Abstract
WNT/CTNNB1 signaling is crucial for balancing cell proliferation and differentiation in all multicellular animals. CTNNB1 accumulation is the hallmark of WNT/CTNNB1 pathway activation and the key downstream event in both a physiological and an oncogenic context. In the absence of WNT stimulation, the cytoplasmic and nuclear levels of CTNNB1 are kept low because of its sequestration and phosphorylation by the so-called destruction complex, which targets CTNNB1 for proteasomal degradation. In the presence of WNT proteins, or as a result of oncogenic mutations, this process is impaired and CTNNB1 levels become elevated.
Here we discuss recent advances in our understanding of destruction complex activity and inactivation, focusing on the individual components and interactions that ultimately control CTNNB1 turnover (in the “WNT off” situation) and stabilization (in the “WNT on” situation). We especially highlight the insights gleaned from recent quantitative, image-based studies, which paint an unprecedentedly detailed picture of the dynamic events that control destruction protein complex composition and function. We argue that these mechanistic details may reveal new opportunities for therapeutic intervention and could result in the destruction complex re-emerging as a target for therapy in cancer.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
Aberle H, Bauer A, Stappert J et al (1997) β-Catenin is a target for the ubiquitin-proteasome pathway. EMBO J 16:3797–3804
Albrecht LV, Ploper D, Tejeda-Muñoz N, De Robertis EM (2018) Arginine methylation is required for canonical Wnt signaling and endolysosomal trafficking. Proc Natl Acad Sci U S A 115:E5317–E5325. https://doi.org/10.1073/pnas.1804091115
Albrecht LV, Tejeda-Muñoz N, Bui MH et al (2020) GSK3 inhibits macropinocytosis and lysosomal activity through the Wnt destruction complex machinery. Cell Rep 32. https://doi.org/10.1016/j.celrep.2020.107973
Albuquerque C, Breukel C, Van Der Luijt R et al (2002) The “just-right” signaling model: APC somatic mutations are selected based on a specific level of activation of the β-catenin signaling cascade. Hum Mol Genet 11:1549–1560. https://doi.org/10.1093/hmg/11.13.1549
Amit S, Hatzubai A, Birman Y et al (2002) Axin-mediated CKI phosphorylation of β-catenin at Ser 45: a molecular switch for the Wnt pathway. Genes Dev 16:1066–1076. https://doi.org/10.1101/gad.230302.somal
Anvarian Z, Nojima H, Van Kappel EC et al (2016) Axin cancer mutants form nanoaggregates to rewire the Wnt signaling network. Nat Struct Mol Biol 23:324–332. https://doi.org/10.1038/nsmb.3191
Austinat M, Dunsch R, Wittekind C et al (2008) Correlation between beta-catenin mutations and expression of Wnt-signaling target genes in hepatocellular carcinoma. Mol Cancer 7:21. https://doi.org/10.1186/1476-4598-7-21
Azzolin L, Panciera T, Soligo S et al (2014) YAP/TAZ incorporation in the beta-catenin destruction complex orchestrates the Wnt response. Cell 158:157–170. https://doi.org/10.1016/j.cell.2014.06.013
Bandmann V, Mirsanaye AS, Schäfer J et al (2019) Membrane capacitance recordings resolve dynamics and complexity of receptor-mediated endocytosis in Wnt signalling. Sci Rep 9:1–11. https://doi.org/10.1038/s41598-019-49082-4
Barker N, van Es JH, Kuipers J et al (2007) Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449:1003–1007. https://doi.org/10.1038/nature06196
Behrens J, von Kries JP, Kühl M et al (1996) Functional interaction of beta-catenin with the transcription factor LEF-1. Nature 382:638–642
Bernkopf DB, Hadjihannas MV, Behrens J (2015) Negative-feedback regulation of the Wnt pathway by conductin/axin2 involves insensitivity to upstream signalling. J Cell Sci 128:33–39. https://doi.org/10.1242/jcs.159145
Bernkopf DB, Brückner M, Hadjihannas MV, Behrens J (2019) An aggregon in conductin/axin2 regulates Wnt/β-catenin signaling and holds potential for cancer therapy. Nat Commun 10. https://doi.org/10.1038/s41467-019-12203-8
Bienz M (2014) Signalosome assembly by domains undergoing dynamic head-to-tail polymerization. Trends Biochem Sci 39:487–495. https://doi.org/10.1016/j.tibs.2014.08.006
Bilic J, Huang Y-L, Davidson G et al (2007) Wnt induces LRP6 signalosomes and promotes dishevelled-dependent LRP6 phosphorylation. Science 316:1619–1622. https://doi.org/10.1126/science.1137065
Blagodatski A, Klimenko A, Jia L, Katanaev VL (2020) Small molecule Wnt pathway modulators from natural sources: history, state of the art and perspectives. Cell 9:589. https://doi.org/10.3390/cells9030589
Blum M, Chang HY, Chuguransky S et al (2021) The InterPro protein families and domains database: 20 years on. Nucleic Acids Res 49:D344–D354. https://doi.org/10.1093/nar/gkaa977
Brunt L, Scholpp S (2018) The function of endocytosis in Wnt signaling. Cell Mol Life Sci 75:785–795. https://doi.org/10.1007/s00018-017-2654-2
Bugter JM, Fenderico N, Maurice MM (2020) Mutations and mechanisms of WNT pathway tumour suppressors in cancer. Nat Rev Cancer. https://doi.org/10.1038/s41568-020-00307-z
Castillo-Ávila W, Abal M, Robine S, Pérez-Tomás R (2005) Non-apoptotic concentrations of prodigiosin (H+/Cl- symporter) inhibit the acidification of lysosomes and induce cell cycle blockage in colon cancer cells. Life Sci 78:121–127. https://doi.org/10.1016/j.lfs.2005.04.059
Cerami E, Gao J, Dogrusoz U et al (2012) The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2:401–404. https://doi.org/10.1158/2159-8290.CD-12-0095
Cheltsov A, Nomura N, Yenugonda VM et al (2020) Allosteric inhibitor of β-catenin selectively targets oncogenic Wnt signaling in colon cancer. Sci Rep 10:1–11. https://doi.org/10.1038/s41598-020-60784-y
Chen A, Koehler AN (2020) Transcription factor inhibition: lessons learned and emerging targets. Trends Mol Med 26:508–518. https://doi.org/10.1016/j.molmed.2020.01.004
