• 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

靶向SMAD3去磷酸化作为一种阻碍转化生长因子-β（TGF-β）信号传导的方法。

Targeted dephosphorylation of SMAD3 as an approach to impede TGF-β signaling.

作者信息

Brewer Abigail, Zhao Jin-Feng, Fasimoye Rotimi, Shpiro Natalia, Macartney Thomas J, Wood Nicola T, Wightman Melanie, Alessi Dario R, Sapkota Gopal P

机构信息

Medical Research Council (MRC) Protein Phosphorylation & Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.

出版信息

iScience. 2024 Jul 5;27(8):110423. doi: 10.1016/j.isci.2024.110423. eCollection 2024 Aug 16.

DOI:10.1016/j.isci.2024.110423
PMID:39104417
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11298613/
Abstract

TGF-β (transforming growth factor-β) signaling is involved in a myriad of cellular processes and its dysregulation has been implicated in many human diseases, including fibrosis and cancer. TGF-β transcriptional responses are controlled by tail phosphorylation of transcription factors SMAD2 and SMAD3 (mothers against decapentaplegic homolog 2/3). Therefore, targeted dephosphorylation of phospho-SMAD3 could provide an innovative mechanism to block some TGF-β-induced transcriptional responses, such as the transcription of , which encodes plasminogen activator inhibitor 1 (PAI-1). Here, by developing and employing a bifunctional molecule, BDPIC (bromoTAG-dTAG proximity-inducing chimera), we redirected multiple phosphatases, tagged with bromoTAG, to dephosphorylate phospho-SMAD3, tagged with dTAG. Using CRISPR-Cas9 technology, we generated homozygous double knock-in A549 cells, in which the BDPIC-induced proximity between bromoTAG-PPM1H and dTAG-SMAD3 led to a robust dephosphorylation of dTAG-SMAD3 and a significant decrease in transcription. Our work demonstrates targeted dephosphorylation of phospho-proteins as an exciting modality for rewiring cell signaling.

摘要

转化生长因子-β（TGF-β）信号传导参与众多细胞过程，其失调与许多人类疾病有关，包括纤维化和癌症。TGF-β转录反应受转录因子SMAD2和SMAD3（抗五体不全同源蛋白2/3）尾部磷酸化的控制。因此，磷酸化SMAD3的靶向去磷酸化可为阻断某些TGF-β诱导的转录反应提供一种创新机制，例如编码纤溶酶原激活物抑制剂1（PAI-1）的转录。在这里，通过开发和应用一种双功能分子BDPIC（溴代标签-dTAG邻近诱导嵌合体），我们将多个用溴代标签标记的磷酸酶重定向，使其对用dTAG标记的磷酸化SMAD3进行去磷酸化。利用CRISPR-Cas9技术，我们生成了纯合双敲入A549细胞，其中BDPIC诱导的溴代标签-PPM1H与dTAG-SMAD3之间的邻近性导致dTAG-SMAD3发生强烈的去磷酸化，并且转录显著减少。我们的工作证明了磷酸化蛋白的靶向去磷酸化是一种用于重新连接细胞信号传导的令人兴奋的方式。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65f3/11298613/ebc02586fca0/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65f3/11298613/5fbd1bfed008/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65f3/11298613/ec486c355a4b/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65f3/11298613/fc2d13880955/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65f3/11298613/d60c8aba5e98/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65f3/11298613/13144da64b91/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65f3/11298613/e744dfdc1008/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65f3/11298613/ebc02586fca0/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65f3/11298613/5fbd1bfed008/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65f3/11298613/ec486c355a4b/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65f3/11298613/fc2d13880955/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65f3/11298613/d60c8aba5e98/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65f3/11298613/13144da64b91/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65f3/11298613/e744dfdc1008/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65f3/11298613/ebc02586fca0/gr6.jpg

