19 WNT ligands and 10 FZD receptors have been identified in human cells; interactions amongst these ligands and receptors vary in a developmental and tissue-specific manner and lead to activation of so-called 'canonical' and 'non-canonical' WNT signaling. In the canonical WNT signaling pathway, binding of a WNT ligand to the Frizzled (FZD) and lipoprotein receptor-related protein (LRP) receptors results in the inactivation of the destruction complex, the stabilization and nuclear translocation of beta-catenin and subsequent activation of T-cell factor/lymphoid enhancing factor (TCF/LEF)-dependent transcription. Transcriptional activation in response to canonical WNT signaling controls processes such as cell fate, proliferation and self renewal of stem cells, as well as contributing to oncogenesis (reviewed in MacDonald et al, 2009; Saito-Diaz et al, 2013; Kim et al, 2013).
View original pathway at:Reactome.
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Takada R, Satomi Y, Kurata T, Ueno N, Norioka S, Kondoh H, Takao T, Takada S.; ''Monounsaturated fatty acid modification of Wnt protein: its role in Wnt secretion.''; PubMedEurope PMCScholia
Bauer A, Huber O, Kemler R.; ''Pontin52, an interaction partner of beta-catenin, binds to the TATA box binding protein.''; PubMedEurope PMCScholia
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Bernatik O, Ganji RS, Dijksterhuis JP, Konik P, Cervenka I, Polonio T, Krejci P, Schulte G, Bryja V.; ''Sequential activation and inactivation of Dishevelled in the Wnt/beta-catenin pathway by casein kinases.''; PubMedEurope PMCScholia
Yamamoto H, Komekado H, Kikuchi A.; ''Caveolin is necessary for Wnt-3a-dependent internalization of LRP6 and accumulation of beta-catenin.''; PubMedEurope PMCScholia
Bovolenta P, Esteve P, Ruiz JM, Cisneros E, Lopez-Rios J.; ''Beyond Wnt inhibition: new functions of secreted Frizzled-related proteins in development and disease.''; PubMedEurope PMCScholia
Bastide P, Darido C, Pannequin J, Kist R, Robine S, Marty-Double C, Bibeau F, Scherer G, Joubert D, Hollande F, Blache P, Jay P.; ''Sox9 regulates cell proliferation and is required for Paneth cell differentiation in the intestinal epithelium.''; PubMedEurope PMCScholia
Juhlin CC, Haglund F, Villablanca A, Forsberg L, Sandelin K, Bränström R, Larsson C, Höög A.; ''Loss of expression for the Wnt pathway components adenomatous polyposis coli and glycogen synthase kinase 3-beta in parathyroid carcinomas.''; PubMedEurope PMCScholia
Hao HX, Xie Y, Zhang Y, Charlat O, Oster E, Avello M, Lei H, Mickanin C, Liu D, Ruffner H, Mao X, Ma Q, Zamponi R, Bouwmeester T, Finan PM, Kirschner MW, Porter JA, Serluca FC, Cong F.; ''ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner.''; PubMedEurope PMCScholia
Lyu J, Yamamoto V, Lu W.; ''Cleavage of the Wnt receptor Ryk regulates neuronal differentiation during cortical neurogenesis.''; PubMedEurope PMCScholia
Zeng X, Huang H, Tamai K, Zhang X, Harada Y, Yokota C, Almeida K, Wang J, Doble B, Woodgett J, Wynshaw-Boris A, Hsieh JC, He X.; ''Initiation of Wnt signaling: control of Wnt coreceptor Lrp6 phosphorylation/activation via frizzled, dishevelled and axin functions.''; PubMedEurope PMCScholia
Luga V, Zhang L, Viloria-Petit AM, Ogunjimi AA, Inanlou MR, Chiu E, Buchanan M, Hosein AN, Basik M, Wrana JL.; ''Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration.''; PubMedEurope PMCScholia
Keeble TR, Cooper HM.; ''Ryk: a novel Wnt receptor regulating axon pathfinding.''; PubMedEurope PMCScholia
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Park JI, Venteicher AS, Hong JY, Choi J, Jun S, Shkreli M, Chang W, Meng Z, Cheung P, Ji H, McLaughlin M, Veenstra TD, Nusse R, McCrea PD, Artandi SE.; ''Telomerase modulates Wnt signalling by association with target gene chromatin.''; PubMedEurope PMCScholia
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He X, Semenov M, Tamai K, Zeng X.; ''LDL receptor-related proteins 5 and 6 in Wnt/beta-catenin signaling: arrows point the way.''; PubMedEurope PMCScholia