Chen H, Lu C, Ouyang B et al (2020) Development of potent, selective surrogate WNT molecules and their application in defining frizzled requirements. Cell Chem Biol 27:598–609.e4. https://doi.org/10.1016/j.chembiol.2020.02.009
Chia IV, Costantini F (2005) Mouse Axin and Axin2/conductin proteins are functionally equivalent in vivo. Mol Cell Biol 25:4371–4376. https://doi.org/10.1128/mcb.25.11.4371-4376.2005
Chouaib R, Safieddine A, Pichon X et al (2020) A dual protein-mRNA localization screen reveals compartmentalized translation and widespread co-translational RNA targeting. Dev Cell 54:1–19. https://doi.org/10.1016/j.devcel.2020.07.010
Christie M, Jorissen RN, Mouradov D et al (2013) Different APC genotypes in proximal and distal sporadic colorectal cancers suggest distinct WNT/β-catenin signalling thresholds for tumourigenesis. Oncogene 32:4675–4682. https://doi.org/10.1038/onc.2012.486
Cliffe A, Hamada F, Bienz M (2003) A role of dishevelled in relocating Axin to the plasma membrane during wingless signaling. Curr Biol 13:960–966. https://doi.org/10.1016/S0960-9822(03)00370-1
Colozza G, Koo B (2021) Wnt/β-catenin signaling: structure, assembly and endocytosis of the signalosome. Develop Growth Differ 3389:dgd.12718. https://doi.org/10.1111/dgd.12718
Colozza G, Jami-Alahmadi Y, Dsouza A et al (2020) Wnt-inducible Lrp6-APEX2 interacting proteins identify ESCRT machinery and Trk-fused gene as components of the Wnt signaling pathway. Sci Rep 10:1–14. https://doi.org/10.1038/s41598-020-78019-5
Cong F, Schweizer L, Varmus H (2004) Wnt signals across the plasma membrane to activate the β-catenin pathway by forming oligomers containing its receptors, frizzled and LRP. Development 131:5103–5115. https://doi.org/10.1242/dev.01318
Cruciat C-M, Ohkawara B, Acebron SP et al (2010) Requirement of prorenin receptor and vacuolar H+-ATPase-mediated acidification for Wnt signaling. Science 327:459–463. https://doi.org/10.1126/science.1179802
Cselenyi CS, Jernigan KK, Tahinci E et al (2008) LRP6 transduces a canonical Wnt signal independently of Axin degradation by inhibiting GSK3’s phosphorylation of β-catenin. Proc Natl Acad Sci U S A 105:8032–8037. https://doi.org/10.1073/pnas.0803025105
Dajani R, Fraser E, Roe SM et al (2003) Structural basis for recruitment of glycogen synthase kinase 3β to the axin-APC scaffold complex. EMBO J 22:494–501. https://doi.org/10.1093/emboj/cdg068
Daly CS, Shaw P, Ordonez LD et al (2017) Functional redundancy between Apc and Apc2 regulates tissue homeostasis and prevents tumorigenesis in murine mammary epithelium. Oncogene 36:1793–1803. https://doi.org/10.1038/onc.2016.342
Darnell JE (2002) Transcription factors as targets for cancer therapy. Nat Rev Cancer 2:740–749. https://doi.org/10.1038/nrc906
Davidson G, Wu W, Shen J et al (2005) Casein kinase 1γ couples Wnt receptor activation to cytoplasmic signal transduction. Nature 438:867–872. https://doi.org/10.1038/nature04170
de Man SMA, Zwanenburg G, van der Wal T, Hink M, van Amerongen R (2021) Quantitative live-cell imaging and computational modelling shed new light on endogenous WNT/CTNNB1 signaling dynamics. eLife 10. https://doi.org/10.7554/eLife.66440
DeAlmeida VI, Miao L, Ernst JA et al (2007) The soluble Wnt receptor Frizzled8CRD-hFc inhibits the growth of teratocarcinomas in vivo. Cancer Res 67:5371–5379. https://doi.org/10.1158/0008-5472.CAN-07-0266
DeBruine ZJ, Ke J, Harikumar KG et al (2017a) Wnt5a promotes Frizzled-4 signalosome assembly by stabilizing cysteine-rich domain dimerization. Genes Dev 31:916–926. https://doi.org/10.1101/gad.298331.117
DeBruine ZJ, Xu HE, Melcher K (2017b) Assembly and architecture of the Wnt/β-catenin signalosome at the membrane. Br J Pharmacol 174:4564–4574. https://doi.org/10.1111/bph.14048
del Valle-Perez B, Arques O, Vinyoles M et al (2011) Coordinated action of CK1 isoforms in canonical Wnt signaling. Mol Cell Biol 31:2877–2888. https://doi.org/10.1128/mcb.01466-10
Diamond JR, Becerra C, Richards D et al (2020) Phase Ib clinical trial of the anti-frizzled antibody vantictumab (OMP-18R5) plus paclitaxel in patients with locally advanced or metastatic HER2-negative breast cancer. Breast Cancer Res Treat 184:53–62. https://doi.org/10.1007/s10549-020-05817-w
Dietrich L, Rathmer B, Ewan K et al (2017) Cell permeable stapled peptide inhibitor of Wnt signaling that targets β-catenin protein-protein interactions. Cell Chem Biol 24:958–968.e5. https://doi.org/10.1016/j.chembiol.2017.06.013
Doble BW, Patel S, Wood GA et al (2007) Functional redundancy of GSK-3α and GSK-3β in Wnt/β-catenin signaling shown by using an allelic series of embryonic stem cell lines. Dev Cell 12:957–971. https://doi.org/10.1016/j.devcel.2007.04.001
Dobrowolski R, Vick P, Ploper D et al (2012) Presenilin deficiency or lysosomal inhibition enhances Wnt signaling through relocalization of GSK3 to the late-endosomal compartment. Cell Rep 2:1316–1328. https://doi.org/10.1016/j.celrep.2012.09.026
Eckert AF, Gao P, Wesslowski J et al (2020) Measuring ligand-cell surface receptor affinities with axial line-scanning fluorescence correlation spectroscopy. eLife 9. https://doi.org/10.7554/eLife.55286
Etheridge SL, Ray S, Li S et al (2008) Murine dishevelled 3 functions in redundant pathways with dishevelled 1 and 2 in normal cardiac outflow tract, cochlea, and neural tube development. PLoS Genet 4. https://doi.org/10.1371/journal.pgen.1000259
Eubelen M, Bostaille N, Cabochette P et al (2018) A molecular mechanism for Wnt ligand-specific signaling. Science 361:eaat1178. https://doi.org/10.1126/science.aat1178
Fagotto F, Jho EH, Zeng L et al (1999) Domains of Axin involved in protein-protein interactions, Wnt pathway inhibition, and intracellular localization. J Cell Biol 145:741–756. https://doi.org/10.1083/jcb.145.4.741
