经典Wnt信号通路中β-catenin在细胞核内外分布的调控机制及潜在治疗靶点的研究进展

顾嘉伟, 牛耿明, 柯重伟

复旦学报(医学版) ›› 2022, Vol. 49 ›› Issue (02) : 300-308.

PDF(977 KB)
欢迎访问《复旦学报(医学版)》官方网站,今天是 2025年5月7日 星期三 分享到:
PDF(977 KB)
复旦学报(医学版) ›› 2022, Vol. 49 ›› Issue (02) : 300-308. DOI: 10.3969/j.issn.1672-8467.2022.02.021
综述

经典Wnt信号通路中β-catenin在细胞核内外分布的调控机制及潜在治疗靶点的研究进展

  • 顾嘉伟, 牛耿明, 柯重伟
作者信息 +

Research progress on the mechanism regulating the cellular sub-localization of β-catenin and potential associated therapeutic targets in canonical Wnt signaling pathway

  • GU Jia-wei, NIU Geng-ming, KE Chong-wei
Author information +
文章历史 +

摘要

经典Wnt信号通路在肿瘤细胞的增殖分化中发挥重要作用,该信号通路中的核心蛋白分子β-catenin介导信号从细胞质传递到细胞核,并在核内参与组成转录复合体,激活下游靶基因转录。β-catenin进入细胞核内是其激活下游转录因子的重要前提,其出入细胞核的方式尚未完全解析。β-catenin入核方式主要为利用经典入核途径关键蛋白直接入核及通过“分子伴侣”协助入核,而出核方式主要为依赖染色体维持区域1(chromosome maintenance region 1,CRM1)的出核途径。细胞膜上的钙黏蛋白、细胞质内的降解复合体相关蛋白及细胞核内的转录复合体相关蛋白等均可导致β-catenin滞留,从而影响其在细胞核内外的分布。在不改变细胞内β-catenin总量的情况下,通过减少β-catenin入核及核内滞留作用、增加其出核及核外滞留作用,从而阻断Wnt/β-catenin信号通路,也是治疗经典Wnt信号通路相关疾病的有效途径。本文总结近年来关于β-catenin在细胞核内外分布状态的调控机制,为进一步研究治疗经典Wnt信号通路相关疾病提供潜在靶点及新思路。

Abstract

Canonical Wnt signaling pathway plays a crucial role in the proliferation and differentiation of cancer cell. The key protein β-catenin mediates signal transmission from the cytoplasm side to the nucleus side and participates in the formation of transcription complex in the nucleus to activate the transcription of downstream target gene.The entry of β-catenin into the cell nucleus is an important prerequisite for its activation of downstream transcription factors. However,the mechanism of its transportation between nucleus and cytoplasm has not yet been fully understood. The way that β-catenin enters into the nucleus mainly includes utilizing the key proteins of the classical import way to directly enter the nucleus and with the assist of "molecular chaperones" to co-enter the nucleus. While nuclear export of β-catenin mainly relies on the chromosome maintenance region 1 (CRM1)-dependent nuclear export.The cadherin on the cell membrane, the degradation complex-related proteins in the cytoplasm,and the transcription complex-related proteins in the nucleus can all retain β-catenin in the corresponding intracellular area,thereby affecting its cellular sub-localization.Therefore, without changing the total amount of β-catenin in the cell,Wnt/β-catenin signaling pathway can also be blocked by reducing its nuclear import and nuclear retention,or increasing its nuclear export and extranuclear retention,which is also an effective way to treat diseases relevant with this pathway. This review summarizes the mechanism regulating the cellular sub-localization of β-catenin,providing potential targets and new idea for further research on the treatment of canonical Wnt signaling pathway-related diseases.

