Oncogenic protein-tyrosine kinases may induce abnormal growth by stimulating signal transduction pathways involved in regulating cell proliferation by growth factor receptors. Research proposed here is concerned with potential signalling pathways that mediate oncogenesis by the viral Src tyrosine kinase encoded In Rous sarcoma virus. GTPase-activating protein (GAP), which regulates the activities of Ras proteins, has been implicated in mitogenic signalling by growth factor receptors and oncogenic tyrosine kinases. Our recent studies suggest that the viral and cellular Src kinases associate with and phosphorylate GAP in a complex. Experiments are proposed herein to explore further the role of GAP in oncogenesis by the viral Src kinase. Complementary genetic and biochemical studies will investigate how activated Src may regulate GAP through either direct or indirect mechanisms. These studies will: i) characterize the protein components that associate with GAP in complexes which may be essential for the regulation or function of GAP In Src oncogenesis; ii) determine the molecular features of GAP that are involved in interactions with Src and other GAP-associated proteins; iii) examine the in vivo phosphorylation state of GAP and its associated proteins to determine whether these correlate with the activation of cellular Ras; and iv) evaluate whether GAP has an indispensable role in Src oncogenesis by using antisense GAP nucleic acids to block expression of GAP in Src transformed cells. Together, experiments proposed in this application will provide new information on how interactions among protein components of GAP complexes might contribute to Src oncogenesis and point the way toward new avenues of investigation. Greater understanding of how activated Src subverts mitogenic signal transduction pathways will suggest possible targets for therapeutic Intervention in human cancers induced by oncogenic tyrosine kinases.
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