Raf family kinases: old dogs have learned new tricks.
Raf family kinases: old dogs have learned new tricks.
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DOI：
10.1177/1947601911407323
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发表时间：
2011-03-01
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影响因子：
--
通讯作者：
Kolch, Walter
中科院分区：
文献类型：
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作者：
Matallanas, David;Birtwistle, Marc;Kolch, Walter
Raf蛋白在20世纪80年代初首次被确定为逆转录病毒致癌基因，一直是人们深入研究的对象。10年后，发现Raf家族成员（Raf-1， B-Raf和A-Raf）是真正的Ras效应器和普遍存在的ERK途径的上游激活剂，增加了对这些蛋白质的兴趣，主要是因为这种级联在癌症发展中起着核心作用。2002年，在大量肿瘤中发现了B-Raf基因突变，证实了Raf在癌症中的重要作用。这导致了针对癌症中Raf信号的药物开发工作的加强。这项工作不仅取得了最近的临床成功，而且对Raf蛋白的同二聚化和异二聚化调控也有了令人惊讶的见解。在寻找英国皇家空军新目标的过程中，也有了令人惊讶的发现。虽然MEK仍然是唯一被广泛接受的Raf底物，但Raf蛋白的新的激酶无关作用已经出现。其中包括通过抑制促凋亡激酶ASK1和MST2的活性来调节细胞凋亡，以及通过控制rok - α的活性来调节细胞运动和分化。在这篇综述中，我们讨论了Raf蛋白的调控及其在癌症中的作用，特别关注了调节Raf信号的相互作用蛋白。我们还描述了由Raf蛋白控制的新途径，并总结了针对Raf的有效抗癌治疗的成功和失败。最后，我们还认为有必要采用更系统的方法来更好地了解Ras-Raf信号网络如何产生生物特异性。
First identified in the early 1980s as retroviral oncogenes, the Raf proteins have been the objects of intense research. The discoveries 10 years later that the Raf family members (Raf-1, B-Raf, and A-Raf) are bona fide Ras effectors and upstream activators of the ubiquitous ERK pathway increased the interest in these proteins primarily because of the central role that this cascade plays in cancer development. The important role of Raf in cancer was corroborated in 2002 with the discovery of B-Raf genetic mutations in a large number of tumors. This led to intensified drug development efforts to target Raf signaling in cancer. This work yielded not only recent clinical successes but also surprising insights into the regulation of Raf proteins by homodimerization and heterodimerization. Surprising insights also came from the hunt for new Raf targets. Although MEK remains the only widely accepted Raf substrate, new kinase-independent roles for Raf proteins have emerged. These include the regulation of apoptosis by suppressing the activity of the proapoptotic kinases, ASK1 and MST2, and the regulation of cell motility and differentiation by controlling the activity of Rok-alpha. In this review, we discuss the regulation of Raf proteins and their role in cancer, with special focus on the interacting proteins that modulate Raf signaling. We also describe the new pathways controlled by Raf proteins and summarize the successes and failures in the development of efficient anticancer therapies targeting Raf. Finally, we also argue for the necessity of more systemic approaches to obtain a better understanding of how the Ras-Raf signaling network generates biological specificity.