• 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

Disabled-2 (Dab2) 通过与 LRP6 结合并通过网格蛋白促进其内化来抑制 Wnt/β-catenin 信号传导。

Disabled-2 (Dab2) inhibits Wnt/β-catenin signalling by binding LRP6 and promoting its internalization through clathrin.

机构信息

Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA.

出版信息

EMBO J. 2012 May 16;31(10):2336-49. doi: 10.1038/emboj.2012.83. Epub 2012 Apr 10.

DOI:10.1038/emboj.2012.83
PMID:22491013
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3364753/
Abstract

Canonical Wnt signalling requires caveolin-dependent internalization of low-density lipoprotein receptor-related protein 6 (LRP6). Here we report that the tumour suppressor and endocytic adaptor disabled-2 (Dab2), previously described as an inhibitor of Wnt/β-catenin signalling, selectively recruits LRP6 to the clathrin-dependent endocytic route, thereby sequestering it from caveolin-mediated endocytosis. Wnt stimulation induces the casein kinase 2 (CK2)-dependent phosphorylation of LRP6 at S1579, promoting its binding to Dab2 and internalization with clathrin. LRP6 receptor mutant (S1579A), deficient in CK2-mediated phosphorylation and Dab2 binding, fails to associate with clathrin, and thus escapes the inhibitory effects of Dab2 on Wnt/β-catenin signalling. Our data suggest that the S1579 site of LRP6 is a negative regulatory point during LRP6-mediated dorsoventral patterning in zebrafish and in allograft mouse tumour models. We conclude that the tumour suppressor functions of Dab2 involve modulation of canonical Wnt signalling by regulating the endocytic fate of the LRP6 receptor.

摘要

经典 Wnt 信号通路需要窖蛋白依赖性低密度脂蛋白受体相关蛋白 6（LRP6）内化。在这里，我们报告肿瘤抑制因子和内吞衔接蛋白Disabled-2（Dab2），先前被描述为 Wnt/β-catenin 信号通路的抑制剂，选择性地将 LRP6 招募到网格蛋白依赖性内吞途径，从而将其与窖蛋白介导的内吞作用隔离开来。Wnt 刺激诱导 LRP6 在 S1579 处发生依赖于酪蛋白激酶 2（CK2）的磷酸化，促进其与 Dab2 结合，并与网格蛋白一起内化。LRP6 受体突变体（S1579A），缺乏 CK2 介导的磷酸化和 Dab2 结合，无法与网格蛋白结合，因此逃避了 Dab2 对 Wnt/β-catenin 信号通路的抑制作用。我们的数据表明，LRP6 的 S1579 位点是斑马鱼和同种异体移植小鼠肿瘤模型中 LRP6 介导的背腹模式形成过程中 LRP6 介导的负调控点。我们得出结论，Dab2 的肿瘤抑制功能涉及通过调节 LRP6 受体的内吞命运来调节经典 Wnt 信号通路。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f05f/3364753/b8963fcc885d/emboj201283f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f05f/3364753/39e6e88526dd/emboj201283f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f05f/3364753/f1f6bb232f59/emboj201283f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f05f/3364753/87b2c9c1d573/emboj201283f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f05f/3364753/910ea0845c45/emboj201283f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f05f/3364753/0daf9d057f66/emboj201283f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f05f/3364753/3c60158db350/emboj201283f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f05f/3364753/8e53cbaaa1c9/emboj201283f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f05f/3364753/b8963fcc885d/emboj201283f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f05f/3364753/39e6e88526dd/emboj201283f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f05f/3364753/f1f6bb232f59/emboj201283f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f05f/3364753/87b2c9c1d573/emboj201283f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f05f/3364753/910ea0845c45/emboj201283f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f05f/3364753/0daf9d057f66/emboj201283f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f05f/3364753/3c60158db350/emboj201283f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f05f/3364753/8e53cbaaa1c9/emboj201283f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f05f/3364753/b8963fcc885d/emboj201283f8.jpg

