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：

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蛋白质酪氨酸磷酸酶的调控机制和新型治疗靶向策略

酪氨酸上适当的蛋白质磷酸化水平对于细胞对细胞外刺激作出反应并维持细胞稳态至关重要。蛋白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机会。长期以来，人们已经认识到蛋白质酪氨酸激酶在协调酪氨酸磷酸化网络和基于靶标的药物发现中的重要性，但由于很大程度上，蛋白质酪氨酸磷酸酶（PTP）在细胞信号传导和疾病生物学中的重要性一直未被重视误以为它们主要是组成型和看家酶。在这里，我们对许多调节机制进行了全面检查，包括氧化还原调节，控制PTP活性的变构调节和蛋白质低聚。这些调节机制是无数PTP介导的生化事件必不可少的部分，并强化了PTP是必不可少的概念以及细胞信号转导的特定调节剂的概念。我们还讨论了这些PTP调控机制的破坏如何导致人类疾病，以及如何利用这些多样的调控机制进行新型治疗。