METABOLISM OF THE EGF-RECEPTOR

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Regulation of epidermal growth factor (EGF) receptor-mediated mitogenesis will be examined in normal and transformed cells and characterization of the platelet-derived growth factor (PDGF) receptor will be initiated. The functional significance of phosphorylation of the EGF receptor induced by EGF or tumor promoters will be investigated in vivo and in vitro in regard to the effects of phosphorylation on receptor protein kinase activity and perhaps on receptor inositol phosphatide kinase activity. The receptor is known to be associated with tyrosine-specific protein kinase activity and may also possess inositol phosphatide kinase activity as recently found for the src and ros gene products of Rous sarcoma virus and UR2 sarcoma virus, respectively. EGF receptor preparations will be assayed for in vitro inositol phosphatide kinase activity and the effects of EGF and TPA on inositol phosphatide metabolism will be determined in vivo. The involvement of EGF receptor phosphorylation during transit of the G1 phase of the cell cycle will be established in studies of the effects of PDGF on EGF receptor phosphorylation using synchronous cultures of human fibroblasts grown in serum-free medium. The roles of inositol phosphatide metabolism and protein kinase C activity in coordinate processes involving the PDGF and EGF systems will also be studied. EGF receptor metabolism in transformed cells in which abnormal forms of the EGF receptor play a direct role in transformation-dependent loss of growth control (avian erythroblastosis virus-transformed cells and B104 neuroblastoma cells) or in which the function of altered EGF receptor metabolism is not clearly established (Rous sarcoma virus transformed cells) will be studied in terms of regulation of kinase activity through receptor phosphorylation, inositol phosphatide metabolism, and receptor biosynthesis and degradation. Monoclonal and polyclonal antibodies against the PDGF receptor will be prepared in order to initiate work concerning the numerous aspects of PDGF receptor function in normal and transformed cells. (J)