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Abstract：
PRL1 and PRL3, members of the protein tyrosine phosphatase family, have been associated with cancer metastasis and poor prognosis. Despite extensive research on their protein phosphatase activity, their potential role as lipid phosphatases remains elusive. Methods: We conducted comprehensive investigations to elucidate the lipid phosphatase activity of PRL1 and PRL3 using a combination of cellular assays, biochemical analyses, and protein interactome profiling. Functional studies were performed to delineate the impact of PRL1/3 on macropinocytosis and its implications in cancer biology. Results: Our study has identified PRL1 and PRL3 as lipid phosphatases that interact with phosphoinositide (PIP) lipids, converting PI(3,4)P2 and PI(3,5)P2 into PI(3)P on the cellular membranes. These enzymatic activities of PRLs promote the formation of membrane ruffles, membrane blebbing and subsequent macropinocytosis, facilitating nutrient extraction, cell migration, and invasion, thereby contributing to tumor development. These enzymatic activities of PRLs promote the formation of membrane ruffles, membrane blebbing and subsequent macropinocytosis. Additionally, we found a correlation between PRL1/3 expression and glioma development, suggesting their involvement in glioma progression. Conclusions: Combining with the knowledge that PRLs have been identified to be involved in mTOR, EGFR and autophagy, here we concluded the physiological role of PRL1/3 in orchestrating the nutrient sensing, absorbing and recycling via regulating macropinocytosis through its lipid phosphatase activity. This mechanism could be exploited by tumor cells facing a nutrient-depleted microenvironment, highlighting the potential therapeutic significance of targeting PRL1/3-mediated macropinocytosis in cancer treatment.
摘要：
PRL1和PRL3，蛋白酪氨酸磷酸酶家族的成员，已与癌症转移和不良预后有关。尽管对它们的蛋白磷酸酶活性进行了广泛的研究，它们作为脂质磷酸酶的潜在作用仍然难以捉摸。方法：我们进行了全面的调查，以阐明PRL1和PRL3的脂质磷酸酶活性，使用细胞试验的组合，生化分析，和蛋白质相互作用组分析。进行了功能研究以描述PRL1/3对巨细胞增殖的影响及其在癌症生物学中的意义。结果：我们的研究已确定PRL1和PRL3为与磷酸肌醇（PIP）脂质相互作用的脂质磷酸酶，在细胞膜上将PI(3,4)P2和PI(3,5)P2转化为PI(3)P。PRL的这些酶活性促进膜皱褶的形成，膜起泡和随后的巨噬细胞增多，促进营养提取，细胞迁移，和入侵,从而促进肿瘤的发展。PRL的这些酶活性促进膜皱褶的形成，膜起泡和随后的巨噬细胞增多。此外,我们发现PRL1/3的表达与胶质瘤的发展之间存在相关性，提示他们参与了神经胶质瘤的进展。结论：结合已确定PRL参与mTOR的知识，EGFR与自噬,在这里，我们总结了PRL1/3在协调营养传感中的生理作用，通过其脂质磷酸酶活性调节巨细胞作用来吸收和再循环。这种机制可以被面临营养耗尽的微环境的肿瘤细胞利用，强调在癌症治疗中靶向PRL1/3介导的巨噬细胞增多症的潜在治疗意义。
