PRL1 和 PRL3 是蛋白酪氨酸磷酸酶家族的成员，与癌症转移和不良预后相关。尽管对其蛋白磷酸酶活性进行了广泛的研究，但它们作为脂质磷酸酶的潜在作用仍然难以捉摸。方法：我们结合细胞测定、生化分析和蛋白质相互作用组分析进行了全面研究，以阐明 PRL1 和 PRL3 的脂质磷酸酶活性。进行功能研究来描述 PRL1/3 对巨胞饮作用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 为脂质磷酸酶，可与磷酸肌醇 (PIP) 脂质相互作用，将 PI(3,4)P2 和 PI(3,5)P2 转化为细胞膜上的 PI(3)P。 PRL 的这些酶活性促进膜皱褶、膜起泡和随后的巨胞饮作用的形成，促进营养物质提取、细胞迁移和侵袭，从而促进肿瘤的发展。 PRL 的这些酶活性促进膜皱褶、膜起泡和随后的巨胞饮作用的形成。此外，我们发现 PRL1/3 表达与神经胶质瘤发展之间存在相关性，表明它们参与神经胶质瘤的进展。结论：结合PRLs已被确定参与mTOR、EGFR和自噬的知识，我们总结了PRL1/3通过其脂质磷酸酶活性调节巨胞饮作用来协调营养物质传感、吸收和回收的生理作用。这种机制可以被面临营养耗尽的微环境的肿瘤细胞利用，突出了针对 PRL1/3 介导的巨胞饮作用在癌症治疗中的潜在治疗意义。© 作者。

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.© The author(s).