Regulatory Mechanisms and Novel Therapeutic Targeting Strategies for Protein Tyrosine Phosphatases.
Regulatory Mechanisms and Novel Therapeutic Targeting Strategies for Protein Tyrosine Phosphatases.
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DOI：
10.1021/acs.chemrev.7b00105
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发表时间：
2018-02-14
期刊：
影响因子：
62.1
通讯作者：
Zhang ZY
中科院分区：
文献类型：
--
作者：
Yu ZH;Zhang ZY
适当水平的酪氨酸蛋白磷酸化对于细胞对细胞外刺激的反应和保持细胞内环境的稳定是必不可少的。蛋白质酪氨酸磷酸化介导的信号通路的错误操作导致了许多人类疾病，这为治疗干预提供了巨大的机会。虽然蛋白酪氨酸激酶在协调酪氨酸磷酸化网络和基于靶点的药物发现中的重要性早已被认识到，但蛋白酪氨酸磷酸酶(PTPs)在细胞信号和疾病生物学中的重要性历来被低估，这在很大程度上是由于人们错误地假设它们主要是结构性和管家酶。在这里，我们提供了一个全面的审查一些调节机制，包括氧化还原调节，变构调节，和蛋白质齐聚，在控制PTP的活性。这些调控机制是PTP介导的众多生化事件中不可或缺的一部分，并强化了PTP是细胞信号不可或缺的特定调节器的概念。我们还讨论了这些PTP调节机制的破坏如何导致人类疾病，以及如何将这些不同的调节机制用于新的治疗开发。
Appropriate level of protein phosphorylation on tyrosine is essential for cells to react to extracellular stimuli and keep cellular homeostasis. Faulty operation of signal pathways mediated by protein tyrosine phosphorylation causes numerous human diseases, which presents enormous opportunities for therapeutic interventions. While the importance of protein tyrosine kinases in orchestrating the tyrosine phosphorylation networks and in target-based drug discovery has long been recognized, the significance of protein tyrosine phosphatases (PTPs) in cellular signaling and disease biology has historically been underappreciated, due to a large extent an erroneous assumption that they are largely constitutive and housekeeping enzymes. Here, we provide a comprehensive examination on a number of regulatory mechanisms including redox modulation, allosteric regulation, and protein oligomerization, in controlling PTP activity. These regulatory mechanisms are integral to the myriad PTP-mediated biochemical events and reinforce the concept that PTPs are indispensable and specific modulators of cellular signaling. We also discuss how disruption of these PTP regulatory mechanisms can cause human diseases and how these diverse regulatory mechanisms can be exploited for novel therapeutic development.
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