The RaLGTPase Regulatory Network

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DESCRIPTION (provided by applicant): Accumulating evidence from both cell and animal-based model systems indicates the Ras-like small GTP-binding proteins RalA and RalB are core components of a regulatory framework supporting tumorigenic transformation. Recently we have established discrete but interlocking contributions of these highly related G-proteins to the regulation of both cancer and cell proliferation and survival. Specifically, chronic activation of RalA is required to maintain anchorage-independent proliferation, while RalB is required to deflect cell-death checkpoint activation. This proposal is directed at defining the composition, organization, and function of cell regulatory networks engaged by Ral family G-proteins. Our focus is on the dominant RalA and RalB effector pathways that directly participate in oncogenic transformation. Our specific aims are 1) identification of the effector pathway(s) mediating RalA support of anchorage-independent proliferation, 2) defining the mechanistic contribution of RalB signaling to cancer cell survival, and 3) evaluating the consequences of perturbations in RalA/RalB signaling networks to tumor initiation and/or progression in xenograft and organotypic model systems.