Fatima I, El-Ayachi I, Taotao L et al (2017) The natural compound Jatrophone interferes with Wnt/β-catenin signaling and inhibits proliferation and EMT in human triple-negative breast cancer. PLoS One 12:1–18. https://doi.org/10.1371/journal.pone.0189864
Faux MC, Coates JL, Catimel B et al (2008) Recruitment of adenomatous polyposis coli and beta-catenin to axin-puncta. Oncogene 27:5808–5820. https://doi.org/10.1038/onc.2008.205
Fiedler M, Mendoza-Topaz C, Rutherford TJ et al (2011) Dishevelled interacts with the DIX domain polymerization interface of Axin to interfere with its function in down-regulating β-catenin. Proc Natl Acad Sci U S A 108:1937–1942. https://doi.org/10.1073/pnas.1017063108
Fiedler M, Graeb M, Mieszczanek J et al (2015) An ancient Pygo-dependent Wnt enhanceosome integrated by chip/LDB-SSDP. eLife 4:1–22. https://doi.org/10.7554/eLife.09073
Flanagan DJ, Barker N, Di Costanzo NS et al (2019) Frizzled-7 is required for Wnt signaling in gastric tumors with and without APC mutations. Cancer Res 79:970–981. https://doi.org/10.1158/0008-5472.CAN-18-2095
Fodde R, Smits R, Hofland N et al (1999) Mechanisms of APC-driven tumorigenesis lessons from mouse models. Cytogenet Cell Genet 86:105–111. https://doi.org/10.1159/000015361
Gammons M, Bienz M (2018) Multiprotein complexes governing Wnt signal transduction. Curr Opin Cell Biol 51:42–49. https://doi.org/10.1016/j.ceb.2017.10.008
Gammons MV, Renko M, Johnson CM et al (2016a) Wnt signalosome assembly by DEP domain swapping of dishevelled. Mol Cell 64:92–104. https://doi.org/10.1016/j.molcel.2016.08.026
Gammons MV, Rutherford TJ, Steinhart Z et al (2016b) Essential role of the dishevelled DEP domain in a Wnt-dependent human-cell-based complementation assay. J Cell Sci 129:3892–3902. https://doi.org/10.1242/jcs.195685
Gao J, Aksoy BA, Dogrusoz U et al (2013) Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 6:pl1. https://doi.org/10.1126/scisignal.2004088
Gaspar C, Franken P, Molenaar L et al (2009) A targeted constitutive mutation in the Apc tumor suppressor gene underlies mammary but not intestinal tumorigenesis. PLoS Genet 5. https://doi.org/10.1371/journal.pgen.1000547
Gavagan M, Fagnan E, Speltz EB, Zalatan JG (2020) The scaffold protein axin promotes signaling specificity within the Wnt pathway by suppressing competing kinase reactions. Cell Syst 10:515–525.e5. https://doi.org/10.1016/j.cels.2020.05.002
Gentzel M, Schambony A (2017) Dishevelled paralogs in vertebrate development: redundant or distinct? Front Cell Dev Biol 5:1–8. https://doi.org/10.3389/fcell.2017.00059
Gerlach JP, Emmink BL, Nojima H et al (2014) Wnt signalling induces accumulation of phosphorylated β-catenin in two distinct cytosolic complexes. Open Biol 4:140120. https://doi.org/10.1098/rsob.140120
Giannakis M, Hodis E, Jasmine Mu X et al (2014) RNF43 is frequently mutated in colorectal and endometrial cancers. Nat Genet 46:1264–1266. https://doi.org/10.1038/ng.3127
Goentoro L, Kirschner MW (2009) Evidence that fold-change, and not absolute level, of β-catenin dictates Wnt signaling. Mol Cell 36:872–884. https://doi.org/10.1016/j.molcel.2009.11.017
Gottardi CJ, Gumbiner BM (2004) Distinct molecular forms of β-catenin are targeted to adhesive or transcriptional complexes. J Cell Biol 167:339–349. https://doi.org/10.1083/jcb.200402153
Gurney A, Axelrod F, Bond CJ et al (2012) Wnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumors. Proc Natl Acad Sci U S A 109:11717–11722. https://doi.org/10.1073/pnas.1120068109
Ha NC, Tonozuka T, Stamos JL et al (2004) Mechanism of phosphorylation-dependent binding of APC to β-catenin and its role in β-catenin degradation. Mol Cell 15:511–521. https://doi.org/10.1016/j.molcel.2004.08.010
Habib SJ, Chen B, Tsai F et al (2013) Asymmetric stem cell division in vitro. Science 1424:1445–1448. https://doi.org/10.1126/science.1231077
Hagemann AIH, Kurz J, Kauffeld S et al (2014) In-vivo analysis of formation and endocytosis of the Wnt/β-catenin signaling complex in zebrafish embryos. J Cell Sci 127(Pt 18):3970–3982. https://doi.org/10.1242/jcs.148767
Hendriksen J, Jansen M, Brown CM et al (2008) Plasma membrane recruitment of dephosphorylated β-catenin upon activation of the Wnt pathway. J Cell Sci 121:1793–1802. https://doi.org/10.1242/jcs.025536
Hernández AR, Klein AM, Kirschner MW (2012) Kinetic responses of β-catenin specify the sites of Wnt control. Science 338:1337–1349. https://doi.org/10.1126/science.1225053
Hirai H, Matoba K, Mihara E et al (2019) Crystal structure of a mammalian Wnt–frizzled complex. Nat Struct Mol Biol 26:372–379. https://doi.org/10.1038/s41594-019-0216-z
Hirota T, Lee JW, Lewis WG et al (2010) High-throughput chemical screen identifies a novel potent modulator of cellular circadian rhythms and reveals CKIα as a clock regulatory kinase. PLoS Biol 8. https://doi.org/10.1371/journal.pbio.1000559
Holstein TW (2012) The evolution of the Wnt pathway. Cold Spring Harb Perspect Biol 4:1–17. https://doi.org/10.1101/cshperspect.a007922
Hori K, Ajioka K, Goda N et al (2018) Discovery of potent disheveled/Dvl inhibitors using virtual screening optimized with NMR-based docking performance index. Front Pharmacol 9:1–14. https://doi.org/10.3389/fphar.2018.00983
Hsu W, Zeng L, Costantini F (1999) Identification of a domain of axin that binds to the serine/threonine protein phosphatase 2A and a self-binding domain. J Biol Chem 274:3439–3445. https://doi.org/10.1074/jbc.274.6.3439
Huang SMA, Mishina YM, Liu S et al (2009) Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature 461:614–620. https://doi.org/10.1038/nature08356
Jacobsen A, Heijmans N, Verkaar F et al (2016) Construction and experimental validation of a petri net model of Wnt/β-catenin signaling. PLoS One 11:1–30. https://doi.org/10.1101/044966
