The long term objectives of this project are to understand the molecular mechanisms of transformation induced by the v-src and v- fms oncogenes. In studies on v-src, experiments will concentrate on studying the interaction of pp60src with cellular adhesion plaques and defining the potential role of these structures in normal and tumor cell growth. To look for a role of adhesion plaques in regulating cell growth, the necessity of adhesion plaque formation will be examined in competent induction experiments and the potential modification and involvement of the fibronectin receptor in growth induction will be explored. Within v-src transformed cells, the role and significance of the tyrosine phosphorylation of the fibronectin receptor beta subunit will be tested by both biochemical and molecular genetic techniques. Alteration in binding talin and fibronectin will be measured in an in vitro binding assay, and deletion and point mutations will be produced in the cloned beta subunit cDNA of the fibronectin receptor. Over expression of these mutants in normal or transformed cells will test for altered function. In addition the role of the fibronectin receptor (especially the alpha subunits) in determining the target tissue for metastasis will be explored via the cloning and expression of various alpha and beta subunits of the fibronectin receptor. Studies on fms will focus on mechanisms of activation of the murine c-fms proto-oncogene. Mutations, over expression, and expression in inappropriate cell type will be examined both in vitro and in vivo. Also, within the v-fms oncogene, molecular biology techniques will be used to identify signals for endocytosis and ask whether this step is necessary for transformation. And finally, the function of the 70 amino acid insert in the tyrosine kinase domain of v-fms will be probed by deletion and substitution analysis. Overall these studies will enhance our understanding of the mechanism of neoplastic transformation of both solid and hematopoietic tumors.
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