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效应物介导的 ERM 激活局部抑制 RhoA 活性以塑造顶端细胞结构域。

Effector-mediated ERM activation locally inhibits RhoA activity to shape the apical cell domain.

机构信息

Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY.

出版信息

J Cell Biol. 2021 Jun 7;220(6). doi: 10.1083/jcb.202007146.

DOI:10.1083/jcb.202007146
PMID:33836044
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8185690/
Abstract

Activated ezrin-radixin-moesin (ERM) proteins link the plasma membrane to the actin cytoskeleton to generate apical structures, including microvilli. Among many kinases implicated in ERM activation are the homologues LOK and SLK. CRISPR/Cas9 was used to knock out all ERM proteins or LOK/SLK in human cells. LOK/SLK knockout eliminates all ERM-activating phosphorylation. The apical domains of cells lacking LOK/SLK or ERMs are strikingly similar and selectively altered, with loss of microvilli and with junctional actin replaced by ectopic myosin-II-containing apical contractile structures. Constitutively active ezrin can reverse the phenotypes of either ERM or LOK/SLK knockouts, indicating that a central function of LOK/SLK is to activate ERMs. Both knockout lines have elevated active RhoA with concomitant enhanced myosin light chain phosphorylation, revealing that active ERMs are negative regulators of RhoA. As RhoA-GTP activates LOK/SLK to activate ERM proteins, the ability of active ERMs to negatively regulate RhoA-GTP represents a novel local feedback loop necessary for the proper apical morphology of epithelial cells.

摘要

激活的埃兹蛋白（ezrin）-根蛋白（radixin）-膜突蛋白（moesin，ERM）蛋白将质膜与肌动蛋白细胞骨架连接起来，形成顶端结构，包括微绒毛。在许多被认为能激活 ERM 的激酶中，包括同源物 LOK 和 SLK。利用 CRISPR/Cas9 敲除人细胞中的所有 ERM 蛋白或 LOK/SLK。LOK/SLK 敲除消除了所有 ERM 激活的磷酸化。缺乏 LOK/SLK 或 ERMs 的细胞的顶端结构域非常相似，并选择性地改变，微绒毛缺失，连接的肌动蛋白被异位含有肌球蛋白-II 的顶端收缩结构取代。组成性激活的 ezrin 可以逆转 ERM 或 LOK/SLK 敲除的表型，表明 LOK/SLK 的一个核心功能是激活 ERMs。两种敲除系均具有升高的活性 RhoA，同时伴有增强的肌球蛋白轻链磷酸化，表明活性 ERMs 是 RhoA 的负调节剂。由于 RhoA-GTP 激活 LOK/SLK 以激活 ERM 蛋白，因此活性 ERMs 负调节 RhoA-GTP 的能力代表了上皮细胞正确顶端形态所必需的新型局部反馈回路。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ad1/8185690/195599809246/JCB_202007146_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ad1/8185690/9877a73e87a2/JCB_202007146_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ad1/8185690/60378ee8ad57/JCB_202007146_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ad1/8185690/7d2b371fc3a0/JCB_202007146_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ad1/8185690/bf3be9bca247/JCB_202007146_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ad1/8185690/84958aa266aa/JCB_202007146_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ad1/8185690/da39dc917c96/JCB_202007146_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ad1/8185690/56c4a7375fc5/JCB_202007146_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ad1/8185690/ffff0dc1928c/JCB_202007146_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ad1/8185690/3ed89b8b3b19/JCB_202007146_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ad1/8185690/1f696a2ce73e/JCB_202007146_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ad1/8185690/8eb849568fe7/JCB_202007146_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ad1/8185690/6355b4334a67/JCB_202007146_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ad1/8185690/195599809246/JCB_202007146_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ad1/8185690/9877a73e87a2/JCB_202007146_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ad1/8185690/60378ee8ad57/JCB_202007146_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ad1/8185690/7d2b371fc3a0/JCB_202007146_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ad1/8185690/bf3be9bca247/JCB_202007146_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ad1/8185690/84958aa266aa/JCB_202007146_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ad1/8185690/da39dc917c96/JCB_202007146_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ad1/8185690/56c4a7375fc5/JCB_202007146_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ad1/8185690/ffff0dc1928c/JCB_202007146_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ad1/8185690/3ed89b8b3b19/JCB_202007146_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ad1/8185690/1f696a2ce73e/JCB_202007146_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ad1/8185690/8eb849568fe7/JCB_202007146_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ad1/8185690/6355b4334a67/JCB_202007146_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ad1/8185690/195599809246/JCB_202007146_Fig8.jpg

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