Janda CY, Waghray D, Levin AM et al (2012) Structural basis of Wnt recognition by frizzled. Science 337:59–64. https://doi.org/10.1126/science.1222879
Janda CY, Dang LT, You C et al (2017) Surrogate Wnt agonists that phenocopy canonical Wnt and β-catenin signalling. Nature 545:234–237. https://doi.org/10.1038/nature22306
Jho E, Zhang T, Domon C et al (2002) Wnt/β-catenin/Tcf signaling induces the transcription of Axin2, a negative regulator of the signaling pathway. Mol Cell Biol 22:1172–1183. https://doi.org/10.1128/mcb.22.4.1172-1183.2002
Ji L, Lu B, Wang Z et al (2018) Identification of ICAT as an APC inhibitor, revealing Wnt-dependent inhibition of APC-Axin interaction. Mol Cell 72:37–47.e4. https://doi.org/10.1016/j.molcel.2018.07.040
Jiang S, Zhang M, Sun J, Yang X (2018) Casein kinase 1α: biological mechanisms and theranostic potential. Cell Commun Signal 16:1–24. https://doi.org/10.1186/s12964-018-0236-z
Jimeno A, Gordon M, Chugh R et al (2017) A first-in-human phase I study of the anticancer stem cell agent ipafricept (OMP-54F28), a decoy receptor for Wnt ligands, in patients with advanced solid tumors. Clin Cancer Res 23:7490–7497. https://doi.org/10.1158/1078-0432.CCR-17-2157
Joslyn G, Richardson DS, White R, Alber T (1993) Dimer formation by an N-terminal coiled coil in the APC protein. Proc Natl Acad Sci U S A 90:11109–11113. https://doi.org/10.1073/pnas.90.23.11109
Jung Y-S, Park J-I (2020) Wnt signaling in cancer: therapeutic targeting of Wnt signaling beyond β-catenin and the destruction complex. Exp Mol Med 52:183–191. https://doi.org/10.1038/s12276-020-0380-6
Kafri P, Hasenson SE, Kanter I et al (2016) Quantifying β-catenin subcellular dynamics and cyclin D1 mRNA transcription during Wnt signaling in single living cells. eLife 5:1–29. https://doi.org/10.7554/eLife.16748
Kan W, Enos MD, Korkmazhan E et al (2020) Limited dishevelled/axin oligomerization determines efficiency of wnt/b-catenin signal transduction. eLife 9:1–33. https://doi.org/10.7554/eLife.55015
Kikuchi A, Yamamoto H, Sato A (2009) Selective activation mechanisms of Wnt signaling pathways. Trends Cell Biol 19:119–129. https://doi.org/10.1016/j.tcb.2009.01.003
Kim S-E, Huang H, Zhao M et al (2013) Wnt stabilization of β-catenin reveals principles for morphogen receptor-scaffold assemblies. Science 340:867–870. https://doi.org/10.1126/science.1232389
Kitazawa M, Hatta T, Ogawa K et al (2017) Determination of rate-limiting factor for formation of beta-catenin destruction complexes using absolute protein quantification. J Proteome Res 16:3576–3584. https://doi.org/10.1021/acs.jproteome.7b00305
Kohler EM, Derungs A, Daum G et al (2008) Functional definition of the mutation cluster region of adenomatous polyposis coli in colorectal tumours. Hum Mol Genet 17:1978–1987. https://doi.org/10.1093/hmg/ddn095
Koo BK, Spit M, Jordens I et al (2012) Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors. Nature 488:665–669. https://doi.org/10.1038/nature11308
Krieghoff E, Behrens J, Mayr B (2006) Nucleo-cytoplasmic distribution of β-catenin is regulated by retention. J Cell Sci 119:1453–1463. https://doi.org/10.1242/jcs.02864
Krishnamurthy N, Kurzrock R (2018) Targeting the Wnt/beta-catenin pathway in cancer: update on effectors and inhibitors. Cancer Treat Rev 62:50–60
Kunttas-Tatli E, Roberts DM, McCartney BM (2014) Self-association of the APC tumor suppressor is required for the assembly, stability, and activity of the Wnt signaling destruction complex. Mol Biol Cell 25:3424–3436. https://doi.org/10.1091/mbc.E14-04-0885
Latres E, Chiaur DS, Pagano M (1999) The human F box protein β-Trcp associates with the Cul1/Skp1 complex and regulates the stability of β-catenin. Oncogene 18:849–854. https://doi.org/10.1038/sj.onc.1202653
Lebensohn AAM, Dubey R, Neitzel LR et al (2016) Comparative genetic screens in human cells reveal new regulatory mechanisms in WNT signaling. eLife 5:e21459. https://doi.org/10.7554/eLife.21459
Lee E, Salic A, Krüger R et al (2003) The roles of APC and axin derived from experimental and theoretical analysis of the Wnt pathway. PLoS Biol 1:116–132. https://doi.org/10.1371/journal.pbio.0000010
Lee YN, Gao Y, Wang H-Y (2008) Differential mediation of the Wnt canonical pathway by mammalian Dishevelleds-1, -2, and -3. Cell Signal 20:443–452. https://doi.org/10.1016/j.cellsig.2007.11.005
Li VSW, Ng SS, Boersema PJ et al (2012) Wnt signaling through inhibition of β-catenin degradation in an intact Axin1 complex. Cell 149:1245–1256. https://doi.org/10.1016/j.cell.2012.05.002
Li B, Orton D, Neitzel LR et al (2017) Differential abundance of CK1a provides selectivity for pharmacological CK1a activators to target WNT-dependent tumors. Sci Signal 10:1–12. https://doi.org/10.1126/scisignal.aak9916
Li W, Yang CJ, Wang LQ et al (2019) A tannin compound from Sanguisorba officinalis blocks Wnt/β-catenin signaling pathway and induces apoptosis of colorectal cancer cells. Chin Med 14:1–13. https://doi.org/10.1186/s13020-019-0244-y
Li B, Liang J, Lu F et al (2020) Discovery of novel inhibitor for Wnt/β-catenin pathway by tankyrase 1/2 structure-based virtual screening. Molecules 25. https://doi.org/10.3390/molecules25071680
Liao H, Li X, Zhao L et al (2020) A PROTAC peptide induces durable β-catenin degradation and suppresses Wnt-dependent intestinal cancer. Cell Discov 6:1–12. https://doi.org/10.1038/s41421-020-0171-1
Lim X, Tan S, Koh WWLC et al (2013) Interfollicular epidermal stem cells self-renew via autocrine Wnt signaling. Science 342:1226–1230. https://doi.org/10.1126/science.1239730.Interfollicular
Liu C, Li Y, Semenov M et al (2002) Control of β-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell 108:837–847. https://doi.org/10.1016/S0092-8674(02)00685-2
Liu X, Rubin JS, Kimmel AR (2005) Rapid, Wnt-induced changes in GSK3β associations that regulate β-catenin stabilization are mediated by Gα proteins. Curr Biol 15:1989–1997. https://doi.org/10.1016/j.cub.2005.10.050