引用本文

导出引用
顾嘉伟, 牛耿明, 柯重伟. 经典Wnt信号通路中β-catenin在细胞核内外分布的调控机制及潜在治疗靶点的研究进展[J]. 复旦学报(医学版), 2022, 49(02): 300-308 https://doi.org/10.3969/j.issn.1672-8467.2022.02.021
GU Jia-wei, NIU Geng-ming, KE Chong-wei. Research progress on the mechanism regulating the cellular sub-localization of β-catenin and potential associated therapeutic targets in canonical Wnt signaling pathway[J]. Fudan University Journal of Medical Sciences, 2022, 49(02): 300-308 https://doi.org/10.3969/j.issn.1672-8467.2022.02.021
中图分类号: R73   

参考文献

[1] NUSSE R,CLEVERS H.Wnt/β-catenin signaling,disease,and emerging therapeutic modalities[J].Cell,2017,169(6):985-999.
[2] JAMIESON C,SHARMA M,HENDERSON B.Targeting the β-catenin nuclear transport pathway in cancer[J].Semin Cancer Biol,2014,27:20-29.
[3] KIM S,XU X,HECHT A,et al.Mediator is a transducer of Wnt/beta-catenin signaling[J].J Biol Chem,2006,281(20):14066-14075.
[4] STEWART M.Molecular mechanism of the nuclear protein import cycle[J].Nat Rev Mol Cell Bio,2007,8(3):195-208.
[5] WäLDE S,THAKAR K,HUTTEN S,et al.The nucleoporin Nup358/RanBP2 promotes nuclear import in a cargo- and transport receptor-specific manner[J].Traffic,2012,13(2):218-233.
[6] HAMADA M,HAEGER A,JEGANATHAN K,et al.Ran-dependent docking of importin-beta to RanBP2/Nup358 filaments is essential for protein import and cell viability[J].J Mol Cell Biol,2011,194(4):597-612.
[7] FAGOTTO F,GLÜCK U,GUMBINER B.Nuclear localization signal-independent and importin/karyopherin-independent nuclear import of beta-catenin[J].Curr Biol,1998,8(4):181-190.
[8] MORGAN R,RIDSDALE J,TONKS A,et al.Factors affecting the nuclear localization of β-catenin in normal and malignant tissue[J].J Cell Biochem,2014,115(8):1351-1361.
[9] YUAN K,XIE K,LAN T,et al.TXNDC12 promotes EMT and metastasis of hepatocellular carcinoma cells via activation of β-catenin[J].Cell Death Differ,2020,27(4):1355-1368.
[10] ASALLY M,YONEDA Y.Beta-catenin can act as a nuclear import receptor for its partner transcription factor,lymphocyte enhancer factor-1 (lef-1)[J].Exp Cell Res,2005,308(2):357-363.
[11] GRIFFIN JN,DEL VISO F,DUNCAN AR,et al.RAPGEF5 regulates nuclear translocation of β-catenin[J].Dev Cell,2018,44(2):248-260.e4.
[12] WU X,TU X,JOENG K,et al.Rac1 activation controls nuclear localization of beta-catenin during canonical Wnt signaling[J].Cell,2008,133(2):340-353.
[13] VUONG L,IOMINI C,BALMER S,et al.Kinesin-2 and IFT-A act as a complex promoting nuclear localization of β-catenin during Wnt signalling[J].Nat Commun,2018,9(1):5304.
[14] SAYAT R,LEBER B,GRUBAC V,et al.O-GlcNAc-glycosylation of beta-catenin regulates its nuclear localization and transcriptional activity[J].Exp Cell Res,2008,314(15):2774-2787.
[15] HUTTEN S,KEHLENBACH R.CRM1-mediated nuclear export:to the pore and beyond[J].Trends Cell Biol,2007,17(4):193-201.
[16] HAO Y,LAFITA-NAVARRO M,ZACHARIAS L,et al.Induction of LEF1 by MYC activates the WNT pathway and maintains cell proliferation[J].Cell Commun Signal,2019,17(1):129.