相似文献

1
Targeted dephosphorylation of SMAD3 as an approach to impede TGF-β signaling.靶向SMAD3去磷酸化作为一种阻碍转化生长因子-β（TGF-β）信号传导的方法。
iScience. 2024 Jul 5;27(8):110423. doi: 10.1016/j.isci.2024.110423. eCollection 2024 Aug 16.
2
Targeted dephosphorylation of TFEB promotes its nuclear translocation.对转录因子EB（TFEB）进行靶向去磷酸化可促进其核转位。
iScience. 2024 Jun 29;27(8):110432. doi: 10.1016/j.isci.2024.110432. eCollection 2024 Aug 16.
3
Transforming growth factor beta-induced phosphorylation of Smad3 is required for growth inhibition and transcriptional induction in epithelial cells.转化生长因子β诱导的Smad3磷酸化是上皮细胞生长抑制和转录诱导所必需的。
Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10669-74. doi: 10.1073/pnas.94.20.10669.
4
Small C-terminal domain phosphatases dephosphorylate the regulatory linker regions of Smad2 and Smad3 to enhance transforming growth factor-beta signaling.小C端结构域磷酸酶使Smad2和Smad3的调节连接区去磷酸化，以增强转化生长因子-β信号传导。
J Biol Chem. 2006 Dec 15;281(50):38365-75. doi: 10.1074/jbc.M607246200. Epub 2006 Oct 10.
5
Bone morphogenetic protein-7 inhibits proximal tubular epithelial cell Smad3 signaling via increased SnoN expression.骨形态发生蛋白 7 通过增加 SnoN 表达抑制近端肾小管上皮细胞 Smad3 信号通路。
Am J Pathol. 2010 Mar;176(3):1139-47. doi: 10.2353/ajpath.2010.090459. Epub 2010 Jan 21.
6
cGMP inhibits TGF-beta signaling by sequestering Smad3 with cytosolic beta2-tubulin in pulmonary artery smooth muscle cells.环磷酸鸟苷（cGMP）通过在肺动脉平滑肌细胞中与胞质β2-微管蛋白隔离Smad3来抑制转化生长因子-β（TGF-β）信号传导。
Mol Endocrinol. 2011 Oct;25(10):1794-803. doi: 10.1210/me.2011-1009. Epub 2011 Aug 25.
7
Inhibition of TGF-β signaling at the nuclear envelope: characterization of interactions between MAN1, Smad2 and Smad3, and PPM1A.核膜上 TGF-β 信号的抑制：MAN1、Smad2 和 Smad3 与 PPM1A 之间相互作用的特征。
Sci Signal. 2013 Jun 18;6(280):ra49. doi: 10.1126/scisignal.2003411.
8
Upregulation of PAI-1 is mediated through TGF-beta/Smad pathway in transplant arteriopathy.在移植性动脉病变中，纤溶酶原激活物抑制剂-1（PAI-1）的上调是通过转化生长因子-β/信号转导和转录激活因子（TGF-β/Smad）途径介导的。
J Heart Lung Transplant. 2002 Sep;21(9):999-1008. doi: 10.1016/s1053-2498(02)00403-5.
9
Functional characterization of transforming growth factor beta signaling in Smad2- and Smad3-deficient fibroblasts.Smad2和Smad3缺陷型成纤维细胞中转化生长因子β信号传导的功能特性
J Biol Chem. 2001 Jun 8;276(23):19945-53. doi: 10.1074/jbc.M102382200. Epub 2001 Mar 21.
10
Transforming growth factor (TGF)-β type I receptor kinase (ALK5) inhibitor alleviates profibrotic TGF-β1 responses in fibroblasts derived from Peyronie's plaque.转化生长因子-β 型 I 受体激酶（ALK5）抑制剂减轻来源于 Peyronie 斑块的成纤维细胞中促纤维化 TGF-β1 反应。
J Sex Med. 2010 Oct;7(10):3385-95. doi: 10.1111/j.1743-6109.2010.01753.x.

