Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA; email:
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
Annu Rev Biochem. 2024 Aug;93(1):289-316. doi: 10.1146/annurev-biochem-052521-040754. Epub 2024 Jul 2.
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).
Raf 家族蛋白激酶是 RAS/RAF/MAP 激酶途径中的一个关键节点，该信号级联反应控制着细胞的增殖、分化和存活，以响应细胞表面生长因子受体的结合。在过去的几年中，结构和生化研究为 RAF 的自身调控、RAS 和 SHOC2 磷酸酶复合物对 RAF 的激活以及 RAF 与 HSP90-CDC37 伴侣复合物的结合提供了新的认识。这些研究对该途径的药物靶向具有重要意义。它们揭示了 RAF 处于不同的调节状态，并表明 RAF 的功能开关是 RAF 与其底物（MEK）和 14-3-3 二聚体的集成复合物。在这里，我们回顾这些进展，并将它们置于 RAF 调节数十年研究的背景下。我们探讨了它们为癌症和 RAS 病（由该途径的组成部分的种系突变引起的发育综合征）中该途径的异常激活提供的见解。
