Sacchetti Cristiano, Bottini Nunzio
Division of Rheumatology, Allergy and Immunology, Department of Medicine, University of California, San Diego, 9500 Gilman Drive MC #0656, La Jolla, CA, 92093, USA.
Curr Rheumatol Rep. 2017 May;19(5):28. doi: 10.1007/s11926-017-0655-7.
The pathogenesis of systemic sclerosis depends on a complex interplay between autoimmunity, vasculopathy, and fibrosis. Reversible phosphorylation on tyrosine residues, in response to growth factors and other stimuli, critically regulates each one of these three key pathogenic processes. Protein tyrosine kinases, the enzymes that catalyze addition of phosphate to tyrosine residues, are known players in systemic sclerosis, and tyrosine kinase inhibitors are undergoing clinical trials for treatment of this disease. Until recently, the role of tyrosine phosphatases-the enzymes that counteract the action of tyrosine kinases by removing phosphate from tyrosine residues-in systemic sclerosis has remained largely unknown. Here, we review the function of tyrosine phosphatases in pathways relevant to the pathogenesis of systemic sclerosis and their potential promise as therapeutic targets to halt progression of this debilitating rheumatic disease.
Protein tyrosine phosphatases are emerging as important regulators of a multitude of signaling pathways and undergoing validation as molecular targets for cancer and other common diseases. Recent advances in drug discovery are paving the ways to develop new classes of tyrosine phosphatase modulators to treat human diseases. Although so far only few reports have focused on tyrosine phosphatases in systemic sclerosis, these enzymes play a role in multiple pathways relevant to disease pathogenesis. Further studies in this field are warranted to explore the potential of tyrosine phosphatases as drug targets for systemic sclerosis.
系统性硬化症的发病机制取决于自身免疫、血管病变和纤维化之间复杂的相互作用。响应生长因子和其他刺激，酪氨酸残基上的可逆磷酸化对这三个关键致病过程中的每一个都起着至关重要的调节作用。蛋白酪氨酸激酶是催化磷酸基团添加到酪氨酸残基上的酶，是系统性硬化症中已知的作用因子，酪氨酸激酶抑制剂正在进行治疗该疾病的临床试验。直到最近，酪氨酸磷酸酶（通过从酪氨酸残基上去除磷酸基团来对抗酪氨酸激酶作用的酶）在系统性硬化症中的作用在很大程度上仍不清楚。在此，我们综述酪氨酸磷酸酶在与系统性硬化症发病机制相关的信号通路中的功能，以及它们作为治疗靶点以阻止这种使人衰弱的风湿性疾病进展的潜在前景。
蛋白酪氨酸磷酸酶正在成为多种信号通路的重要调节因子，并正在作为癌症和其他常见疾病的分子靶点进行验证。药物研发的最新进展为开发新型酪氨酸磷酸酶调节剂来治疗人类疾病铺平了道路。尽管到目前为止仅有少数报道关注系统性硬化症中的酪氨酸磷酸酶，但这些酶在与疾病发病机制相关的多个信号通路中发挥作用。该领域需要进一步研究以探索酪氨酸磷酸酶作为系统性硬化症药物靶点的潜力。
