• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

CDC42 中心信号单元是内皮完整性的主要正向调节因子。

A CDC42-centered signaling unit is a dominant positive regulator of endothelial integrity.

机构信息

Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands.

Department of Molecular Cytology, Swammerdam Institute for Life Sciences, van Leeuwenhoek Centre for Advanced Microscopy, University of Amsterdam, Amsterdam, The Netherlands.

出版信息

Sci Rep. 2017 Aug 31;7(1):10132. doi: 10.1038/s41598-017-10392-0.

DOI:10.1038/s41598-017-10392-0
PMID:28860633
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5579287/
Abstract

Endothelial barrier function is carefully controlled to protect tissues from edema and damage inflicted by extravasated leukocytes. RhoGTPases, in conjunction with myriad regulatory proteins, exert both positive and negative effects on the endothelial barrier integrity. Precise knowledge about the relevant mechanisms is currently fragmented and we therefore performed a comprehensive analysis of endothelial barrier regulation by RhoGTPases and their regulators. Combining RNAi with electrical impedance measurements we quantified the relevance of 270 Rho-associated genes for endothelial barrier function. Statistical analysis identified 10 targets of which six promoted- and four reduced endothelial barrier function upon downregulation. We analyzed in more detail two of these which were not previously identified as regulators of endothelial integrity. We found that the Rac1-GEF (Guanine nucleotide Exchange Factor) TIAM2 is a positive regulator and the Cdc42(Rac1)-GAP (GTPase-Activating Protein) SYDE1 is a negative regulator of the endothelial barrier function. Finally, we found that the GAP SYDE1 is part of a Cdc42-centered signaling unit, also comprising the Cdc42-GEF FARP1 and the Cdc42 effector PAK7 which controls the integrity of the endothelial barrier. In conclusion, using a siRNA-based screen, we identified new regulators of barrier function and found that Cdc42 is a dominant positive regulator of endothelial integrity.

摘要

内皮细胞屏障功能受到严密调控，以防止组织水肿和免受渗出白细胞的损伤。RhoGTPases 与众多调节蛋白一起，对内皮细胞屏障完整性产生正向和负向影响。目前，关于相关机制的精确知识是零散的，因此我们对 RhoGTPases 及其调节因子对内皮细胞屏障的调节进行了全面分析。我们将 RNAi 与电阻抗测量相结合，定量分析了 270 个与 Rho 相关的基因对内皮细胞屏障功能的相关性。统计分析确定了 10 个靶点，其中 6 个靶点的下调促进了内皮细胞屏障功能，4 个靶点的下调降低了内皮细胞屏障功能。我们详细分析了其中两个靶点，它们以前没有被确定为内皮完整性的调节因子。我们发现 Rac1-GEF（鸟嘌呤核苷酸交换因子）TIAM2 是内皮屏障功能的正向调节因子，而 Cdc42（Rac1）-GAP（GTPase 激活蛋白）SYDE1 是内皮屏障功能的负向调节因子。最后，我们发现 GAP SYDE1 是一个以 Cdc42 为中心的信号单元的一部分，该信号单元还包括 Cdc42-GEF FARP1 和 Cdc42 效应物 PAK7，它们控制内皮屏障的完整性。总之，我们通过 siRNA 筛选鉴定了新的屏障功能调节因子，并发现 Cdc42 是内皮完整性的主要正向调节因子。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8509/5579287/517759c07cb5/41598_2017_10392_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8509/5579287/3740eb38b378/41598_2017_10392_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8509/5579287/aaef296010e7/41598_2017_10392_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8509/5579287/342cba80d0d6/41598_2017_10392_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8509/5579287/8a5671f8ebb6/41598_2017_10392_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8509/5579287/517759c07cb5/41598_2017_10392_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8509/5579287/3740eb38b378/41598_2017_10392_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8509/5579287/aaef296010e7/41598_2017_10392_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8509/5579287/342cba80d0d6/41598_2017_10392_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8509/5579287/8a5671f8ebb6/41598_2017_10392_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8509/5579287/517759c07cb5/41598_2017_10392_Fig5_HTML.jpg

