Regulation of Ras-Dependent Signal Transduction Pathways

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Ras is a small, evolutionarily conserved GTPase that functions in the transmission of signals mediating cell growth and differentiation. Oncogenic Ras proteins, which are consistutively activated forms of Ras, cause inappropriate cell proliferation and are associated with approximately 30% of all human carcinomas. Because Ras plays such a critical role in both normal and abnormal growth processes, our laboratory has focused its research on elucidating the components involved in and the mechanisms regulating Ras-dependent signal transduction. Specifically, our studies can be divided into three main areas: 1. Regulation of the Raf family of serine/threonine kinases. The Raf kinase family serves as a central intermediate in many signaling cascades, functioning to link activated tyrosine kinases and Ras with mitogen activated protein kinase (MAPK) and MAPK kinase (MKK or MEK). Our goal in this project is to examine the means by which Raf becomes activated and inactivated during growth, development, and oncogenesis. 2. Function of Kinase Suppressor of Ras (KSR). KSR was discovered to be a positive effector of Ras signaling by genetic studies performed in Drosophila and C. elegans. Our investigation of the mammalian KSR protein has been to determine the specific mechanism(s) by which KSR functions to transduce Ras-dependent signals.3. Ras signaling pathways in Drosophila. Due to the complex nature of cellular signal transduction, our laboratory has had an ongoing interest in using Drosophila as a model system for studying signaling events. We are currently using this system to identify novel proteins involved in Ras-dependent signal transduction.