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Phosphatidylinositol 3,4-bisphosphate synthesis and turnover are spatially segregated in the endocytic pathway.
Journal of Biological Chemistry ( IF 5.5 ) Pub Date : 2019-12-12 , DOI: 10.1074/jbc.ra119.011774
Haibin Wang 1 , Dinah Loerke 2 , Caroline Bruns 1 , Rainer Müller 3 , Philipp-Alexander Koch 1 , Dmytro Puchkov 1 , Carsten Schultz 3, 4 , Volker Haucke 5, 6
Affiliation  

Phosphoinositides play crucial roles in intracellular membrane dynamics and cell signaling, with phosphatidylinositol (PI) 3-phosphates being the predominant phosphoinositide lipids at endosomes and lysosomes, whereas PI 4-phosphates, such as phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), are enriched at the cell surface including sites of endocytosis. How PI 4-phosphates and PI 3-phosphates are dynamically interconverted within the endocytic pathway and how this is controlled in space and time remains poorly understood. Here, combining live imaging, genome engineering, and acute chemical and genetic manipulations, we found that local synthesis of PI(3,4)P2 by phosphatidylinositol 3-kinase C2α at plasma membrane clathrin-coated pits is spatially segregated from its hydrolysis by the PI(3,4)P2-specific inositol polyphosphate 4-phosphatase 4A (INPP4A). We observed that INPP4A is dispensable for clathrin-mediated endocytosis and is undetectable in endocytic clathrin-coated pits. Instead, we found that INPP4A partially localizes to endosomes and that loss of INPP4A in HAP1 cancer cells perturbs signaling via AKT kinase and mTOR complex 1. These results reveal a function for INPP4-mediated PI(3,4)P2 hydrolysis in local regulation of growth factor and nutrient signals at endosomes in cancer cells. They further suggest a model whereby synthesis and turnover of PI(3,4)P2 are spatially segregated within the endocytic pathway to couple endocytic membrane traffic to growth factor and nutrient signaling.

中文翻译:

磷脂酰肌醇 3,4-二磷酸合成和周转在内吞途径中空间分离。

磷酸肌醇在细胞内膜动力学和细胞信号传导中起着至关重要的作用,其中磷脂酰肌醇 (PI) 3-磷酸盐是核内体和溶酶体中主要的磷酸肌醇脂质,而 PI 4-磷酸盐,例如磷脂酰肌醇 4,5-二磷酸盐 (PI(4,5 )P2),在细胞表面富集,包括内吞作用位点。PI 4-磷酸盐和 PI 3-磷酸盐如何在内吞途径中动态相互转化,以及如何在空间和时间上对其进行控制仍然知之甚少。在这里,结合实时成像、基因组工程以及急性化学和遗传操作,我们发现磷脂酰肌醇 3-激酶 C2α 在质膜网格蛋白包被的凹坑处局部合成 PI(3,4)P2 与其水解在空间上是分离的圆周率(3, 4)P2特异性肌醇多磷酸4-磷酸酶4A (INPP4A)。我们观察到 INPP4A 对于网格蛋白介导的内吞作用是可有可无的,并且在内吞网格蛋白包被的小坑中检测不到。相反,我们发现 INPP4A 部分定位于核内体,并且 HAP1 癌细胞中 INPP4A 的缺失扰乱了通过 AKT 激酶和 mTOR 复合物 1 的信号传导。这些结果揭示了 INPP4 介导的 PI(3,4)P2 水解在局部调节癌细胞核内体的生长因子和营养信号。他们进一步提出了一个模型,其中 PI(3,4)P2 的合成和周转在内吞途径中空间分离,以将内吞膜交通与生长因子和营养信号传导耦合。相反,我们发现 INPP4A 部分定位于核内体,并且 HAP1 癌细胞中 INPP4A 的缺失扰乱了通过 AKT 激酶和 mTOR 复合物 1 的信号传导。这些结果揭示了 INPP4 介导的 PI(3,4)P2 水解在局部调节癌细胞核内体的生长因子和营养信号。他们进一步提出了一个模型,其中 PI(3,4)P2 的合成和周转在内吞途径中空间分离,以将内吞膜交通与生长因子和营养信号传导耦合。相反,我们发现 INPP4A 部分定位于核内体,并且 HAP1 癌细胞中 INPP4A 的缺失扰乱了通过 AKT 激酶和 mTOR 复合物 1 的信号传导。这些结果揭示了 INPP4 介导的 PI(3,4)P2 水解在局部调节癌细胞核内体的生长因子和营养信号。他们进一步提出了一个模型,其中 PI(3,4)P2 的合成和周转在内吞途径中空间分离,以将内吞膜交通与生长因子和营养信号传导耦合。
更新日期:2020-01-24
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