CELL TRANSFORMATION BY INSULIN AND IGF1 RECEPTORS

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The goal of the proposed study is to elucidate signal transduction pathways that are important in mediating the oncogenic insulin and insulin-like growth factor I receptors (IR and IGFR)-induced cell growth and transformation, and to explore novel signaling molecules for these receptors. IR and IGFR are two receptor tyrosine kinases which play important roles in regulating cellular metabolic activities, growth and differentiation. The focus will be on identifying the specific Rho/Rac/Cdc42-mediated signaling pathways and molecules involved in regulating distinct cell transforming properties. The major approach will employ loss-of-function mutants of the oncogenic IR and IGFR, as well as various activated and dominant inhibitory mutants of the signaling molecules of Rho/Rac/Cdc42, IRS-1 and P13 kinase to dissect their signal transduction pathways important for cell growth and transformation. The specific aims are: 1. To investigate the effect of oncogenic IR and IGFR and their loss-of-function mutants on Rho/Rac/Cdc42-mediated signaling functions. 2. To elucidate the Rho/Rac/Cdc42-mediated signaling pathways involved in regulating the oncogenic IR and IGFR-induced cell growth and transformation. 3. To explore the role of IRS-1 and P13 kinase in the oncogenic IR and IGFR- induced cell growth and transformation. 4. To explore the role of an IGFR-interacting G beta-related protein, named IGIP, in IGFR signaling functions.