Queen Mary School, Nanchang University, Nanchang 330031, China.
Provincial Key Laboratory of Tumor Pathogens and Molecular Pathology, Nanchang University, Nanchang 330031, China.
Int J Mol Sci. 2022 May 5;23(9):5158. doi: 10.3390/ijms23095158.
The Ras-Raf-MEK-ERK signaling pathway, the first well-established MAPK pathway, plays essential roles in cell proliferation, survival, differentiation and development. It is activated in over 40% of human cancers owing to mutations of Ras, membrane receptor tyrosine kinases and other oncogenes. The Raf family consists of three isoforms, A-Raf, B-Raf and C-Raf. Since the first discovery of a truncated mutant of C-Raf as a transforming oncogene carried by a murine retrovirus, forty years of extensive studies have provided a wealth of information on the mechanisms underlying the activation, regulation and biological functions of the Raf family. However, the mechanisms by which activation of A-Raf and C-Raf is accomplished are still not completely understood. In contrast, B-Raf can be easily activated by binding of Ras-GTP, followed by -autophosphorylation of the activation loop, which accounts for the fact that this isoform is frequently mutated in many cancers, especially melanoma. The identification of oncogenic B-Raf mutations has led to accelerated drug development that targets Raf signaling in cancer. However, the effort has not proved as effective as anticipated, inasmuch as the mechanism of Raf activation involves multiple steps, factors and phosphorylation of different sites, as well as complex interactions between Raf isoforms. In this review, we will focus on the physiological complexity of the regulation of Raf kinases and their connection to the ERK phosphorylation cascade and then discuss the role of Raf in tumorigenesis and the clinical application of Raf inhibitors in the treatment of cancer.
Ras-Raf-MEK-ERK 信号通路是第一个被充分证实的 MAPK 通路，在细胞增殖、存活、分化和发育中发挥着重要作用。由于 Ras、膜受体酪氨酸激酶和其他癌基因的突变，该通路在超过 40%的人类癌症中被激活。Raf 家族由三种异构体组成，即 A-Raf、B-Raf 和 C-Raf。自第一个携带鼠逆转录病毒的截断突变型 C-Raf 被发现作为转化癌基因以来，四十年的广泛研究为 Raf 家族的激活、调节和生物学功能的机制提供了丰富的信息。然而，A-Raf 和 C-Raf 激活的机制仍不完全清楚。相比之下，B-Raf 可以通过 Ras-GTP 的结合而被轻易激活，随后激活环的自动磷酸化，这就是为什么该异构体在许多癌症中经常发生突变，尤其是黑色素瘤的原因。致癌 B-Raf 突变的鉴定加速了针对癌症中 Raf 信号的药物开发。然而，这一努力并没有像预期的那样有效，因为 Raf 激活的机制涉及多个步骤、因素和不同位点的磷酸化，以及 Raf 异构体之间的复杂相互作用。在这篇综述中，我们将重点讨论 Raf 激酶调节的生理复杂性及其与 ERK 磷酸化级联的联系，然后讨论 Raf 在肿瘤发生中的作用以及 Raf 抑制剂在癌症治疗中的临床应用。
