Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, U.S.A.
Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, U.S.A.
Biochem Soc Trans. 2021 Feb 26;49(1):253-267. doi: 10.1042/BST20200507.
The RAF-MEK-ERK mitogen-activated protein kinase (MAPK) cascade is aberrantly activated in a diverse set of human cancers and the RASopathy group of genetic developmental disorders. This protein kinase cascade is one of the most intensely studied cellular signaling networks and has been frequently targeted by the pharmaceutical industry, with more than 30 inhibitors either approved or under clinical evaluation. The ERK-MAPK cascade was originally depicted as a serial and linear, unidirectional pathway that relays extracellular signals, such as mitogenic stimuli, through the cytoplasm to the nucleus. However, we now appreciate that this three-tiered protein kinase cascade is a central core of a complex network with dynamic signaling inputs and outputs and autoregulatory loops. Despite our considerable advances in understanding the ERK-MAPK network, the ability of cancer cells to adapt to the inhibition of key nodes reveals a level of complexity that remains to be fully understood. In this review, we summarize important developments in our understanding of the ERK-MAPK network and identify unresolved issues for ongoing and future study.
RAF-MEK-ERK 丝裂原活化蛋白激酶（MAPK）级联在多种人类癌症和 RAS 病遗传发育障碍组中异常激活。这个蛋白激酶级联是研究最深入的细胞信号网络之一，制药行业经常针对它进行研究，已有超过 30 种抑制剂被批准或正在临床评估中。ERK-MAPK 级联最初被描绘为一个串行和线性的、单向的途径，将细胞外信号（如有丝分裂刺激）从细胞质传递到细胞核。然而，我们现在意识到，这个三层蛋白激酶级联是一个复杂网络的核心，具有动态的信号输入和输出以及自调节环。尽管我们在理解 ERK-MAPK 网络方面取得了相当大的进展，但癌细胞适应关键节点抑制的能力揭示了仍有待充分理解的复杂性水平。在这篇综述中，我们总结了我们对 ERK-MAPK 网络的理解的重要进展，并确定了正在进行和未来研究中未解决的问题。
