Reiner David J
Department of Pharmacology and Lineberger Comprehensive Cancer Center; University of North Carolina; Chapel Hill, NC USA.
Small GTPases. 2011 Mar;2(2):109-112. doi: 10.4161/sgtp.2.2.15775.
Organisms pattern and specify cell fates with remarkably high fidelity and robustness, and cancer may be considered in part to be a disease of fate specification gone awry. During C. elegans vulval development an initial EGF signal prompts Ras to activate its canonical effector pathway, Raf-MEK-ERK, to induce a primary cell, which subsequently signals its 2 neighbors via Notch to develop as secondary cells. We have shown that Ras signaling through an alternate effector pathway, RalGEF-Ral, antagonizes Ras-Raf pro-primary signaling. Ras-RalGEF-Ral instead promotes secondary fate in support of Notch. We validated a previous model that EGF can also contribute to secondary fate, and argue that Ras-RalGEF-Ral mediates this EGF pro-secondary activity. Ras-Raf-MEK-ERK signaling was previously shown to be extinguished from secondary cells by secondary-specific expression of MAP kinase phosphatase, and we found that Ral expression is transcriptionally restricted to secondary cells. Thus during vulval development Ras switches effectors from Raf to RalGEF to promote divergent and mutually antagonistic cell fates, perhaps mirroring divergent effector usage in Ras-dependent tumors with differential pharmacological responsiveness.
生物体以极高的保真度和稳健性决定并指定细胞命运，癌症在一定程度上可被视为一种命运指定出错的疾病。在秀丽隐杆线虫的外阴发育过程中，最初的表皮生长因子（EGF）信号促使Ras激活其经典效应器途径，即Raf-MEK-ERK，以诱导一个初级细胞，该初级细胞随后通过Notch向其两个相邻细胞发出信号，使其发育为次级细胞。我们已经表明，Ras通过一条替代效应器途径RalGEF-Ral发出信号，拮抗Ras-Raf促进初级细胞形成的信号。相反，Ras-RalGEF-Ral促进次级细胞命运以支持Notch信号。我们验证了先前的一个模型，即EGF也可促进次级细胞命运，并认为Ras-RalGEF-Ral介导了这种EGF促进次级细胞形成的活性。先前的研究表明，通过丝裂原活化蛋白激酶磷酸酶的次级特异性表达，Ras-Raf-MEK-ERK信号在次级细胞中被消除，我们发现Ral的表达在转录水平上被限制于次级细胞。因此，在外阴发育过程中，Ras将效应器从Raf切换到RalGEF，以促进不同且相互拮抗的细胞命运，这可能反映了在具有不同药理学反应性的Ras依赖性肿瘤中效应器的不同使用情况。
