The goal of the proposed study is to elucidate and identify the signal transduction pathways that are important in mediating malignant cell transformation of the oncogenic receptor protein tyrosine kinase (RPTK) Ros which was originally discovered as the oncogene of an avian sarcoma virus called UR2. The PTK domain of Ros shares high homology with those of insulin and insulin-like growth factor I receptors (IR and IGFR). However, the physiological function of Ros appears to be rather different than those of IR and IGFR. The focus of this study will be to identify specific signaling pathways and molecules required for the distinct cell transforming functions of Ros. The major approach will employ loss-of- function mutants of Ros as well as various activated and dominant inhibitory mutants of signaling molecules to dissect the signal transduction pathways of Ros.
The specific aims are: l. To establish mutant Ros expressing mammalian cell lines and to characterize their biological and biochemical properties. 2. To elucidate the role ofRho/Rac1/Cdc42-mediated signaling pathways in Ros-induced cell growth and transformation. 3. To explore the role of IRS-1 and PI3 kinase in Ros-induced cell growth and transformation. 4. To inquire the role of cytoskeletal protein-mediated signaling in Ros- induced cell growth and transformation. 5. To assess the role of IGF-I receptor in Ros-induced cell growth and transformation.
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