Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology, 2-3-26, Aomi, Koto-ku, Tokyo, 135-0064, Japan.
Nat Commun. 2017 Nov 1;8(1):1246. doi: 10.1038/s41467-017-01255-3.
Yes-associated protein (YAP) is a recently discovered growth-promoting transcription coactivator that has been shown to regulate the malignancy of various cancers. How YAP is regulated is not fully understood. Here, we show that one of the factors regulating YAP is phosphatidylserine (PS) in recycling endosomes (REs). We use proximity biotinylation to find proteins proximal to PS. Among these proteins are YAP and multiple proteins related to YAP signalling. Knockdown of ATP8A1 (an RE PS-flippase) or evectin-2 (an RE-resident protein) and masking of PS in the cytoplasmic leaflet of membranes, all suppress nuclear localization of YAP and YAP-dependent transcription. ATP8A1 knockdown increases the phosphorylated (activated) form of Lats1 that phosphorylates and inactivates YAP, whereas evectin-2 knockdown reduces the ubiquitination and increased the level of Lats1. The proliferation of YAP-dependent metastatic cancer cells is suppressed by knockdown of ATP8A1 or evectin-2. These results suggest a link between a membrane phospholipid and cell proliferation.
Yes 相关蛋白（YAP）是一种新发现的促进生长的转录共激活因子，已被证明可调节多种癌症的恶性程度。YAP 的调节机制尚未完全阐明。在这里，我们表明，调节 YAP 的因素之一是再循环内体（REs）中的磷脂酰丝氨酸（PS）。我们使用邻近生物素化来寻找与 PS 接近的蛋白质。在这些蛋白质中，有 YAP 和多个与 YAP 信号相关的蛋白质。敲低 ATP8A1（RE PS 翻转酶）或 evectin-2（RE 驻留蛋白），并掩盖膜细胞质层中的 PS，均可抑制 YAP 的核定位和 YAP 依赖性转录。ATP8A1 敲低增加了磷酸化（激活）形式的 Lats1，该磷酸化并失活 YAP，而 evectin-2 敲低减少了泛素化并增加了 Lats1 的水平。YAP 依赖性转移性癌细胞的增殖被敲低 ATP8A1 或 evectin-2 抑制。这些结果表明膜磷脂与细胞增殖之间存在联系。
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