TISSUE SPECIFIC ONCOGENESIS MEDIATED BY C-ERBB

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The product of avian c-erbB gene is a growth factor receptor that is structurally and perhaps functionally related to the human epidermal growth factor receptor. Overexpression of both the avian and human receptors results in anchorage independent growth of primary cells in culture (chick embryo fibroblasts) and of established rodent cell lines. Transformation of cells resulting from overexpression of these receptors is probably mediated by an autocrine mechanism, since transformation is dependent on addition of ligand. We have shown that it is possible to deregulate the growth controlling function(s) of the avian receptor by altering specific structural domains in the carboxy-terminal region of this protein 6-9. By characterizing naturally occurring mutant forms of c-erb B (induced by retroviruses) we have been able to correlate lesions in specific structural domains of the c-erb B gene product with tumorigenicity in three distinct avian tissues: endothelial mesenchymal, and hematopoietic 6-7. These studies suggest that several distinct cellular pathways facilitate c-erb B mediated transformation. In this application, we propose to further dissect the cellular and molecular basis of c-erb B mediated oncogenesis. We will determine whether tyrosine kinase activity, an intrinsic enzymatic activity associated with the c-erb B gene product, is required for transformation in all three target tissues. If kinase activity is essential for expression of the transformed phenotype, what are the critical substrates? Is autophosphorylation sufficient, or is phosphorylation of exogeneous substrates also required? Tissue-specific substrates will be identified using biochemical and genetic techniques. And finally, if kinase activity is essential for transformation, how is kinase activity regulated? Biochemical parameters of kinase activity will be compared both in vitro and in vivo, using mutant forms of c-erb B expressed in the three avian target tissues described above.