相似文献

1
A CDC42-centered signaling unit is a dominant positive regulator of endothelial integrity.CDC42 中心信号单元是内皮完整性的主要正向调节因子。
Sci Rep. 2017 Aug 31;7(1):10132. doi: 10.1038/s41598-017-10392-0.
2
Oncogenic Dbl, Cdc42, and p21-activated kinase form a ternary signaling intermediate through the minimum interactive domains.致癌性Dbl、Cdc42和p21激活激酶通过最小相互作用结构域形成三元信号中间体。
Biochemistry. 2004 Nov 23;43(46):14584-93. doi: 10.1021/bi048574u.
3
Cdc42 and Rac1 activity is reduced in human pheochromocytoma and correlates with FARP1 and ARHGEF1 expression.在人类嗜铬细胞瘤中，Cdc42和Rac1活性降低，且与FARP1和ARHGEF1表达相关。
Endocr Relat Cancer. 2016 Apr;23(4):281-93. doi: 10.1530/ERC-15-0502. Epub 2016 Feb 24.
4
Identification of guanine nucleotide exchange factors that increase Cdc42 activity in primary human endothelial cells.鉴定在原代人内皮细胞中增加 Cdc42 活性的鸟嘌呤核苷酸交换因子。
Small GTPases. 2021 May;12(3):226-240. doi: 10.1080/21541248.2019.1658509. Epub 2019 Aug 30.
5
The Cool-2/alpha-Pix protein mediates a Cdc42-Rac signaling cascade.Cool-2/α-Pix蛋白介导Cdc42-Rac信号级联反应。
Curr Biol. 2005 Jan 11;15(1):1-10. doi: 10.1016/j.cub.2004.12.040.
6
An extracellular-matrix-specific GEF-GAP interaction regulates Rho GTPase crosstalk for 3D collagen migration.一种细胞外基质特异性鸟嘌呤核苷酸交换因子-鸟苷酸激活蛋白相互作用调节Rho GTP酶串扰以实现三维胶原迁移。
Nat Cell Biol. 2014 Sep;16(9):909-17. doi: 10.1038/ncb3026. Epub 2014 Aug 24.
7
Dock6, a Dock-C subfamily guanine nucleotide exchanger, has the dual specificity for Rac1 and Cdc42 and regulates neurite outgrowth.Dock6是一种Dock-C亚家族鸟嘌呤核苷酸交换因子，对Rac1和Cdc42具有双重特异性，并调节神经突生长。
Exp Cell Res. 2007 Feb 15;313(4):791-804. doi: 10.1016/j.yexcr.2006.11.017. Epub 2006 Dec 6.
8
The minor histocompatibility antigen 1 (HMHA1)/ArhGAP45 is a RacGAP and a novel regulator of endothelial integrity.次要组织相容性抗原 1（HMHA1）/ArhGAP45 是 RacGAP，也是内皮完整性的新型调节因子。
Vascul Pharmacol. 2018 Feb;101:38-47. doi: 10.1016/j.vph.2017.11.007. Epub 2017 Nov 21.
9
Stress-dependent inhibition of polarized cell growth through unbalancing the GEF/GAP regulation of Cdc42.通过失衡 Cdc42 的 GEF/GAP 调控，应激依赖性抑制极化细胞生长。
Cell Rep. 2021 Nov 2;37(5):109951. doi: 10.1016/j.celrep.2021.109951.
10
Tiam1 and betaPIX mediate Rac-dependent endothelial barrier protective response to oxidized phospholipids.Tiam1和βPIX介导Rac依赖性内皮细胞对氧化磷脂的屏障保护反应。
J Cell Physiol. 2007 Jun;211(3):608-17. doi: 10.1002/jcp.20966.

引用本文的文献

1
Tetraspanin-enriched membrane domains regulate vascular leakage by altering membrane cholesterol accessibility to balance antagonistic GTPases.富含四跨膜蛋白的膜结构域通过改变膜胆固醇的可及性来调节血管渗漏，以平衡拮抗性GTP酶。
Nat Cardiovasc Res. 2025 Jul 29. doi: 10.1038/s44161-025-00686-2.
2
A large-scale genome-wide study of gene-sleep duration interactions for blood pressure in 811,405 individuals from diverse populations.一项针对来自不同人群的811,405人的血压基因-睡眠时间相互作用的大规模全基因组研究。
Mol Psychiatry. 2025 Apr 4. doi: 10.1038/s41380-025-02954-w.
3
AAMP and MTSS1 Are Novel Negative Regulators of Endothelial Barrier Function Identified in a Proteomics Screen.

