IDENTIFICATION OF NOVEL EFFECTORS FOR THE RAP 1 GTP-ASE

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Recently, the role of the Rap1 GTPase in signal transduction has expanded dramatically. Originally isolated as an antagonist of Ras signal transduction, Rap1 has been found to participate in morphogenesis, IL-2 transcription, platelet function, and the production of the respiratory burst in phagocytic cells. The role of contitutively activated Rap1 in human tuberous sclerosis, the presence of Rap1 overexpression or activation in 60 percent of human gliomas, and the recent finding of the EGF-induced association of the Rap1 activator, c3G, with the Crk-Cbl complex in breast cancer cells suggests that Rap1 may also play a role in human oncogenesis. The long-term objective of this proposal is the identification of novel downstream signaling partners for Rap1. Rap1 cDNAs will be used to probe a mouse brain cDNA library using the yeast two-hybrid assay to find cDNAs that encode potential binding proteins for activated Rap1. PCR and DNA sequence analysis will be used to identify proteins that are potential Rap1 effectors. In vitro and in vivo binding studies between Rap1 mutants and identified proteins will be done to identify authentic effector proteins. Identification and characterization of novel Rap1 effectors will provide links between the many different functions of Rap1 and will help elucidate the role of Rap1 in the EGF receptor signaling pathway in breast cancer.