This proposed research program builds upon and significantly expands our currently funded Program Project which has successfully integrated complementary scientific thrusts to study growth factor receptor-mediated signal transduction mechanisms in normal and malignant cells. In this proposed Program, seven carefully integrated projects with the support of four core facilities will utilize a variety of model systems to test hypotheses about cellular signalling pathways at the plasma membrane, cytoplasmic, and nuclear levels. Projects 1 (R. Davis) and 2 (H. Robinson and D. Gamett) will seek to identify regulated phosphorylation sites on the EGF receptor and erb B proteins and to evaluate their role in modulating receptor function and erb B disease potential. Project 3 (M. Czech and J. Klarlund) will test the hypothesis that tyrosine phosphorylation of a multi-subunit serine kinase, casein kinase II, activates this latter enzyme as part of a major signalling phosphorylation cascade for receptor and oncogene tyrosine kinases. Project 4 (G. Johnson) seeks to define the function of specific G proteins in growth factor receptor signalling events using in vitro mutagenesis and expression of cDNA for Gi alpha proteins. This study will assess interactions of expressed alpha subunits with other G protein subunits and their role in mediating metabolic responses to growth factors. Project 5 (F. Fay) will explore mechanisms that underly growth factor- mediated chemotactic responses by analysis of local changes in intracellular calcium and (H+) using computer-based image intensification of fluorescence signals in neutrophils. Projects 6 (J. Massague) and 7 (J. and G. and G. Stein) involve efforts of two groups toward defining the molecular basis of TGF-beta action. Project 6 will focus on the mechanisms by which TGF-beta modulate expression and function of cell surface receptors for extracellular matrix molecules (integrins). Project 7 will seek to identify specific genes which are differentially expressed in the presence and absence to TGF-beta and which are involved in regulating 3T3- L1 cell differentiation. Four core facilities will provide support, instrumentation, technology and reagents for the above integrated efforts by making available (1.) media and technical time for tissue culture, (2.) peptide synthesis, (3.) cell science technology including immunohistology and micromanipulations and, (4.) recombinant DNA techniques and reagents. Core facilities will be directed by established investigators with extensive experience and training in the areas of expertise provided by each core.
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