MECHANISM OF ACTION OF EPIDERMAL GROWTH FACTOR

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The basic goal of this Program Project is to consolidate studies of growth factor tyrosine kinase signal transduction pathways and to utilize a broad range of technological and intellectual skills to realize this goal. The basic focus is the epidermal growth factor (EGF) system, but studies of the platelet-derived growth factor (PDGF) system are included for comparative and distinct information. In these proposed studies, several elements of the basic signal transduction pathway are to be explored. The different projects utilize biochemistry, cell biology, histology, molecular biology, and biophysics as experimental techniques. As the first element in these signal transduction pathways is the growth factor receptors, Project 7 will use biophysical methods to explore EGF- receptor interactions and project 4 will utilize cell biological approaches to explore physiological differences in response generation by the alpha and beta PDGF receptors. Tyrosine kinase substrates constitute the second intracellular step in the signaling pathways and the Program includes three distinct projects to explore phospholipase C-gamma1 (PLC-gamma1), as well as other tyrosine kinase substrates. Project 2 will use biochemical and, to a lesser extent, biophysical approaches to explore PLC-gamma1 activation by the EGF receptor. Finally, two projects will explore more distal elements of this pathway. Project 5 will use biochemical approaches to study a growth factor-activated serine kinase, casein kinase II and Project 8 will use molecular biological techniques to investigate the growth factor activation of transcription factors. The Program Project mechanism provides a unifying vehicle to maximize the concentration of specialized resources, both technical and intellectual, of the investigators for the benefit of individual research efforts and the long range goals. Personal collaborations among the investigators and a technically broad, but focused and integrated system of experimental approaches will be uniquely available through the Program Project.