引用本文的文献

1
The contribution of native protein complexes to targeted protein degradation.天然蛋白质复合物对靶向蛋白质降解的作用。
bioRxiv. 2025 Jun 17:2025.06.17.660125. doi: 10.1101/2025.06.17.660125.
2
Melatonin Promotes Cerebral Angiogenesis in Ischemic Mice via BMP6/Smad1/5/9 Pathway.褪黑素通过BMP6/Smad1/5/9信号通路促进缺血小鼠的脑内血管生成。
Mol Neurobiol. 2025 Apr 25. doi: 10.1007/s12035-025-04969-4.

本文引用的文献

1
Targeted dephosphorylation of TFEB promotes its nuclear translocation.对转录因子EB（TFEB）进行靶向去磷酸化可促进其核转位。
iScience. 2024 Jun 29;27(8):110432. doi: 10.1016/j.isci.2024.110432. eCollection 2024 Aug 16.
2
Mapping the substrate landscape of protein phosphatase 2A catalytic subunit PPP2CA.绘制蛋白磷酸酶2A催化亚基PPP2CA的底物图谱。
iScience. 2024 Feb 19;27(3):109302. doi: 10.1016/j.isci.2024.109302. eCollection 2024 Mar 15.
3
Targeted Dephosphorylation of Tau by Phosphorylation Targeting Chimeras (PhosTACs) as a Therapeutic Modality.
通过磷酸化靶向嵌合体（PhosTACs）对tau蛋白进行靶向去磷酸化作为一种治疗方式。
J Am Chem Soc. 2023 Feb 8. doi: 10.1021/jacs.2c11706.
4
An affinity-directed phosphatase, AdPhosphatase, system for targeted protein dephosphorylation.一种用于靶向蛋白质去磷酸化的亲和导向磷酸酶（AdPhosphatase）系统。
Cell Chem Biol. 2023 Feb 16;30(2):188-202.e6. doi: 10.1016/j.chembiol.2023.01.003. Epub 2023 Jan 30.
5
Protein Phosphatase 5-Recruiting Chimeras for Accelerating Apoptosis-Signal-Regulated Kinase 1 Dephosphorylation with Antiproliferative Activity.蛋白磷酸酶 5 募集嵌合体加速促凋亡信号调节激酶 1 去磷酸化并具有抗增殖活性。
J Am Chem Soc. 2023 Jan 18;145(2):1118-1128. doi: 10.1021/jacs.2c10759. Epub 2022 Dec 22.
6
VHL-recruiting PROTAC attenuates renal fibrosis and preserves renal function via simultaneous degradation of Smad3 and stabilization of HIF-2α.招募VHL的PROTAC通过同时降解Smad3和稳定HIF-2α来减轻肾纤维化并保护肾功能。
Cell Biosci. 2022 Dec 19;12(1):203. doi: 10.1186/s13578-022-00936-x.
7
Target protein localization and its impact on PROTAC-mediated degradation.目标蛋白定位及其对 PROTAC 介导降解的影响。
Cell Chem Biol. 2022 Oct 20;29(10):1482-1504.e7. doi: 10.1016/j.chembiol.2022.08.004. Epub 2022 Sep 7.
8
Modulation of Phosphoprotein Activity by Phosphorylation Targeting Chimeras (PhosTACs).磷酸化靶向嵌合体（PhosTACs）对磷酸化蛋白活性的调控。
ACS Chem Biol. 2021 Dec 17;16(12):2808-2815. doi: 10.1021/acschembio.1c00693. Epub 2021 Nov 15.
9
Development of BromoTag: A "Bump-and-Hole"-PROTAC System to Induce Potent, Rapid, and Selective Degradation of Tagged Target Proteins.溴结构域蛋白标记物（BromoTag）的开发：一种用于诱导标记靶蛋白高效、快速和选择性降解的“凸起-凹陷”-PROTAC 系统。
J Med Chem. 2021 Oct 28;64(20):15477-15502. doi: 10.1021/acs.jmedchem.1c01532. Epub 2021 Oct 15.
10
Structural basis for the specificity of PPM1H phosphatase for Rab GTPases.PPM1H 磷酸酶对 Rab GTPases 特异性的结构基础。
EMBO Rep. 2021 Nov 4;22(11):e52675. doi: 10.15252/embr.202152675. Epub 2021 Sep 28.