Campbell S L, Khosravi-Far R, Rossman K L, Clark G J, Der C J
Department of Biochemistry and Biophysics, MIT, Cambridge, Massachusetts 02139, USA.
Oncogene. 1998 Sep 17;17(11 Reviews):1395-413. doi: 10.1038/sj.onc.1202174.
The initial discovery that ras genes endowed retroviruses with potent carcinogenic properties and the subsequent determination that mutated ras genes were present in a wide variety of human cancers, prompted a strong suspicion that the growth-promoting actions of mutated Ras proteins contribute to their aberrant regulation of growth stimulatory signaling pathways. In 1993, a remarkable convergence of experimental observations from genetic analyses of Drosophila, S. cerevisiae and C. elegans as well as biochemical and biological studies in mammalian cells came together to define a clear role for Ras in signal transduction. What emerged was an elegant linear signaling pathway where Ras functions as a relay switch that is positioned downstream of cell surface receptor tyrosine kinases and upstream of a cytoplasmic cascade of kinases that included the mitogen-activated protein kinases (MAPKs). Activated MAPKs in turn regulated the activities of nuclear transcription factors. Thus, a signaling cascade where every component between the cell surface and the nucleus was defined and conserved in worms, flies and man. This was a remarkable achievement in our efforts to appreciate how the aberrant function of Ras proteins may contribute to the malignant growth properties of the cancer cell. However, the identification of this pathway has proven to be just the beginning, rather than the culmination, of our understanding of Ras in signal transduction. Instead, we now appreciate that this simple linear pathway represents but a minor component of a very complex signaling circuitry. Ras signaling has emerged to involve a complex array of signaling pathways, where cross-talk, feedback loops, branch points and multi-component signaling complexes are recurring themes. The simplest concept of a signaling cascade, where each component simply relays the same message to the next, is clearly not the case. In this review, we summarize our current understanding of Ras signal transduction with an emphasis on new complexities associated with the recognition and/or activation of cellular effectors, and the diverse array of signaling pathways mediated by interaction between Ras and Ras-subfamily proteins with multiple effectors.
最初发现ras基因赋予逆转录病毒强大的致癌特性，随后又确定在多种人类癌症中存在突变的ras基因，这引发了人们强烈的怀疑，即突变的Ras蛋白的促生长作用导致了其对生长刺激信号通路的异常调节。1993年，来自果蝇、酿酒酵母和秀丽隐杆线虫的遗传分析以及哺乳动物细胞的生化和生物学研究的一系列实验观察结果汇聚在一起，明确了Ras在信号转导中的作用。由此出现了一条优雅的线性信号通路，其中Ras作为一个中继开关，位于细胞表面受体酪氨酸激酶的下游和包括丝裂原活化蛋白激酶（MAPK）在内的细胞质激酶级联的上游。活化的MAPK进而调节核转录因子的活性。因此，这是一个信号级联，其中细胞表面和细胞核之间的每个组分在蠕虫、果蝇和人类中都是明确且保守的。这是我们在理解Ras蛋白的异常功能如何导致癌细胞的恶性生长特性方面取得的一项显著成就。然而，这条通路的确定仅仅被证明是我们对Ras信号转导理解的开始，而非终点。相反，我们现在认识到这条简单的线性通路只是一个非常复杂的信号回路的一小部分。Ras信号转导已涉及一系列复杂的信号通路，其中相互作用、反馈回路、分支点和多组分信号复合物是反复出现的主题。信号级联的最简单概念，即每个组分只是简单地将相同的信息传递给下一个组分，显然并非如此。在这篇综述中，我们总结了我们目前对Ras信号转导的理解，重点关注与细胞效应器的识别和/或激活相关以及由Ras与具有多种效应器的Ras亚家族蛋白之间的相互作用介导的各种信号通路的新复杂性。