Loh KM, van Amerongen R, Nusse R (2016) Generating cellular diversity and spatial form: Wnt signaling and the evolution of multicellular animals. Dev Cell 38:643–655. https://doi.org/10.1016/j.devcel.2016.08.011
Luo W, Peterson A, Garcia BA et al (2007) Protein phosphatase 1 regulates assembly and function of the β-catenin degradation complex. EMBO J 26:1511–1521. https://doi.org/10.1038/sj.emboj.7601607
Lustig B, Jerchow B, Sachs M et al (2002) Negative feedback loop of Wnt signaling through upregulation of conductin/axin2 in colorectal and liver tumors. Mol Cell Biol 22:1184–1193. https://doi.org/10.1128/mcb.22.4.1184-1193.2002
Lybrand DB, Naiman M, Laumann JM et al (2019) Destruction complex dynamics: Wnt/β-catenin signaling alters Axin-GSK3β interactions in vivo. Development 146. https://doi.org/10.1242/dev.164145
Ma W, Chen M, Kang H et al (2020) Single-molecule dynamics of dishevelled at the plasma membrane and Wnt pathway activation. Proc Natl Acad Sci U S A 117:16690–16701. https://doi.org/10.1073/pnas.1910547117
Mao J, Wang J, Liu B et al (2001) Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway. Mol Cell 7:801–809. https://doi.org/10.1016/S1097-2765(01)00224-6
Massey J, Liu Y, Alvarenga O et al (2019) Synergy with TGFβ ligands switches WNT pathway dynamics from transient to sustained during human pluripotent cell differentiation. Proc Natl Acad Sci U S A 116:4989–4998. https://doi.org/10.1073/pnas.1815363116
Matoba K, Mihara E, Tamura-Kawakami K et al (2017) Conformational freedom of the LRP6 ectodomain is regulated by N-glycosylation and the binding of the Wnt antagonist Dkk1. Cell Rep 18:32–40. https://doi.org/10.1016/j.celrep.2016.12.017
McGough IJ, Vecchia L, Bishop B et al (2020) Glypicans shield the Wnt lipid moiety to enable signalling at a distance. Nature 585:85–90. https://doi.org/10.1038/s41586-020-2498-z
Mehta CC, Bhatt HG (2021) Tankyrase inhibitors as antitumor agents: a patent update (2013 - 2020). Expert Opin Ther Pat 00:1–17. https://doi.org/10.1080/13543776.2021.1888929
Mendoza-Topaz C, Mieszczanek J, Bienz M (2011) The adenomatous polyposis coli tumour suppressor is essential for Axin complex assembly and function and opposes Axin’s interaction with Dishevelled. Open Biol 1:110013. https://doi.org/10.1098/rsob.110013
Metcalfe C, Mendoza-Topaz C, Mieszczanek J, Bienz M (2010) Stability elements in the LRP6 cytoplasmic tail confer efficient signalling upon DIX-dependent polymerization. J Cell Sci 123:1588–1599. https://doi.org/10.1242/jcs.067546
Mii Y, Yamamoto T, Takada R et al (2017) Roles of two types of heparan sulfate clusters in Wnt distribution and signaling in Xenopus. Nat Commun 8:1–19. https://doi.org/10.1038/s41467-017-02076-0
Molenaar M, van de Wetering M, Oosterwegel M et al (1996) XTcf-3 transcription factor mediates beta-catenin-induced axis formation in Xenopus embryos. Cell 86:391–399. https://doi.org/10.1016/S0092-8674(00)80112-9
Moore KN, Gunderson CC, Sabbatini P et al (2019) A phase 1b dose escalation study of ipafricept (OMP—54F28) in combination with paclitaxel and carboplatin in patients with recurrent platinum-sensitive ovarian cancer. Gynecol Oncol 154:294–301. https://doi.org/10.1016/j.ygyno.2019.04.001
Mukherjee A, Dhar N, Stathos M et al (2018) Understanding how Wnt influences destruction complex activity and β-catenin dynamics. iScience 6:13–21. https://doi.org/10.1016/j.isci.2018.07.007
Munemitsu S, Souza B, Muller O et al (1994) The APC gene product associates with microtubules in vivo and promotes their assembly in vitro. Cancer Res 54:3676–3681
Munthe E, Raiborg C, Stenmark H, Wenzel EM (2020) Clathrin regulates Wnt/β-catenin signaling by affecting Golgi to plasma membrane transport of transmembrane proteins. J Cell Sci 133. https://doi.org/10.1242/jcs.244467
Nakamura T, Hamada F, Ishidate T et al (1998) Axin, an inhibitor of the Wnt signalling pathway, interacts with β-catenin, GSK-3β and APC and reduces the β-catenin level. Genes Cells 3:395–403. https://doi.org/10.1046/j.1365-2443.1998.00198.x
Ngo J, Hashimoto M, Hamada H, Wynshaw-Boris A (2020) Deletion of the Dishevelled family of genes disrupts anterior-posterior axis specification and selectively prevents mesoderm differentiation. Dev Biol 464:161–175. https://doi.org/10.1016/j.ydbio.2020.05.010
Nile AH, Mukund S, Stanger K et al (2017) Unsaturated fatty acyl recognition by frizzled receptors mediates dimerization upon Wnt ligand binding. Proc Natl Acad Sci U S A 114:4147–4152. https://doi.org/10.1073/pnas.1618293114
Nong J, Kang K, Shi Q et al (2021) Phase separation of Axin organizes the β-catenin destruction complex. J Cell Biol 220. https://doi.org/10.1083/jcb.202012112
Nusse R, Clevers H (2017) Wnt/β-catenin signaling, disease, and emerging therapeutic modalities. Cell 169:985–999. https://doi.org/10.1016/j.cell.2017.05.016
Nusse R, Varmus HE (1982) Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell 31:99–109
Nusse R, van Ooyen A, Cox D et al (1984) Mode of proviral activation of a putative mammary oncogene (int-1) on mouse chromosome 15. Nature 307:131–136. https://doi.org/10.1038/307131a0
Nusse R, Brown A, Papkoff J, Scambler P, Shackleford G, McMahon A, Moon R, Varmus H (1991) A new nomenclature for int-1 and related genes: the Wnt gene family. Cell 64:231–232. https://doi.org/10.1002/mus.880140612
Nusslein-Volhard C, Wieschaus E (1980) Mutations affecting segment number and polarity in Drosophila. Nature 287:795–801
Parker TW, Neufeld KL (2020) APC controls Wnt-induced β-catenin destruction complex recruitment in human colonocytes. Sci Rep 10:1–14. https://doi.org/10.1038/s41598-020-59899-z
Petersen J, Wright SC, Rodríguez D et al (2017) Agonist-induced dimer dissociation as a macromolecular step in G protein-coupled receptor signaling. Nat Commun 8:226. https://doi.org/10.1038/s41467-017-00253-9
