Evaluation of Chronic RalGTPase Activation as a Core Specifier of Oncogenic Transformation
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Ral (RAS-Like) GTPases, RalA and RalB, were originally identified based on sequence similarity to Ras and are directly activated via the Ras effector family Ral guanine nucleotide exchange factors (RalGEFs). Previous studies have demonstrated that RalA and RalB collaborate to maintain tumorigenicity through regulating both proliferation and survival. Remarkably, RalB is specifically required for survival in Ras-dependent tumor cells rather than normal cells, while RalA is required for anchorage-independent proliferation but dispensable for survival. However, the spectrum of cancer cell lineages dependent upon Ral functions for tumor formation is currently unknown. We examined whether Ral pathway activation is required for proliferation of cancer cells with activated Ras, Raf, or PI3K. Our data indicate that the Ral pathway is aberrantly activated and required for maintaining tumorigenicity of cancers that are driven by oncogenes other than Ras. In order to begin to understand how the Ral pathway may be chronically engaged in diverse oncogenic backgrounds, we further examined the expression of RalGEFs in a variety of cells derived from different tissue origin. Our results showed a divergent and complex distribution of RalGEFs among different cell types. In addition, through examination of historical tumor resequenceing efforts, we found several somatic mutations in RalGEFs, including RalGDS and RGL1. Through biochemical and cell biological studies, we find that the RGL1 mutations identified in human breast cancers are gain-of -function mutations, and found the mutations contribute to tumor cell survival through RalB pathway. Furthermore, we showed that chronic activation of RGL1 is sufficient to transform immortalized human mammary epithelial cells. Together, our data suggest RGL1 is a bona fide oncogene. These studies broaden our knowledge about RalGEF-Ral contributions in tumorigenicity, and provide a potential target for cancer therapeutic interventions.