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PTEN 去磷酸化 Abi1 以促进上皮形态发生。

PTEN dephosphorylates Abi1 to promote epithelial morphogenesis.

机构信息

Department of Surgery, Rutgers University Robert Wood Johnson Medical School, New Brunswick, NJ.

Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada.

出版信息

J Cell Biol. 2020 Sep 7;219(9). doi: 10.1083/jcb.201910041.

DOI:10.1083/jcb.201910041
PMID:32673396
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7480098/
Abstract

The tumor suppressor PTEN is essential for early development. Its lipid phosphatase activity converts PIP3 to PIP2 and antagonizes the PI3K-Akt pathway. In this study, we demonstrate that PTEN's protein phosphatase activity is required for epiblast epithelial differentiation and polarization. This is accomplished by reconstitution of PTEN-null embryoid bodies with PTEN mutants that lack only PTEN's lipid phosphatase activity or both PTEN's lipid and protein phosphatase activities. Phosphotyrosine antibody immunoprecipitation and mass spectrometry were used to identify Abi1, a core component of the WASP-family verprolin homologous protein (WAVE) regulatory complex (WRC), as a new PTEN substrate. We demonstrate that PTEN dephosphorylation of Abi1 at Y213 and S216 results in Abi1 degradation through the calpain pathway. This leads to down-regulation of the WRC and reorganization of the actin cytoskeleton. The latter is critical to the transformation of nonpolar pluripotent stem cells into the polarized epiblast epithelium. Our findings establish a link between PTEN and WAVE-Arp2/3-regulated actin cytoskeletal dynamics in epithelial morphogenesis.

摘要

肿瘤抑制因子 PTEN 对早期发育至关重要。它的脂质磷酸酶活性将 PIP3 转化为 PIP2，并拮抗 PI3K-Akt 途径。在这项研究中，我们证明了 PTEN 的蛋白磷酸酶活性对于上胚层上皮细胞的分化和极化是必需的。这是通过用仅缺乏 PTEN 的脂质磷酸酶活性或同时缺乏 PTEN 的脂质和蛋白磷酸酶活性的 PTEN 突变体重建 PTEN 缺陷的胚胎体来实现的。使用磷酸酪氨酸抗体免疫沉淀和质谱分析鉴定出 Abi1，即 WASP 家族 verprolin 同源蛋白 (WAVE) 调节复合物 (WRC) 的核心组成部分，是一种新的 PTEN 底物。我们证明，PTEN 在 Y213 和 S216 处使 Abi1 去磷酸化，导致 Abi1 通过钙蛋白酶途径降解。这导致 WRC 的下调和肌动蛋白细胞骨架的重组。后者对于将非极性多能干细胞转化为极化的上胚层上皮至关重要。我们的发现确立了 PTEN 与 WAVE-Arp2/3 调节的上皮形态发生中的肌动蛋白细胞骨架动力学之间的联系。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64a6/7480098/c164545d17c6/JCB_201910041_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64a6/7480098/cd6a257710c0/JCB_201910041_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64a6/7480098/53fc9c23d23b/JCB_201910041_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64a6/7480098/199a1f343a7e/JCB_201910041_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64a6/7480098/3f02e0bb3809/JCB_201910041_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64a6/7480098/8e35a7c5c100/JCB_201910041_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64a6/7480098/697ddd4a3bd2/JCB_201910041_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64a6/7480098/762c32ef0ff4/JCB_201910041_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64a6/7480098/a6848b9e96a1/JCB_201910041_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64a6/7480098/a07a3bf4945f/JCB_201910041_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64a6/7480098/ab6a175b5cda/JCB_201910041_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64a6/7480098/9913f3457b21/JCB_201910041_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64a6/7480098/c164545d17c6/JCB_201910041_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64a6/7480098/cd6a257710c0/JCB_201910041_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64a6/7480098/53fc9c23d23b/JCB_201910041_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64a6/7480098/199a1f343a7e/JCB_201910041_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64a6/7480098/3f02e0bb3809/JCB_201910041_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64a6/7480098/8e35a7c5c100/JCB_201910041_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64a6/7480098/697ddd4a3bd2/JCB_201910041_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64a6/7480098/762c32ef0ff4/JCB_201910041_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64a6/7480098/a6848b9e96a1/JCB_201910041_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64a6/7480098/a07a3bf4945f/JCB_201910041_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64a6/7480098/ab6a175b5cda/JCB_201910041_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64a6/7480098/9913f3457b21/JCB_201910041_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64a6/7480098/c164545d17c6/JCB_201910041_FigS5.jpg

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