Peterson-Nedry W, Erdeniz N, Kremer S et al (2008) Unexpectedly robust assembly of the Axin destruction complex regulates Wnt/Wg signaling in Drosophila as revealed by analysis in vivo. Dev Biol 320:226–241. https://doi.org/10.1016/j.ydbio.2008.05.521
Piao S, Lee SJH, Kim H et al (2008) Direct inhibition of GSK3β by the phosphorylated cytoplasmic domain of LRP6 in Wnt/β-catenin signaling. PLoS One 3:e4046. https://doi.org/10.1371/journal.pone.0004046
Plummer R, Dua D, Cresti N et al (2020) First-in-human study of the PARP/tankyrase inhibitor E7449 in patients with advanced solid tumours and evaluation of a novel drug-response predictor. Br J Cancer 123:525–533. https://doi.org/10.1038/s41416-020-0916-5
Polakis P (2000) Wnt signaling and cancer. Genes Dev 14:1837–1851. https://doi.org/10.1038/nature03319
Pronobis MI, Rusan NM, Peifer M (2015) A novel GSK3-regulated APC:Axin interaction regulates Wnt signaling by driving a catalytic cycle of efficient βcatenin destruction. eLife 4:1–31. https://doi.org/10.7554/eLife.08022
Pronobis MI, Deuitch N, Posham V et al (2017) Reconstituting regulation of the canonical Wnt pathway by engineering a minimal β-catenin destruction machine. Mol Biol Cell 28:41–53. https://doi.org/10.1091/mbc.E16-07-0557
Raisch J, Côté-Biron A, Rivard N (2019) A role for the WNT co-receptor LRP6 in pathogenesis and therapy of epithelial cancers. Cancers (Basel) 11:1–23. https://doi.org/10.3390/cancers11081162
Repina NA, Bao X, Zimmermann JA et al (2019) Optogenetic control of Wnt signaling for modeling early embryogenic patterning with human pluripotent stem cells. bioRxiv. https://doi.org/10.1101/665695
Rijsewijk F, Schuermann M, Wagenaar E et al (1987) The Drosophila homolog of the mouse mammary oncogene int-1 is identical to the segment polarity gene wingless. Cell 50:649–657. https://doi.org/10.1016/0092-8674(87)90038-9
Rim EY, Kinney LK, Nusse R (2020) Beta-catenin-mediated Wnt signal transduction proceeds through an endocytosis-independent mechanism. Mol Biol Cell 31(13):1425–1436. https://doi.org/10.1091/mbc.E20-02-0114
Roberts DM, Pronobis MI, Poulton JS et al (2011) Deconstructing the βcatenin destruction complex: mechanistic roles for the tumor suppressor APC in regulating Wnt signaling. Mol Biol Cell 22:1845–1863. https://doi.org/10.1091/mbc.E10-11-0871
Rodriguez-Blanco J, Li B, Long J et al (2019) A CK1a activator penetrates the brain and shows efficacy against drug-resistant metastatic medulloblastoma. Clin Cancer Res 25:1379–1388. https://doi.org/10.1158/1078-0432.CCR-18-1319
Rubinfeld B, Souza B, Albert I et al (1993) Association of the APC gene product with β-catenin. Science 262:1731–1734. https://doi.org/10.1126/science.8259518
Rubinfeld B, Albert I, Porfiri E et al (1996) Binding of GSK3β to the APC-β-catenin complex and regulation of complex assembly. Science 272:1023–1026
Sakanaka C, Williams LT (1999) Functional domains of Axin: importance of the C terminus as an oligomerization domain. J Biol Chem 274:14090–14093. https://doi.org/10.1074/jbc.274.20.14090
Salinas PC (2007) Modulation of the microtubule cytoskeleton: a role for a divergent canonical Wnt pathway. Trends Cell Biol 17:333–342. https://doi.org/10.1016/j.tcb.2007.07.003
Sayat R, Leber B, Grubac V et al (2008) O-GlcNAc-glycosylation of β-catenin regulates its nuclear localization and transcriptional activity. Exp Cell Res 314:2774–2787. https://doi.org/10.1016/j.yexcr.2008.05.017
Schaefer KN, Peifer M (2019) Wnt/beta-catenin signaling regulation and a role for biomolecular condensates. Dev Cell 48:429–444. https://doi.org/10.1016/j.devcel.2019.01.025
Schaefer MH, Serrano L (2016) Cell type-specific properties and environment shape tissue specificity of cancer genes. Sci Rep 6:1–14. https://doi.org/10.1038/srep20707
Schaefer KN, Bonello TT, Zhang S et al (2018) Supramolecular assembly of the beta-catenin destruction complex and the effect of Wnt signaling on its localization, molecular size, and activity in vivo. PLoS Genet 14:e1007339. https://doi.org/10.1371/journal.pgen.1007339
Schaefer KN, Pronobis M, Williams CE et al (2020) Wnt regulation: exploring Axin-disheveled interactions and defining mechanisms by which the SCF E3 ubiquitin ligase is recruited to the destruction complex. Mol Biol Cell 31(10):992–1014. https://doi.org/10.1091/mbc.e19-11-0647
Schatoff EM, Goswami S, Zafra MP et al (2019) Distinct colorectal cancer–associated apc mutations dictate response to tankyrase inhibition. Cancer Discov 9:1358–1371. https://doi.org/10.1158/2159-8290.CD-19-0289
Schihada H, Kowalski-Jahn M, Turku A, Schulte G (2021) Deconvolution of WNT-induced Frizzled conformational dynamics with fluorescent biosensors. Biosens Bioelectron 177:112948. https://doi.org/10.1016/j.bios.2020.112948
Schneider G, Schmidt-Supprian M, Rad R, Saur D (2017) Tissue-specific tumorigenesis: context matters. Nat Rev Cancer 17:239–253. https://doi.org/10.1038/nrc.2017.5
Schneikert J, Grohmann A, Behrens J (2007) Truncated APC regulates the transcriptional activity of β-catenin in a cell cycle dependent manner. Hum Mol Genet 16:199–209. https://doi.org/10.1093/hmg/ddl464
Schneikert J, Vijaya Chandra SH, Ruppert JG et al (2013) Functional comparison of human adenomatous polyposis coli (APC) and APC-like in targeting Beta-catenin for degradation. PLoS One 8. https://doi.org/10.1371/journal.pone.0068072
Schwarz-Romond T, Fiedler M, Shibata N et al (2007a) The DIX domain of Dishevelled confers Wnt signaling by dynamic polymerization. Nat Struct Mol Biol 14:484–492. https://doi.org/10.1038/nsmb1247
Schwarz-Romond T, Metcalfe C, Bienz M (2007b) Dynamic recruitment of axin by Dishevelled protein assemblies. J Cell Sci 120:2402–2412. https://doi.org/10.1242/jcs.002956
