Roles of small GTPase Ral in tumorigenesis

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Small GTPases are signaling switches acting downstream of many growth factor receptors. Their activity is regulated by the balance between positive and negative regulators, guanine nucleotide factors (GEFs) and GTPase activating proteins, respectively. Ras, an oncogene whose mutations are frequently detected in various human cancers, takes Raf, PI3 kinase, and RalGEF as direct effectors. Many reports have indicated that the signaling pathway mediated by the RalGEF-Ral pathway is important in human tumorigenesis. We have very recently identified RalGAPs for the first time (JBC, 2009). Then, we analyzed the role of RalGAP in bladder cancer progression. We reported in a paper in Oncogene, 2013 that 1) the dominant catalytic subunit of RalGAP in bladder is alpha-2 and it is strongly downregulated in invasive bladder cancer cell line compared with non-invasive cells, resulted in elevated activation of Ral in invasive cells, 2) exogenous expression of RalGAPalpha2 in invasive bladder cancer cells inhibited lung metastasis when injected to nude mice, 3) in a chemichally-induced bladder cancer model, invasive bladder cancers were detected in 42% of RalGAPalpha2-KO mice whereas none in control mice, 4) low expression of RalGAPalpha2 was correlated with poor prognosis of bladder cancer patients. Thus, reduced expression of RalGAPalpha2 is deeply associated with bladder cancer progression.