Promoting the activity of a receptor tyrosine phosphatase with a novel pH-responsive transmembrane agonist inhibits cancer-associated phenotypes.
Promoting the activity of a receptor tyrosine phosphatase with a novel pH-responsive transmembrane agonist inhibits cancer-associated phenotypes.
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DOI：
10.1002/pro.4742
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发表时间：
2023-09
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通过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）的平衡作用的严格控制。由于它们在减弱RTK的信号引发效力中的作用，RPTP长期以来一直被视为治疗靶点。然而，RPTP激活剂的开发仍然有限。我们以前报道过，同源二聚化的RPTP家族的代表性成员（蛋白酪氨酸磷酸酶受体J或PTPRJ）是由特定的跨膜（TM）残基。通过单点突变破坏这种相互作用促进PTPRJ接近其RTK底物（例如，EGFR和FLT3），减少RTK的磷酸化和下游信号传导，并最终拮抗RTK驱动的细胞表型。在这里，我们设计并测试了一系列PTPRJ的一流pH响应性TM肽激动剂，它们可溶于水溶液，但当pH降低至与肿瘤的酸性微环境相匹配时，它们作为螺旋TM结构域插入脂质膜中。最有希望的肽减少EGFR的磷酸化并抑制癌细胞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靶向肽结合剂可以提供一种潜在的变革性方法来研究RPTP的选择性机制，而无需较少的特异性抑制剂，并代表了一类针对RTK驱动的癌症的新型治疗方法。
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.
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