Shah K, Panchal S, Patel B (2021) Porcupine inhibitors: novel and emerging anti-cancer therapeutics targeting the Wnt signaling pathway. Pharmacol Res 167:105532. https://doi.org/10.1016/j.phrs.2021.105532
Shen C, Nayak A, Melendez RA et al (2020) Casein kinase 1α as a regulator of Wnt-driven cancer. Int J Mol Sci 21:1–16. https://doi.org/10.3390/ijms21165940
Stamos JL, Weis WI (2013) The β-catenin destruction complex. Cold Spring Harb Perspect Biol 5:a007898
Stamos JL, Chu ML-HH, Enos MD et al (2014) Structural basis of GSK-3 inhibition by N-terminal phosphorylation and by the Wnt receptor LRP6. eLife 2014:e01998. https://doi.org/10.7554/eLife.01998
Steinhart Z, Pavlovic Z, Chandrashekhar M et al (2016) Genome-wide CRISPR screens reveal a Wnt–FZD5 signaling circuit as a druggable vulnerability of RNF43-mutant pancreatic tumors. Nat Med 23:60–68. https://doi.org/10.1038/nm.4219
Stolz A, Bastians H (2015) Fresh WNT into the regulation of mitosis. Cell Cycle 14:2566–2570. https://doi.org/10.1080/15384101.2015.1064569
Su LK, Vogelstein B, Kinzler KW (1993) Association of the APC tumor suppressor protein with catenins. Science 262:1734–1737. https://doi.org/10.1126/science.8259519
Su YY, Fu C, Ishikawa S et al (2008) APC is essential for targeting phosphorylated β-catenin to the SCFβ-TrCP ubiquitin ligase. Mol Cell 32:652–661
Suzuki H, Watkins DN, Jair KW et al (2004) Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer. Nat Genet 36:417–422. https://doi.org/10.1038/ng1330
Tacchelly-Benites O, Wang Z, Yang E et al (2018) Axin phosphorylation in both Wnt-off and Wnt-on states requires the tumor suppressor APC. PLoS Genet 14:1–24. https://doi.org/10.1371/journal.pgen.1007178
Taelman VF, Dobrowolski R, Plouhinec JL et al (2010) Wnt signaling requires sequestration of glycogen synthase kinase 3 inside multivesicular endosomes. Cell 143:1136–1148. https://doi.org/10.1016/j.cell.2010.11.034
Tamai K, Zeng X, Liu C et al (2004) A mechanism for Wnt coreceptor activation. Mol Cell 13:149–156. https://doi.org/10.1016/S1097-2765(03)00484-2
Tan CW, Gardiner BS, Hirokawa Y et al (2012) Wnt signalling pathway parameters for mammalian cells. PLoS One 7:31882. https://doi.org/10.1371/journal.pone.0031882
Tanaka N, Mashima T, Mizutani A et al (2017) APC mutations as a potential biomarker for sensitivity to tankyrase inhibitors in colorectal cancer. Mol Cancer Ther 16:752–762. https://doi.org/10.1158/1535-7163.MCT-16-0578
Tao Y, Mis M, Blazer L et al (2019) Tailored tetravalent antibodies potently and specifically activate wnt/frizzled pathways in cells, organoids and mice. eLife 8:1–16. https://doi.org/10.7554/eLife.46134
Tauriello DVF, Jordens I, Kirchner K et al (2012) Wnt/β-catenin signaling requires interaction of the Dishevelled DEP domain and C terminus with a discontinuous motif in frizzled. Proc Natl Acad Sci U S A 109:E812–E820. https://doi.org/10.1073/pnas.1114802109
Tejeda-Muñoz N, Albrecht LV, Bui MH, De Robertis EM (2019) Wnt canonical pathway activates macropinocytosis and lysosomal degradation of extracellular proteins. Proc Natl Acad Sci U S A 116:10402–10411. https://doi.org/10.1073/pnas.1903506116
Thorne CA, Hanson AJ, Schneider J et al (2010) Small-molecule inhibition of Wnt signaling through activation of casein kinase 1α. Nat Chem Biol 6:829–836. https://doi.org/10.1038/nchembio.453
Thorvaldsen TE, Pedersen NM, Wenzel EM et al (2015) Structure, dynamics, and functionality of tankyrase inhibitor-induced degradasomes. Mol Cancer Res 13:1487–1501. https://doi.org/10.1158/1541-7786.MCR-15-0125
Tolwinski NS, Wehrli M, Rives A et al (2003) Wg/Wnt signal can be transmitted through arrow/LRP5,6 and Axin independently of Zw3/Gsk3β activity. Dev Cell 4:407–418. https://doi.org/10.1016/S1534-5807(03)00063-7
Tortelote GG, Reis RR, de Almeida MF, Abreu JG (2017) Complexity of the Wnt/β-catenin pathway: searching for an activation model. Cell Signal 40:30–43. https://doi.org/10.1016/j.cellsig.2017.08.008
Tran H, Polakis P (2012) Reversible modification of adenomatous polyposis coli (APC) with K63-linked polyubiquitin regulates the assembly and activity of the β-catenin destruction complex. J Biol Chem 287:28552–28563. https://doi.org/10.1074/jbc.M112.387878
Ueno K, Hirata H, Hinoda Y, Dahiya R (2013) Frizzled homolog proteins, microRNAs and Wnt signaling in cancer. Int J Cancer 132:1731–1740. https://doi.org/10.1002/ijc.27746
Umbhauer M (2000) The C-terminal cytoplasmic Lys-Thr-X-X-X-Trp motif in frizzled receptors mediates Wnt/beta-catenin signalling. EMBO J 19:4944–4954. https://doi.org/10.1093/emboj/19.18.4944
Valenta T, Hausmann G, Basler K (2012) The many faces and functions of β-catenin. EMBO J 31:2714–2736. https://doi.org/10.1038/emboj.2012.150
Valvezan AJ, Zhang F, Diehl JA, Klein PS (2012) Adenomatous polyposis coli (APC) regulates multiple signaling pathways by enhancing glycogen synthase kinase-3 (GSK-3) activity. J Biol Chem 287:3823–3832. https://doi.org/10.1074/jbc.M111.323337
Van Amerongen R, Nawijn M, Franca-Koh J et al (2005) Frat is dispensable for canonical Wnt signaling in mammals. Genes Dev 19:425–430. https://doi.org/10.1101/gad.326705
van Amerongen R, Bowman AN, Nusse R (2012) Developmental stage and time dictate the fate of Wnt/β-catenin-responsive stem cells in the mammary gland. Cell Stem Cell 11:387–400. https://doi.org/10.1016/j.stem.2012.05.023
van der Wal T, van Amerongen R (2020) Walking the tight wire between cell adhesion and WNT signalling: a balancing act for β-catenin. Open Biol 10:200267. https://doi.org/10.1098/rsob.200267
van Tienen LM, Mieszczanek J, Fiedler M et al (2017) Constitutive scaffolding of multiple Wnt enhanceosome components by legless/BCL9. eLife 6:1–23. https://doi.org/10.7554/eLife.20882
Vinyoles M, DelValle-Pérez B, Curto J et al (2014) Multivesicular GSK3 sequestration upon Wnt signaling is controlled by p120-catenin/cadherin interaction with LRP5/6. Mol Cell 53:444–457. https://doi.org/10.1016/j.molcel.2013.12.010
