Regulation of Ras-Dependent Signal Transduction Pathways

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Ras is a small, evolutionarily conserved GTPase that functions to transmit signals regulating cellular proliferation, differentiation, survival and transformation. Oncogenic Ras proteins, which are constitutively activated forms of Ras, cause inappropriate cell proliferation and are associated with approximately 30% of all human malignancies. 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 four main areas: 1. Regulation of the Raf family of serine/threonine kinases. The Raf kinase family serves as an essential intermediate in many signaling cascades, functioning to relay signals from activated Ras to the downstream protein kinases MEK and ERK. Moreover, deregulated or constitutively active Raf proteins can themselves cause cell transformation and mutations in the Raf family member B-Raf have been observed in 67% of malignant melanomas as well as in many colorectal, ovarian and papillary thyroid carcinomas. Our goal in this project is to examine the means by which the Raf kinases 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. Mass spectrometry analysis of Ras pathway components. Several components of the Ras pathway, such as the Raf kinases and the scaffolding proteins KSR, CNK and SUR8, are found in high molecular weight complexes in mammalian cells. To identify the constituents of these complexes and to isolate other potential regulators of the Ras pathway, our laboratory has begun a comprehensive analysis of these protein complexes utilizing the NCI mass spectrometry facility. 4. 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.