相似文献

1
Disabled-2 (Dab2) inhibits Wnt/β-catenin signalling by binding LRP6 and promoting its internalization through clathrin.Disabled-2 (Dab2) 通过与 LRP6 结合并通过网格蛋白促进其内化来抑制 Wnt/β-catenin 信号传导。
EMBO J. 2012 May 16;31(10):2336-49. doi: 10.1038/emboj.2012.83. Epub 2012 Apr 10.
2
Dab2 stabilizes Axin and attenuates Wnt/beta-catenin signaling by preventing protein phosphatase 1 (PP1)-Axin interactions.Dab2通过阻止蛋白磷酸酶1（PP1）与Axin相互作用来稳定Axin并减弱Wnt/β-连环蛋白信号传导。
Oncogene. 2009 Aug 20;28(33):2999-3007. doi: 10.1038/onc.2009.157. Epub 2009 Jul 6.
3
Clathrin and AP2 are required for PtdIns(4,5)P2-mediated formation of LRP6 signalosomes.网格蛋白和衔接蛋白 2 对于 PtdIns(4,5)P2 介导的 LRP6 信号小体的形成是必需的。
J Cell Biol. 2013 Feb 18;200(4):419-28. doi: 10.1083/jcb.201206096. Epub 2013 Feb 11.
4
Down-regulation of Wt1 activates Wnt/β-catenin signaling through modulating endocytic route of LRP6 in podocyte dysfunction in vitro.在体外足细胞功能障碍中，Wt1的下调通过调节低密度脂蛋白受体相关蛋白6（LRP6）的内吞途径激活Wnt/β-连环蛋白信号通路。
Cell Signal. 2015 Sep;27(9):1772-80. doi: 10.1016/j.cellsig.2015.05.018. Epub 2015 Jun 3.
5
WNT Activates the AAK1 Kinase to Promote Clathrin-Mediated Endocytosis of LRP6 and Establish a Negative Feedback Loop.WNT 激活 AAK1 激酶促进 LRP6 的网格蛋白介导内吞作用并建立负反馈回路。
Cell Rep. 2019 Jan 2;26(1):79-93.e8. doi: 10.1016/j.celrep.2018.12.023.
6
Exploring the mechanistic and temporal regulation of LRP6 endocytosis in canonical WNT signaling.探索经典WNT信号通路中LRP6内吞作用的机制及时间调控。
J Cell Sci. 2020 Aug 14;133(15):jcs243675. doi: 10.1242/jcs.243675.
7
Regulation of the Wnt signaling pathway by disabled-2 (Dab2).失活蛋白2（Dab2）对Wnt信号通路的调控
EMBO J. 2003 Jun 16;22(12):3084-94. doi: 10.1093/emboj/cdg286.
8
Tyrosine-based signal mediates LRP6 receptor endocytosis and desensitization of Wnt/β-catenin pathway signaling.基于酪氨酸的信号介导LRP6受体内吞作用以及Wnt/β-连环蛋白信号通路的脱敏。
J Biol Chem. 2014 Oct 3;289(40):27562-70. doi: 10.1074/jbc.M113.533927. Epub 2014 Aug 20.
9
The inhibitory effects of Disabled-2 (Dab2) on Wnt signaling are mediated through Axin.失活蛋白2（Dab2）对Wnt信号通路的抑制作用是通过轴抑制蛋白介导的。
Oncogene. 2008 Mar 20;27(13):1865-75. doi: 10.1038/sj.onc.1210829. Epub 2007 Oct 8.
10
Mesd is a universal inhibitor of Wnt coreceptors LRP5 and LRP6 and blocks Wnt/beta-catenin signaling in cancer cells.Mesd 是 Wnt 核心受体 LRP5 和 LRP6 的通用抑制剂，可阻断癌细胞中的 Wnt/β-连环蛋白信号通路。
Biochemistry. 2010 Jun 8;49(22):4635-43. doi: 10.1021/bi1001486.

引用本文的文献

1
Multi-omics characterization of the monkeypox virus infection.猴痘病毒感染的多组学特征分析
Nat Commun. 2024 Aug 8;15(1):6778. doi: 10.1038/s41467-024-51074-6.
2
Dab2 (Disabled-2), an adaptor protein, regulates self-renewal of hair follicle stem cells.衔接蛋白Dab2（Disabled-2）调节毛囊干细胞的自我更新。
Commun Biol. 2024 May 3;7(1):525. doi: 10.1038/s42003-024-06047-2.
3
Perturbation of intestinal stem cell homeostasis and radiation enteritis recovery via dietary titanium dioxide nanoparticles.通过膳食二氧化钛纳米颗粒扰乱肠道干细胞内稳态和辐射性肠炎的恢复。