[17] WIECHENS N,FAGOTTO F.CRM1- and Ran-independent nuclear export of beta-catenin[J].Curr Biol,2001,11(1):18-27.
[18] HENDRIKSEN J,FAGOTTO F,VAN DER VELDE H,et al.RanBP3 enhances nuclear export of active (beta)-catenin independently of CRM1[J].J Cell Biol,2005,171(5):785-797.
[19] FRANKLIN-MURRAY A,MALLYA S,JANKEEL A,et al.Toxoplasma gondii dysregulates barrier function and mechanotransduction signaling in human endothelial cells[J].mSphere,2020,5(1):e00550-19.
[20] YAN W,LIN C,GUO Y,et al.N-cadherin overexpression mobilizes the protective effects of mesenchymal stromal cells against ischemic heart injury through a β-catenin-dependent manner[J].Circ Res,2020,126(7):857-874.
[21] NADANAKA S,KINOUCHI H,KITAGAWA H.Chondroitin sulfate-mediated N-cadherin/β-catenin signaling is associated with basal-like breast cancer cell invasion[J].J Bio Chem,2018,293(2):444-465.
[22] LE S,YU M,YAN J.Phosphorylation reduces the mechanical stability of the α-catenin/β-catenin complex[J].Angew Chem Int Ed Engl,2019,58(51):18663-18669.
[23] SILVA-GARCÍA O,VALDEZ-ALARCóN J,BAIZABAL-AGUIRRE V.Wnt/β-catenin signaling as a molecular target by pathogenic bacteria[J].Front Immunol,2019,10:2135.
[24] HUA K,LI Y,ZHOU H,et al.Haemophilus parasuis infection disrupts adherens junctions and initializes EMT dependent on canonical Wnt/β-catenin signaling pathway[J].Front Cell Infect Microbiol,2018,8:324.
[25] COTT C,THUENAUER R,LANDI A,et al.Pseudomonas aeruginosa lectin LecB inhibits tissue repair processes by triggering β-catenin degradation[J].Biochim Biophys Acta 2016,1863:1106-1118.
[26] LIN S,XIA W,WANG J,et al.Beta-catenin,a novel prognostic marker for breast cancer:its roles in cyclin D1 expression and cancer progression[J].P Natl Acad SCI USA,2000,97(8):4262-4266.
[27] ZELJKO M,PECINA-SLAUS N,MARTIC T,et al.Molecular alterations of E-cadherin and beta-catenin in brain metastases[J].Front Biosci,2011,3:616-624.
[28] PRASAD C,MIRZA S,SHARMA G,et al.Epigenetic alterations of CDH1 and APC genes:relationship with activation of Wnt/beta-catenin pathway in invasive ductal carcinoma of breast[J].Life Sci,2008,83:318-325.
[29] COX O,EDMUNDS S,SIMON-KELLER K,et al.PDLIM2 is a marker of adhesion and β-catenin activity in triple-negative breast cancer[J].Cancer Res,2019,79(10):2619-2633.
[30] YU Y,WANG X,ZHANG X,et al.ERK inhibition promotes neuroectodermal precursor commitment by blocking self-renewal and primitive streak formation of the epiblast[J].Stem Cell Res Ther,2018,9(1):2.
[31] ZHOU X,CHADAREVIAN J,RUIZ B,et al.Cytoplasmic and nuclear TAZ exert distinct functions in regulating primed pluripotency[J].Stem Cell Reports,2017,9(3):732-741.
[32] STEINHART Z,ANGERS S.Wnt signaling in development and tissue homeostasis[J].Development,2018,145(11):dev146589.
[33] KRIEGHOFF E,BEHRENS J,MAYR B.Nucleo-cytoplasmic distribution of beta-catenin is regulated by retention[J].J Cell Sci,2006,119:1453-1463.
[34] AOKI K,TAKETO M.Adenomatous polyposis coli (APC):a multi-functional tumor suppressor gene[J].J Cell Sci,2007,120:3327-3335.