Voloshanenko O, Erdmann G, Dubash TD et al (2013) Wnt secretion is required to maintain high levels of Wnt activity in colon cancer cells. Nat Commun 4:1–13. https://doi.org/10.1038/ncomms3610
Wang Z, Li B, Zhou L et al (2016) Prodigiosin inhibits Wnt/β-catenin signaling and exerts anticancer activity in breast cancer cells. Proc Natl Acad Sci U S A 113:13150–13155. https://doi.org/10.1073/pnas.1616336113
Wang X, Feng M, Xiao T et al (2021a) BCL9/BCL9L promotes tumorigenicity through immune-dependent and independent mechanisms in triple negative breast cancer. Oncogene. https://doi.org/10.1038/s41388-021-01756-y
Wang Z, Li Z, Ji H (2021b) Direct targeting of β-catenin in the Wnt signaling pathway: current progress and perspectives. Med Res Rev 41(4):2109–2129. https://doi.org/10.1002/med.21787
Wesslowski J, Kozielewicz P, Wang X et al (2020) eGFP-tagged Wnt-3a enables functional analysis of Wnt trafficking and signaling and kinetic assessment of Wnt binding to full-length frizzled. J Biol Chem 295:8759–8774. https://doi.org/10.1074/jbc.RA120.012892
Wiese KE, Nusse R, van Amerongen R (2018) Wnt signalling: conquering complexity. Development 145:dev165902. https://doi.org/10.1242/dev.165902
Willert K, Shibamoto S, Nusse R (1999) Wnt-induced dephosphorylation of Axin releases β-catenin from the Axin complex. Genes Dev 13:1768–1773. https://doi.org/10.1101/gad.13.14.1768
Wong HC, Bourdelas A, Krauss A et al (2003) Direct binding of the PDZ domain of Dishevelled to a conserved internal sequence in the C-terminal region of frizzled. Mol Cell 12:1251–1260. https://doi.org/10.1016/S1097-2765(03)00427-1
Wu X, Tu X, Joeng KS et al (2008) Rac1 activation controls nuclear localization of β-catenin during canonical Wnt signaling. Cell 133:340–353. https://doi.org/10.1016/j.cell.2008.01.052
Wu G, Huang H, Abreu JG, He X (2009) Inhibition of GSK3 phosphorylation of β-catenin via phosphorylated PPPSPXS motifs of Wnt coreceptor LRP6. PLoS One 4:e4926. https://doi.org/10.1371/journal.pone.0004926
Wu YC, Chiang YC, Chou SH, Pan CL (2020) Wnt signalling and endocytosis: mechanisms, controversies and implications for stress responses. Biol Cell:1–12. https://doi.org/10.1111/boc.202000099
Xiong Y, Zhou L, Su Z et al (2019) Longdaysin inhibits Wnt/β-catenin signaling and exhibits antitumor activity against breast cancer. Onco Targets Ther 12:993–1005. https://doi.org/10.2147/OTT.S193024
Yamamoto H, Kishida S, Kishida M et al (1999) Phosphorylation of axin, a Wnt signal negative regulator, by glycogen synthase kinase-3β regulates its stability. J Biol Chem 274:10681–10684. https://doi.org/10.1074/jbc.274.16.10681
Yamamoto H, Umeda D, Matsumoto S, Kikuchi A (2017) LDL switches the LRP6 internalization route from flotillin dependent to clathrin dependent in hepatic cells. J Cell Sci 130:3542–3556. https://doi.org/10.1242/jcs.202135
Yamulla RJ, Kane EG, Moody AE et al (2014) Testing models of the APC tumor suppressor/β-catenin interaction reshapes our view of the destruction complex in Wnt signaling. Genetics 197:1285–1302. https://doi.org/10.1534/genetics.114.166496
Yang J, Zhang W, Evans PM et al (2006) Adenomatous polyposis coli (APC) differentially regulates β-catenin phosphorylation and ubiquitination in colon cancer cells. J Biol Chem 281:17751–17757. https://doi.org/10.1074/jbc.M600831200
Yang L, Wu X, Wang Y et al (2011) FZD7 has a critical role in cell proliferation in triple negative breast cancer. Oncogene 30:4437–4446. https://doi.org/10.1038/onc.2011.145
Yokoyama N, Golebiewska U, Wang H, Malbon CC (2010) Wnt-dependent assembly of supermolecular Dishevelled-3-based complexes. J Cell Sci 123:3693–3702. https://doi.org/10.1242/jcs.075275
Yokoyama N, Markova NG, Wang H, Malbon CC (2012) Assembly of dishevelled 3-based supermolecular complexes via phosphorylation and axin. J Mol Signal 7:8. https://doi.org/10.1186/1750-2187-7-8
Yost C, Farr GH, Pierce SB et al (1998) GBP, an inhibitor of GSK-3, is implicated in Xenopus development and oncogenesis. Cell 93:1031–1041. https://doi.org/10.1016/S0092-8674(00)81208-8
Zeng X, Tamai K, Doble B et al (2005) A dual-kinase mechanism for Wnt co-receptor phosphorylation and activation. Nature 438:873–877. https://doi.org/10.1038/nature04185
Zeng X, Huang H, Tamai K et al (2007) Initiation of Wnt signaling: control of Wnt coreceptor Lrp6 phosphorylation/activation via frizzled, dishevelled and axin functions. Development 135:367–375. https://doi.org/10.1242/dev.013540
Zhan T, Rindtorff N, Boutros M (2017) Wnt signaling in cancer. Oncogene 36:1461–1473. https://doi.org/10.1038/onc.2016.304
Acknowledgements
We thank Tomas Noordzij for literature research that helped shape the section on therapeutic targeting. We thank Tanne van der Wal for critically reading the manuscript. RvA acknowledges funding by the Netherlands Science Foundation NWO (VIDI 864.13.002 and OC.ENW.169) and KWF kankerbestrijding (2017-1/11082). SdM acknowledges funding by the Fulbright Foundation and Nijbakker-Morra Foundation.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2021 The Author(s), under exclusive license to Springer Nature Switzerland AG
About this chapter
Cite this chapter
de Man, S.M.A., van Amerongen, R. (2021). Zooming in on the WNT/CTNNB1 Destruction Complex: Functional Mechanistic Details with Implications for Therapeutic Targeting. In: Schulte, G., Kozielewicz, P. (eds) Pharmacology of the WNT Signaling System. Handbook of Experimental Pharmacology, vol 269. Springer, Cham. https://doi.org/10.1007/164_2021_522
Download citation
DOI: https://doi.org/10.1007/164_2021_522
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-85498-0
Online ISBN: 978-3-030-85499-7
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)