本文引用的文献

1
Rspo3 binds syndecan 4 and induces Wnt/PCP signaling via clathrin-mediated endocytosis to promote morphogenesis.Rspo3 结合 syndecan 4，并通过网格蛋白介导的内吞作用诱导 Wnt/PCP 信号通路，从而促进形态发生。
Dev Cell. 2011 Mar 15;20(3):303-14. doi: 10.1016/j.devcel.2011.01.006.
2
Identification of an mRNP complex regulating tumorigenesis at the translational elongation step.鉴定出一种在翻译延伸步骤中调节肿瘤发生的 mRNP 复合物。
Mol Cell. 2011 Feb 18;41(4):419-31. doi: 10.1016/j.molcel.2011.02.003.
3
Wnt signaling requires sequestration of glycogen synthase kinase 3 inside multivesicular endosomes.
Cell Prolif. 2023 Aug;56(8):e13427. doi: 10.1111/cpr.13427. Epub 2023 Feb 16.
4
Disabled-2 (): A Key Regulator of Anti- and Pro-Tumorigenic Pathways.Disabled-2（）：抑癌和促癌途径的关键调节因子。
Int J Mol Sci. 2022 Dec 31;24(1):696. doi: 10.3390/ijms24010696.
5
Chemotherapy induces feedback up-regulation of CD44v6 in colorectal cancer initiating cells through -catenin/MDR1 signaling to sustain chemoresistance.化疗通过β-连环蛋白/多药耐药蛋白1信号通路诱导结直肠癌起始细胞中CD44v6的反馈上调，以维持化疗耐药性。
Front Oncol. 2022 Oct 18;12:906260. doi: 10.3389/fonc.2022.906260. eCollection 2022.
6
MicroRNA-145, Wnt3a, and Dab2 Genes Expression Changes of the Cardiomyocytes in Hypercholesterolemic Rats Exposed to the Aerobic Training.有氧运动训练对高胆固醇血症大鼠心肌细胞中MicroRNA-145、Wnt3a和Dab2基因表达的影响
Int J Mol Cell Med. 2021 Fall;10(4):288-296. doi: 10.22088/IJMCM.BUMS.10.4.288. Epub 2022 Jun 6.
7
A network pharmacology-based approach to explore mechanism of action of medicinal herbs for alopecia treatment.基于网络药理学的方法探索治疗脱发的草药作用机制。
Sci Rep. 2022 Feb 18;12(1):2852. doi: 10.1038/s41598-022-06811-6.
8
DAB2 suppresses gastric cancer migration by regulating the Wnt/β-catenin and Hippo-YAP signaling pathways.DAB2通过调节Wnt/β-连环蛋白和Hippo-YAP信号通路抑制胃癌转移。
Transl Cancer Res. 2020 Feb;9(2):1174-1184. doi: 10.21037/tcr.2019.12.96.
9
Regulation of the Low-Density Lipoprotein Receptor-Related Protein LRP6 and Its Association With Disease: Wnt/β-Catenin Signaling and Beyond.低密度脂蛋白受体相关蛋白LRP6的调控及其与疾病的关联：Wnt/β-连环蛋白信号通路及其他
Front Cell Dev Biol. 2021 Sep 13;9:714330. doi: 10.3389/fcell.2021.714330. eCollection 2021.
10
Cholesterol activates the Wnt/PCP-YAP signaling in SOAT1-targeted treatment of colon cancer.胆固醇在SOAT1靶向治疗结肠癌中激活Wnt/PCP-YAP信号通路。
Cell Death Discov. 2021 Feb 26;7(1):38. doi: 10.1038/s41420-021-00421-3.
Wnt 信号通路需要将糖原合酶激酶 3（GSK3）隔离在多泡内体（MVEs）中。
Cell. 2010 Dec 23;143(7):1136-48. doi: 10.1016/j.cell.2010.11.034.
4
Putative tumour-suppressor gene DAB2 is frequently down regulated by promoter hypermethylation in nasopharyngeal carcinoma.抑癌基因 DAB2 常因启动子甲基化而在鼻咽癌中下调。
BMC Cancer. 2010 Jun 3;10:253. doi: 10.1186/1471-2407-10-253.
5
Wnt5a regulates distinct signalling pathways by binding to Frizzled2.Wnt5a 通过与 Frizzled2 结合来调节不同的信号通路。
EMBO J. 2010 Jan 6;29(1):41-54. doi: 10.1038/emboj.2009.322. Epub 2009 Nov 12.
6
Wnt/beta-catenin signaling: components, mechanisms, and diseases.Wnt/β-连环蛋白信号传导：组成部分、机制及相关疾病
Dev Cell. 2009 Jul;17(1):9-26. doi: 10.1016/j.devcel.2009.06.016.
7
Dab2 stabilizes Axin and attenuates Wnt/beta-catenin signaling by preventing protein phosphatase 1 (PP1)-Axin interactions.Dab2通过阻止蛋白磷酸酶1（PP1）与Axin相互作用来稳定Axin并减弱Wnt/β-连环蛋白信号传导。
Oncogene. 2009 Aug 20;28(33):2999-3007. doi: 10.1038/onc.2009.157. Epub 2009 Jul 6.
8
Mechanisms of endocytosis.内吞作用的机制。
Annu Rev Biochem. 2009;78:857-902. doi: 10.1146/annurev.biochem.78.081307.110540.
9
Wnt3a-mediated formation of phosphatidylinositol 4,5-bisphosphate regulates LRP6 phosphorylation.Wnt3a介导的磷脂酰肌醇4,5-二磷酸形成调节低密度脂蛋白受体相关蛋白6（LRP6）的磷酸化。
Science. 2008 Sep 5;321(5894):1350-3. doi: 10.1126/science.1160741.
10
Wnt3a and Dkk1 regulate distinct internalization pathways of LRP6 to tune the activation of beta-catenin signaling.Wnt3a和Dkk1调节低密度脂蛋白受体相关蛋白6（LRP6）不同的内化途径，以调节β-连环蛋白信号通路的激活。
Dev Cell. 2008 Jul;15(1):37-48. doi: 10.1016/j.devcel.2008.04.015.