[35] ZHANG Y,LIU S,MICKANIN C,et al.RNF146 is a poly(ADP-ribose)-directed E3 ligase that regulates axin degradation and Wnt signalling[J].Nat Cell Biol,2011,13(5):623-629.
[36] DAROSA P,WANG Z,JIANG X,et al.Allosteric activation of the RNF146 ubiquitin ligase by a poly(ADP-ribosyl)ation signal[J].Nature,2015,517(7533):223-226.
[37] HE J,ZHANG J,DONG L,et al.Dihydromyricetin attenuates metabolic syndrome and improves insulin sensitivity by upregulating insulin receptor substrate-1 (Y612) tyrosine phosphorylation in db/db mice[J].Diabetes Metab Syndr Obes,2019,12:2237-2249.
[38] HUANG S,MISHINA Y,LIU S,et al.Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling[J].Nature,2009,461(7264):614-620.
[39] COLUCCIA A,VACCA A,DUñACH M,et al.Bcr-Abl stabilizes beta-catenin in chronic myeloid leukemia through its tyrosine phosphorylation[J].Embo J,2007,26(5):1456-1466.
[40] KAJIGUCHI T,CHUNG E,LEE S,et al.FLT3 regulates beta-catenin tyrosine phosphorylation,nuclear localization,and transcriptional activity in acute myeloid leukemia cells[J].Leukemia,2007,21(12):2476-2484.
[41] KAJIGUCHI T,LEE S,LEE M,et al.KIT regulates tyrosine phosphorylation and nuclear localization of beta-catenin in mast cell leukemia[J].Leukemia Res,2008,32(5):761-770.
[42] ANTHONY CC,ROBBINS DJ,AHMED Y,et al.Nuclear regulation of Wnt/β-catenin signaling:it's a complex situation[J].Genes (Basel),2020,11(8):886.
[43] MIESZCZANEK J,VAN TIENEN L,IBRAHIM A,et al.Bcl9 and Pygo synergise downstream of Apc to effect intestinal neoplasia in FAP mouse models[J].Nat Commun,2019,10(1):724.
[44] HENDERSON B,GALEA M,SCHUECHNER S,et al.Lymphoid enhancer factor-1 blocks adenomatous polyposis coli-mediated nuclear export and degradation of beta-catenin.Regulation by histone deacetylase 1[J].J Biol Chem,2002,277(27):24258-24264.
[45] MORGAN R,RIDSDALE J,PAYNE M,et al.LEF-1 drives aberrant β-catenin nuclear localization in myeloid leukemia cells[J].Haematologica,2019,104(7):1365-1377.
[46] LU Y,XIE S,ZHANG W,et al.Twa1/Gid8 is a β-catenin nuclear retention factor in Wnt signaling and colorectal tumorigenesis[J].Cell Res,2017,27(12):1422-1440.
[47] ROSENBLUH J,NIJHAWAN D,COX A,et al.β-catenin-driven cancers require a YAP1 transcriptional complex for survival and tumorigenesis[J].Cell,2012,151(7):1457-1473.
[48] SHIN H,ISLAM R,YOON W,et al.Pin1-mediated modification prolongs the nuclear retention of β-catenin in Wnt3a-induced osteoblast differentiation[J].J Biol Chem,2016,291(11):5555-5565.
[49] BALDUS S,MÖNIG S,HUXEL S,et al.MUC1 and nuclear beta-catenin are coexpressed at the invasion front of colorectal carcinomas and are both correlated with tumor prognosis[J].Clin Cancer Res,2004,10(8):2790-2796.
[50] ANNA C,IIDA M,SILLS R,et al.Expression of potential beta-catenin targets,cyclin D1,c-Jun,c-Myc,E-cadherin,and EGFR in chemically induced hepatocellular neoplasms from B6C3F1 mice[J].Toxicol Appl Pharm,2003,190(2):135-145.
[51] WANG B,LI X,LIU L,et al.β-catenin:oncogenic role and therapeutic target in cervical cancer[J].Biol Res,2020,53(1):33.
