Regulatory Mechanisms and Novel Therapeutic Targeting Strategies for Protein Tyrosine Phosphatases,Chemical Reviews

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Regulatory Mechanisms and Novel Therapeutic Targeting Strategies for Protein Tyrosine Phosphatases
Chemical Reviews ( IF 51.4 ) Pub Date : 2017-05-25 00:00:00 , DOI: 10.1021/acs.chemrev.7b00105
Zhi-Hong Yu ₁ , Zhong-Yin Zhang ₁

Affiliation

An appropriate level of protein phosphorylation on tyrosine is essential for cells to react to extracellular stimuli and maintain cellular homeostasis. Faulty operation of signal pathways mediated by protein tyrosine phosphorylation causes numerous human diseases, which presents enormous opportunities for therapeutic intervention. 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 to an erroneous assumption that they are largely constitutive and housekeeping enzymes. Here, we provide a comprehensive examination of a number of regulatory mechanisms, including redox modulation, allosteric regulation, and protein oligomerization, that control 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.

中文翻译：

蛋白酪氨酸磷酸酶的调控机制和新型治疗靶向策略

酪氨酸上适当水平的蛋白质磷酸化对于细胞对细胞外刺激做出反应并维持细胞稳态至关重要。蛋白质酪氨酸磷酸化介导的信号通路的错误操作会导致多种人类疾病，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 (PTP) 在细胞信号传导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错误地认为它们主要是组成酶和管家酶。在这里，我们对控制 PTP 活性的多种调控机制进行了全面检查，包括氧化还原调节、变构调节和蛋白质寡聚化。这些调节机制是无数 PTP 介导的生化事件的组成部分，并强化了 PTP 是细胞信号传导不可或缺的特异性调节剂的概念。我们还讨论了这些 PTP 调节机制的破坏如何导致人类疾病，以及如何利用这些不同的调节机制来开发新的治疗方法。

更新日期：2017-05-25

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