TISSUE SPECIFIC ONCOGENESIS MEDIATED BY C-ERBB

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.