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Abstract：
Cell signaling by receptor protein tyrosine kinases (RTKs) is tightly controlled by the counterbalancing actions of receptor protein tyrosine phosphatases (RPTPs). Due to their role in attenuating the signal-initiating potency of RTKs, RPTPs have long been viewed as therapeutic targets. However, the development of activators of RPTPs has remained limited. We previously reported that the homodimerization of a representative member of the RPTP family (protein tyrosine phosphatase receptor J or PTPRJ) is regulated by specific transmembrane (TM) residues. Disrupting this interaction by single point mutations promotes PTPRJ access to its RTK substrates (e.g., EGFR and FLT3), reduces RTK\'s phosphorylation and downstream signaling, and ultimately antagonizes RTK-driven cell phenotypes. Here, we designed and tested a series of first-in-class pH-responsive TM peptide agonists of PTPRJ that are soluble in aqueous solution but insert as a helical TM domain in lipid membranes when the pH is lowered to match that of the acidic microenvironment of tumors. The most promising peptide reduced EGFR\'s phosphorylation and inhibited cancer cell EGFR-driven migration and proliferation, similar to the PTPRJ\'s TM point mutations. Developing tumor-selective and TM-targeting peptide binders of critical RPTPs could afford a potentially transformative approach to studying RPTP\'s selectivity mechanism without requiring less specific inhibitors and represent a novel class of therapeutics against RTK-driven cancers.
摘要：
受体蛋白酪氨酸激酶（RTK）的细胞信号传导受到受体蛋白酪氨酸磷酸酶（RPTP）的抵消作用的严格控制。由于它们在衰减RTK的信号启动效能中的作用，RPTP长期以来一直被视为治疗靶标。然而,RPTP激活剂的开发仍然有限。我们先前报道了RPTP家族的代表性成员（蛋白酪氨酸磷酸酶受体J或PTPRJ）的同二聚体化受特异性跨膜（TM）残基的调节。通过单点突变破坏这种相互作用会促进PTPRJ访问其RTK底物（例如，EGFR和FLT3），减少RTK的磷酸化和下游信号，并最终拮抗RTK驱动的细胞表型。这里,我们设计并测试了一系列一流的PTPRJ的pH响应性TM肽激动剂,这些激动剂可溶于水溶液,但当pH降低至与肿瘤酸性微环境相匹配时,作为螺旋TM结构域插入脂质膜中.最有前途的肽减少EGFR的磷酸化和抑制癌细胞EGFR驱动的迁移和增殖，类似于PTPRJ的TM点突变。开发关键RPTP的肿瘤选择性和TM靶向肽结合物可以提供一种潜在的转化方法来研究RPTP的选择性机制，而不需要特异性较少的抑制剂，并且代表了针对RTK驱动的癌症的新型疗法。本文受版权保护。保留所有权利。
