Institute for Research in Immunology and Cancer, Montreal, Quebec, Canada (S.Ma., C.T., S.Me.); and Molecular Biology Program, Faculty of Medicine (C.T., S.Me.) and Department of Pharmacology and Physiology (S.Me.), Université de Montréal, Montreal, Quebec, Canada.
Institute for Research in Immunology and Cancer, Montreal, Quebec, Canada (S.Ma., C.T., S.Me.); and Molecular Biology Program, Faculty of Medicine (C.T., S.Me.) and Department of Pharmacology and Physiology (S.Me.), Université de Montréal, Montreal, Quebec, Canada
Pharmacol Rev. 2021 Oct;73(4):263-296. doi: 10.1124/pharmrev.120.000170.
Mitogen-activated protein kinase (MAPK) cascades are evolutionarily conserved signaling pathways that play essential roles in transducing extracellular environmental signals into diverse cellular responses to maintain homeostasis. These pathways are classically organized into an architecture of three sequentially acting protein kinases: a MAPK kinase kinase that phosphorylates and activates a MAPK kinase, which in turn phosphorylates and activates the effector MAPK. The activity of MAPKs is tightly regulated by phosphorylation of their activation loop, which can be modulated by positive and negative feedback mechanisms to control the amplitude and duration of the signal. The signaling outcomes of MAPK pathways are further regulated by interactions of MAPKs with scaffolding and regulatory proteins. Accumulating evidence indicates that, in addition to these mechanisms, MAPK signaling is commonly regulated by ubiquitin-proteasome system (UPS)-mediated control of the stability and abundance of MAPK pathway components. Notably, the biologic activity of some MAPKs appears to be regulated mainly at the level of protein turnover. Recent studies have started to explore the potential of targeted protein degradation as a powerful strategy to investigate the biologic functions of individual MAPK pathway components and as a new therapeutic approach to overcome resistance to current small-molecule kinase inhibitors. Here, we comprehensively review the mechanisms, physiologic importance, and pharmacological potential of UPS-mediated protein degradation in the control of MAPK signaling. SIGNIFICANCE STATEMENT: Accumulating evidence highlights the importance of targeted protein degradation by the ubiquitin-proteasome system in regulating and fine-tuning the signaling output of mitogen-activated protein kinase (MAPK) pathways. Manipulating protein levels of MAPK cascade components may provide a novel approach for the development of selective pharmacological tools and therapeutics.
丝裂原活化蛋白激酶（MAPK）级联反应是进化上保守的信号通路，在将细胞外环境信号转导为各种细胞反应以维持内稳态方面发挥着重要作用。这些途径通常被组织成一个由三个依次作用的蛋白激酶组成的结构：一个 MAPK 激酶激酶磷酸化并激活 MAPK 激酶，后者又磷酸化并激活效应 MAPK。MAPK 的活性受到其激活环磷酸化的严格调控，正反馈和负反馈机制可以调节该磷酸化过程，从而控制信号的幅度和持续时间。MAPK 途径的信号转导结果进一步受到 MAPK 与支架和调节蛋白相互作用的调节。越来越多的证据表明，除了这些机制之外，MAPK 信号还通常受到泛素-蛋白酶体系统（UPS）介导的 MAPK 途径成分稳定性和丰度调控。值得注意的是，一些 MAPK 的生物学活性似乎主要受到蛋白质周转率的调节。最近的研究开始探索靶向蛋白降解作为一种强大策略的潜力，以研究单个 MAPK 途径成分的生物学功能，并作为克服对当前小分子激酶抑制剂耐药性的新治疗方法。在这里，我们全面综述了 UPS 介导的蛋白质降解在 MAPK 信号调控中的机制、生理重要性和药理学潜力。意义陈述：越来越多的证据强调了泛素-蛋白酶体系统的靶向蛋白降解在调节和微调丝裂原活化蛋白激酶（MAPK）途径的信号输出方面的重要性。操纵 MAPK 级联成分的蛋白质水平可能为开发选择性药理学工具和治疗方法提供一种新方法。
