RAF family protein kinases are a key node in the RAS/RAF/MAP kinase pathway, the signaling cascade that controls cellular proliferation, differentiation, and survival in response to engagement of growth factor receptors on the cell surface. Over the past few years, structural and biochemical studies have provided new understanding of RAF autoregulation, RAF activation by RAS and the SHOC2 phosphatase complex, and RAF engagement with HSP90–CDC37 chaperone complexes. These studies have important implications for pharmacologic targeting of the pathway. They reveal RAF in distinct regulatory states and show that the functional RAF switch is an integrated complex of RAF with its substrate (MEK) and a 14-3-3 dimer. Here we review these advances, placing them in the context of decades of investigation of RAF regulation. We explore the insights they provide into aberrant activation of the pathway in cancer and RASopathies (developmental syndromes caused by germline mutations in components of the pathway).Expected final online publication date for the Annual Review of Biochemistry , Volume 93 is June 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

中文翻译：

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从 RAS 到 RAF 的信号传导：分子及其机制

RAF 家族蛋白激酶是 RAS/RAF/MAP 激酶通路中的关键节点，该通路是响应细胞表面生长因子受体的参与而控制细胞增殖、分化和存活的信号级联。在过去的几年中，结构和生化研究为 RAF 自身调节、RAS 和 SHOC2 磷酸酶复合物激活 RAF 以及 RAF 与 HSP90-CDC37 分子伴侣复合物的结合提供了新的认识。这些研究对该通路的药理学靶向具有重要意义。他们揭示了处于不同调节状态的 RAF，并表明功能性 RAF 开关是 RAF 与其底物 (MEK) 和 14-3-3 二聚体的集成复合物。在这里，我们回顾这些进步，将它们置于英国皇家空军数十年监管调查的背景下。我们探讨了他们对癌症和 RASopathies 中通路异常激活（由通路组成部分种系突变引起的发育综合征）提供的见解。《生物化学年度评论》第 93 卷的预计最终在线出版日期为 2024 年 6 月。请参阅http://www.annualreviews.org/page/journal/pubdates 了解修订后的估计。