Elucidating the Regulation and Function of the NF1 tumor suppressor

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 DESCRIPTION (provided by applicant): The Ras pathway is one of the most commonly deregulated pathways in cancer. Mutations in RAS genes, upstream regulators, or downstream effectors occur in the majority of human tumors. One important Ras regulatory gene involved in cancer is the NF1 tumor suppressor, which encodes a Ras GTPase-activating protein (RasGAP). NF1 catalyzes the hydrolysis of Ras-GTP to Ras-GDP and normally terminates Ras signaling. Accordingly, loss-of-function mutations in NF1 result in hyperactivated Ras. NF1 mutations underlie a common familial cancer syndrome neurofibromatosis type I (NF1). More recently, NF1 has been shown to play a role in a variety of sporadic tumors including melanoma, glioblastoma, and lung cancer. However, while the gene was cloned in 1990, surprisingly little is known about how the NF1 protein is normally regulated or functions. In addition, there are no effective therapies for NF1-mutant tumors. In this application we aim to tackle both of these important problems. Specifically, we will 1) determine how the NF1 protein is normally regulated and terminates Ras signaling, 2) deconstruct downstream and converging signaling pathways, and 3) identify broad signaling networks that are deregulated in NF1-mutant tumors. Collectively, these studies should not only reveal novel insight into NF1 and Ras signaling, but will identify key regulators and effectors in NF1-mutant tumors that may ultimately serve as therapeutic targets.