Cell signalling governs cellular behaviour and is therefore subject to tight spatiotemporal regulation. Signalling output is modulated by specialized cell membranes and vesicles which contain unique combinations of lipids and proteins. The phosphatidylinositol 4,5‐bisphosphate (PI(4,5)P₂), an important component of the plasma membrane as well as other subcellular membranes, is involved in multiple processes, including signalling. However, which enzymes control the turnover of non‐plasma membrane PI(4,5)P₂, and their impact on cell signalling and function at the organismal level are unknown. Here, we identify Paladin as a vascular PI(4,5)P₂ phosphatase regulating VEGFR2 endosomal signalling and angiogenesis. Paladin is localized to endosomal and Golgi compartments and interacts with vascular endothelial growth factor receptor 2 (VEGFR2) in vitro and in vivo. Loss of Paladin results in increased internalization of VEGFR2, over‐activation of extracellular regulated kinase 1/2, and hypersprouting of endothelial cells in the developing retina of mice. These findings suggest that inhibition of Paladin, or other endosomal PI(4,5)P₂ phosphatases, could be exploited to modulate VEGFR2 signalling and angiogenesis, when direct and full inhibition of the receptor is undesirable.

中文翻译：

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Paladin 是一种磷酸肌醇磷酸酶，可调节内体 VEGFR2 信号传导和血管生成

细胞信号控制细胞行为，因此受到严格的时空调节。信号输出由特殊的细胞膜和囊泡调节，这些细胞膜和囊泡含有独特的脂质和蛋白质组合。磷脂酰肌醇 4,5-二磷酸 (PI(4,5)P ₂ ) 是质膜和其他亚细胞膜的重要组成部分，参与多个过程，包括信号传导。然而，哪些酶控制着非质膜 PI(4,5)P ₂的转换，以及它们在有机体水平上对细胞信号传导和功能的影响是未知的。在这里，我们将 Paladin 识别为血管 PI(4,5)P ₂磷酸酶调节 VEGFR2 内体信号传导和血管生成。Paladin 定位于内体和高尔基体区室，并在体外和体内与血管内皮生长因子受体 2 (VEGFR2) 相互作用。Paladin 的缺失导致 VEGFR2 的内化增加，细胞外调节激酶 1/2 的过度激活，以及小鼠发育中的视网膜中内皮细胞的过度生长。这些发现表明，当不希望直接和完全抑制受体时，可以利用对Paladin 或其他内体 PI(4,5)P _{2磷酸酶的抑制来调节 VEGFR2 信号传导和血管生成。}