the association of proteins with the EGF receptor.
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