Roles of small GTPase Ral in tumorigenesis

小GTP酶是在许多生长因子受体下游起作用的信号转导开关。它们的活性分别由正和负调节因子、鸟嘌呤核苷酸因子（GEF）和GTP酶激活蛋白之间的平衡调节。Ras是一种癌基因，其突变经常在各种人类癌症中检测到，Raf，PI 3激酶和RalGEF作为直接效应子。许多研究表明，RalGEF-Ral信号通路在人类肿瘤发生中起重要作用。我们最近首次确定了RalGAP（JBC，2009）。然后，我们分析了RalGAP在膀胱癌进展中的作用。我们在Oncogene，2013的一篇论文中报道，1）RalGAP在膀胱中的主要催化亚基是α-2，并且与非侵袭性细胞相比，其在侵袭性膀胱癌细胞系中强烈下调，导致侵袭性细胞中Ral的活化升高，2）当注射到裸鼠时，侵袭性膀胱癌细胞中RalGAPalpha 2的外源性表达抑制肺转移，3）在化学诱导的膀胱癌模型中，在42%的RalGAPalpha 2-KO小鼠中检测到浸润性膀胱癌，而在对照小鼠中没有检测到浸润性膀胱癌。4）RalGAPalpha 2的低表达与膀胱癌患者的不良预后相关。因此，RalGAPalpha 2的表达减少与膀胱癌进展密切相关。

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.