[52] KOSUGI S,HASEBE M,ENTANI T,et al.Design of peptide inhibitors for the importin alpha/beta nuclear import pathway by activity-based profiling[J].Chem Biol,2008,15(9):940-949.
[53] AMBRUS G,WHITBY L,SINGER E,et al.Small molecule peptidomimetic inhibitors of importin α/β mediated nuclear transport[J].Bioorgan Med Chem,2010,18(21):7611-7620.
[54] HINTERSTEINER M,AMBRUS G,BEDNENKO J,et al.Identification of a small molecule inhibitor of importin β mediated nuclear import by confocal on-bead screening of tagged one-bead one-compound libraries[J].ACS Chem Biol,2010,5(10):967-979.
[55] SODERHOLM J,BIRD S,KALAB P,et al.Importazole,a small molecule inhibitor of the transport receptor importin-β[J].ACS Chem Biol,2011,6(7):700-708.
[56] GASIOROWSKI J,DEAN D.Mechanisms of nuclear transport and interventions[J].Adv Drug Deliver Rev,2003,55(6):703-716.
[57] PÁLMER H,GONZáLEZ-SANCHO J,ESPADA J,et al.Vitamin D(3) promotes the differentiation of colon carcinoma cells by the induction of E-cadherin and the inhibition of beta-catenin signaling[J].J Cell Biol,2001,154(2):369-387.
[58] NG K,MEYERHARDT J,WU K,et al.Circulating 25-hydroxyvitamin d levels and survival in patients with colorectal cancer[J].J Clin Oncol,2008,26(18):2984-2991.
[59] NG K,WOLPIN B,MEYERHARDT J,et al.Prospective study of predictors of vitamin D status and survival in patients with colorectal cancer[J].Brit J Cancer,2009,101(6):916-923.
[60] NG K,SARGENT D,GOLDBERG R,et al.Vitamin D status in patients with stage Ⅳ colorectal cancer:findings from intergroup trial N9741[J].J Clin Oncol,2011,29(12):1599-1606.
[61] SHERMAN M,YU R,ENGLE D,et al.Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy[J].Cell,2014,159(1):80-93.
[62] HOPE C,PLANUTIS K,PLANUTIENE M,et al.Low concentrations of resveratrol inhibit Wnt signal throughput in colon-derived cells:implications for colon cancer prevention[J].Mol Nutr Food Res,2008:S52-S61.
[63] LEOW P,TIAN Q,ONG Z,et al.Antitumor activity of natural compounds,curcumin and PKF118-310,as Wnt/β-catenin antagonists against human osteosarcoma cells[J].Invest New Drug,2010,28(6):766-782.
[64] MUKHERJEE S,MAZUMDAR M,CHAKRABORTY S,et al.Curcumin inhibits breast cancer stem cell migration by amplifying the E-cadherin/β-catenin negative feedback loop[J].Stem Cell Res Ther,2014,5(5):116.
[65] DAUGHERTY R,GOTTARDI C.Phospho-regulation of beta-catenin adhesion and signaling functions[J].Physiology,2007,22:303-309.
[66] BREMBECK F,SCHWARZ-ROMOND T,BAKKERS J,et al.Essential role of BCL9-2 in the switch between beta-catenin's adhesive and transcriptional functions[J].Gene Dev,2004,18(18):2225-2230.
[67] TAURIN S,SANDBO N,QIN Y,et al.Phosphorylation of beta-catenin by cyclic AMP-dependent protein kinase[J].J Biol Chem,2006,281(15):9971-9976.
[68] GAMMONS M,BIENZ M.Multiprotein complexes governing Wnt signal transduction[J].Curr Opin Cell Biol,2018,51:42-49.

基金

上海市闵行区大学科建设项目(2020MWDXK02)
PDF(977 KB)

2714

Accesses

0

Citation

Detail

段落导航
相关文章

/