文章：

发育障碍和癌症中过度活跃的Ras

Hyperactive Ras in developmental disorders and cancer

原文发布日期：2007-04-01

DOI: 10.1038/nrc2109

类型: Review Article

开放获取: 否

要点：

1. Ras proteins regulate signalling pathways that control many cellular responses such as proliferation, survival and differentiation.
2. Ras proteins are activated when guanosine triphosphate (GTP) is bound. SOS1, and other exchange factors stimulate guanine nucleotide dissociation from Ras, which results in increased levels of Ras–GTP.
3. Ras–GTP signalling is terminated by hydrolysis to Ras–guanosine diphosphate (Ras–GDP), a reaction catalysed by the GTPase-activating proteins (GAPs), including p120GAP and neurofibromin.
4. Ras–GTP binds to various effector proteins to stimulate signalling pathways; among these effector pathways is the Raf–mitogen-activated and extracellular-signal regulated kinase kinase (MEK)–extracellular signal-regulated kinase (ERK) cascade.
5. Activating somatic mutations in the Ras genes and mutations that activate regulators and effectors of Ras proteins are common in tumour development and cancer.
6. Germline mutations that affect components of the Ras–Raf–MEK–ERK pathway are now known to underlie a group of developmental disorders, such as Noonan syndrome, Costello syndrome and cardio-facio-cutaneous syndrome.
7. Germline mutations in human syndromes frequently encode novel mutant proteins. Studies performed to date suggest that strength and/or duration of signalling through the Ras–Raf–MEK–ERK pathway regulates developmental programmes. Further structural, biochemical and functional analyses of these mutant proteins will extend our understanding of Ras signalling in development and cancer.

要点翻译：

1. Ras蛋白通过调控信号通路来控制多种细胞反应，如增殖、存活与分化。
2. 当鸟苷三磷酸（GTP）结合时，Ras蛋白被激活。SOS1及其他交换因子会刺激Ras释放鸟嘌呤核苷酸，从而提升Ras-GTP的水平。
3. Ras-GTP信号通过水解为Ras-鸟苷二磷酸（Ras-GDP）而终止，该反应由GTP酶激活蛋白（GAPs）催化，包括p120GAP和神经纤维蛋白。
4. Ras-GTP通过与多种效应蛋白结合来激活信号通路，其中重要的效应通路包括Raf-丝裂原活化蛋白激酶激酶（MEK）-细胞外信号调节激酶（ERK）级联反应。
5. 在肿瘤发生和癌症发展中，常见Ras基因的体细胞激活突变，以及激活Ras蛋白调控因子和效应因子的突变。
6. 目前研究发现，影响Ras-Raf-MEK-ERK通路组分的种系突变是一组发育障碍疾病的致病基础，例如努南综合征、科斯特洛综合征及心-面-皮肤综合征。
7. 人类综合征中的种系突变常编码新型突变蛋白。现有研究表明，Ras-Raf-MEK-ERK通路的信号强度和/或持续时间对发育进程具有调控作用。对这些突变蛋白开展进一步的结构、生化及功能分析，将深化我们对Ras信号在发育和癌症中作用机制的理解。

英文摘要：

Ras genes are the most common targets for somatic gain-of-function mutations in human cancer. Recently, germline mutations that affect components of the Ras–Raf–mitogen-activated and extracellular-signal regulated kinase kinase (MEK)–extracellular signal-regulated kinase (ERK) pathway were shown to cause several developmental disorders, including Noonan, Costello and cardio-facio-cutaneous syndromes. Many of these mutant alleles encode proteins with aberrant biochemical and functional properties. Here we will discuss the implications of germline mutations in the Ras–Raf–MEK–ERK pathway for understanding normal developmental processes and cancer pathogenesis.

摘要翻译： 

Ras基因是人类癌症中最常见的体细胞获得功能性突变靶点。近期研究发现，影响Ras-Raf-MEK-ERK信号通路组分的胚系突变可导致多种发育异常疾病，包括努南综合征、科斯特洛综合征以及心-面-皮肤综合征。这些突变等位基因编码的蛋白质多表现出异常的生化特性和功能障碍。本文将探讨Ras-Raf-MEK-ERK通路胚系突变对理解正常发育过程及癌症发病机制的重要意义。

原文链接：

Hyperactive Ras in developmental disorders and cancer