本文引用的文献

1
Systematic high-content genome-wide RNAi screens of endothelial cell migration and morphology.内皮细胞迁移和形态的系统高内涵全基因组 RNAi 筛选
Sci Data. 2017 Mar 1;4:170009. doi: 10.1038/sdata.2017.9.
2
RNAi screens for Rho GTPase regulators of cell shape and YAP/TAZ localisation in triple negative breast cancer.RNAi 筛选调节细胞形态和 YAP/TAZ 定位的 Rho GTPase 调节剂在三阴性乳腺癌中的作用。
Sci Data. 2017 Mar 1;4:170018. doi: 10.1038/sdata.2017.18.
3
Association of dysfunctional synapse defective 1 (SYDE1) with restricted fetal growth - SYDE1 regulates placental cell migration and invasion.
AAMP 和 MTSS1 是通过蛋白质组学筛选鉴定出的内皮屏障功能的新型负调控因子。
Cells. 2024 Sep 25;13(19):1609. doi: 10.3390/cells13191609.
4
A Large-Scale Genome-Wide Study of Gene-Sleep Duration Interactions for Blood Pressure in 811,405 Individuals from Diverse Populations.一项针对来自不同人群的811,405人的血压基因-睡眠时间相互作用的大规模全基因组研究。
Res Sq. 2024 Jul 17:rs.3.rs-4163414. doi: 10.21203/rs.3.rs-4163414/v1.
5
LncRNA MALAT1 facilitates BM-MSCs differentiation into endothelial cells and ameliorates erectile dysfunction via the miR-206/CDC42/PAK1/paxillin signalling axis.长链非编码 RNA MALAT1 通过 miR-206/CDC42/PAK1/paxillin 信号轴促进 BM-MSCs 向内皮细胞分化并改善勃起功能障碍。
Reprod Biol Endocrinol. 2024 Jun 25;22(1):74. doi: 10.1186/s12958-024-01240-8.
6
Tyrosine-protein kinase Yes controls endothelial junctional plasticity and barrier integrity by regulating VE-cadherin phosphorylation and endocytosis.酪氨酸蛋白激酶Yes通过调节血管内皮钙黏蛋白的磷酸化和内吞作用来控制内皮细胞连接可塑性和屏障完整性。
Nat Cardiovasc Res. 2022 Dec 7;1(12):1156-1173. doi: 10.1038/s44161-022-00172-z.
7
The clinical utility of circulating cell division control 42 in small-vessel coronary artery disease patients undergoing drug-coated balloon treatment.在接受药物涂层球囊治疗的小血管冠状动脉疾病患者中，循环细胞分裂控制蛋白 42 的临床应用价值。
BMC Cardiovasc Disord. 2023 Oct 7;23(1):496. doi: 10.1186/s12872-023-03476-5.
8
DjFARP Contributes to the Regeneration and Maintenance of the Brain through Activation of DjRac1 in Dugesia japonica.DjFARP通过激活日本三角涡虫中的DjRac1对大脑的再生和维持起作用。
Mol Neurobiol. 2023 Nov;60(11):6294-6306. doi: 10.1007/s12035-023-03478-6. Epub 2023 Jul 13.
9
Low-Dose Anti-HIV Drug Efavirenz Mitigates Retinal Vascular Lesions in a Mouse Model of Alzheimer's Disease.低剂量抗艾滋病毒药物依法韦仑可减轻阿尔茨海默病小鼠模型中的视网膜血管病变。
Front Pharmacol. 2022 Jun 1;13:902254. doi: 10.3389/fphar.2022.902254. eCollection 2022.
10
Fixing the GAP: The role of RhoGAPs in cancer.修复缺口：RhoGAPs 在癌症中的作用。
Eur J Cell Biol. 2022 Apr;101(2):151209. doi: 10.1016/j.ejcb.2022.151209. Epub 2022 Feb 10.
突触功能障碍缺陷 1 (SYDE1) 与胎儿生长受限的关联-SYDE1 调节胎盘细胞迁移和侵袭。
J Pathol. 2017 Feb;241(3):324-336. doi: 10.1002/path.4835. Epub 2016 Dec 15.
4
IL-4 Causes Hyperpermeability of Vascular Endothelial Cells through Wnt5A Signaling.白细胞介素-4通过Wnt5A信号通路导致血管内皮细胞的高通透性。
PLoS One. 2016 May 23;11(5):e0156002. doi: 10.1371/journal.pone.0156002. eCollection 2016.
5
Spatiotemporal analysis of RhoA/B/C activation in primary human endothelial cells.原代人内皮细胞中RhoA/B/C激活的时空分析
Sci Rep. 2016 May 5;6:25502. doi: 10.1038/srep25502.
6
RhoB controls endothelial barrier recovery by inhibiting Rac1 trafficking to the cell border.RhoB通过抑制Rac1向细胞边界的转运来控制内皮屏障的恢复。
J Cell Biol. 2016 May 9;213(3):385-402. doi: 10.1083/jcb.201504038. Epub 2016 May 2.
7
Cdc42 and Rac1 activity is reduced in human pheochromocytoma and correlates with FARP1 and ARHGEF1 expression.在人类嗜铬细胞瘤中，Cdc42和Rac1活性降低，且与FARP1和ARHGEF1表达相关。
Endocr Relat Cancer. 2016 Apr;23(4):281-93. doi: 10.1530/ERC-15-0502. Epub 2016 Feb 24.
8
F-actin-rich contractile endothelial pores prevent vascular leakage during leukocyte diapedesis through local RhoA signalling.富含F-肌动蛋白的收缩性内皮孔隙通过局部RhoA信号传导防止白细胞渗出过程中的血管渗漏。
Nat Commun. 2016 Jan 27;7:10493. doi: 10.1038/ncomms10493.
9
A New Generation of FRET Sensors for Robust Measurement of Gαi1, Gαi2 and Gαi3 Activation Kinetics in Single Cells.新一代用于单细胞中Gαi1、Gαi2和Gαi3激活动力学稳健测量的荧光共振能量转移（FRET）传感器。
PLoS One. 2016 Jan 22;11(1):e0146789. doi: 10.1371/journal.pone.0146789. eCollection 2016.
10
Rapid Remodeling of Invadosomes by Gi-coupled Receptors: DISSECTING THE ROLE OF Rho GTPases.Gi偶联受体对侵袭性伪足的快速重塑：剖析Rho GTP酶的作用
J Biol Chem. 2016 Feb 26;291(9):4323-33. doi: 10.1074/jbc.M115.695940. Epub 2016 Jan 6.