The overall objective of these studies is to elucidate the biological significance of the presence in higher organisms (including human) of both the hormone-like polypeptide, epidermal growth factor (EGF), and receptors for this peptide. At the molecular level we hope to understand the biochemical steps leading from the binding of EGF by receptors on the cell membrane to the induction of DNA synthesis. EGF is a very potent mitogen for a variety of cells both in vivo and in cell culture. The amino acid sequence and many of the chemical and physical properties of this molecule have been determined. The binding and internalization of EGF have been described in detail. The interaction of EGF with responsive cells is one of the very few instances in biology in which a direct effect of a hormone may be demonstrated in a cell free system. The plasma membrane receptor for EGF is a tyrosine specific protein kinase whose activity is enhanced by binding EGF. The EGF receptor/kinase has been isolated from A-431 cells and mouse liver; the receptor and kinase are parts of the same 170,000 MW glycoprotein. This system has served as a model for the discovery of the insulin receptor tyrosine kinase and to relate the mechanisms of cell transformations to hormonal mechanisms.
My specific aims are: 1. Examine the role of receptor/kinase internalization in response to EGF in mediating the cellular response; trace the pathway of receptor internalization immunologically 2. Identify, isolate and characterize the cellular components phosphorylated by the EGF-receptor kinase 3. Detect an in vitro interaction between the EGF-receptor/kinase membrane system or a substrate of the kinase with a nuclear component which may lead to the observed activation of DNA transcription.
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