Roles of small GTPase Ral in tumorigenesis

小的GTP酶是作用于许多生长因子受体下游的信号开关。它们的活性分别受正负调控因子、鸟嘌呤核苷酸因子和GTP酶激活蛋白的调节。RAS是一种在多种人类癌症中经常检测到突变的癌基因，它以Raf、PI3激酶和Ralgef为直接效应因子。许多报道表明，Ralgef途径介导的信号通路在人类肿瘤发生中起着重要作用。我们最近首次发现了RalGAP(JBC，2009)。然后，我们分析了RalGAP在膀胱癌进展中的作用。我们在2013年发表的一篇论文中指出，1)RalGAP在膀胱中的主要催化亚单位是α-2，并且在浸润性膀胱癌细胞系中与非侵袭性细胞相比，它的表达显著下调，导致侵袭性细胞中RAL的激活水平上升；2)RalGAPalpha2在浸润性膀胱癌细胞中的外源表达抑制了裸鼠的肺转移；3)在化学诱导的膀胱癌模型中，42%的RalGAPalpha2-KO小鼠检测到浸润性膀胱癌，而在对照组小鼠中没有检测到；4)RalGAPalpha2的低表达与膀胱癌患者的不良预后相关。因此，RalGAPalpha2的表达降低与膀胱癌的进展密切相关。

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.