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Biechele S, Cox BJ, Rossant J.; ''Porcupine homolog is required for canonical Wnt signaling and gastrulation in mouse embryos.''; PubMedEurope PMCScholia
Qin Y, Li L, Pan W, Wu D.; ''Regulation of phosphatidylinositol kinases and metabolism by Wnt3a and Dvl.''; PubMedEurope PMCScholia
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Daniels DL, Weis WI.; ''ICAT inhibits beta-catenin binding to Tcf/Lef-family transcription factors and the general coactivator p300 using independent structural modules.''; PubMedEurope PMCScholia
Poy F, Lepourcelet M, Shivdasani RA, Eck MJ.; ''Structure of a human Tcf4-beta-catenin complex.''; PubMedEurope PMCScholia
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Topol L, Chen W, Song H, Day TF, Yang Y.; ''Sox9 inhibits Wnt signaling by promoting beta-catenin phosphorylation in the nucleus.''; PubMedEurope PMCScholia
Bauer A, Chauvet S, Huber O, Usseglio F, Rothbächer U, Aragnol D, Kemler R, Pradel J.; ''Pontin52 and reptin52 function as antagonistic regulators of beta-catenin signalling activity.''; PubMedEurope PMCScholia
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Hsieh JC, Kodjabachian L, Rebbert ML, Rattner A, Smallwood PM, Samos CH, Nusse R, Dawid IB, Nathans J.; ''A new secreted protein that binds to Wnt proteins and inhibits their activities.''; PubMedEurope PMCScholia
Kim W, Kim M, Jho EH.; ''Wnt/β-catenin signalling: from plasma membrane to nucleus.''; PubMedEurope PMCScholia
Li X, Zhang Y, Kang H, Liu W, Liu P, Zhang J, Harris SE, Wu D.; ''Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling.''; PubMedEurope PMCScholia
Bafico A, Gazit A, Pramila T, Finch PW, Yaniv A, Aaronson SA.; ''Interaction of frizzled related protein (FRP) with Wnt ligands and the frizzled receptor suggests alternative mechanisms for FRP inhibition of Wnt signaling.''; PubMedEurope PMCScholia
Berndt JD, Aoyagi A, Yang P, Anastas JN, Tang L, Moon RT.; ''Mindbomb 1, an E3 ubiquitin ligase, forms a complex with RYK to activate Wnt/β-catenin signaling.''; PubMedEurope PMCScholia
Glinka A, Dolde C, Kirsch N, Huang YL, Kazanskaya O, Ingelfinger D, Boutros M, Cruciat CM, Niehrs C.; ''LGR4 and LGR5 are R-spondin receptors mediating Wnt/β-catenin and Wnt/PCP signalling.''; PubMedEurope PMCScholia
Ikeda S, Kishida M, Matsuura Y, Usui H, Kikuchi A.; ''GSK-3beta-dependent phosphorylation of adenomatous polyposis coli gene product can be modulated by beta-catenin and protein phosphatase 2A complexed with Axin.''; PubMedEurope PMCScholia
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Yokoya F, Imamoto N, Tachibana T, Yoneda Y.; ''beta-catenin can be transported into the nucleus in a Ran-unassisted manner.''; PubMedEurope PMCScholia
Zhang N, Wei P, Gong A, Chiu WT, Lee HT, Colman H, Huang H, Xue J, Liu M, Wang Y, Sawaya R, Xie K, Yung WK, Medema RH, He X, Huang S.; ''FoxM1 promotes β-catenin nuclear localization and controls Wnt target-gene expression and glioma tumorigenesis.''; PubMedEurope PMCScholia
Li FQ, Mofunanya A, Fischer V, Hall J, Takemaru K.; ''Nuclear-cytoplasmic shuttling of Chibby controls beta-catenin signaling.''; PubMedEurope PMCScholia
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Mao J, Wang J, Liu B, Pan W, Farr GH, Flynn C, Yuan H, Takada S, Kimelman D, Li L, Wu D.; ''Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway.''; PubMedEurope PMCScholia
Lustig B, Jerchow B, Sachs M, Weiler S, Pietsch T, Karsten U, van de Wetering M, Clevers H, Schlag PM, Birchmeier W, Behrens J.; ''Negative feedback loop of Wnt signaling through upregulation of conductin/axin2 in colorectal and liver tumors.''; PubMedEurope PMCScholia
Takemaru KI, Moon RT.; ''The transcriptional coactivator CBP interacts with beta-catenin to activate gene expression.''; PubMedEurope PMCScholia
Chen B, Dodge ME, Tang W, Lu J, Ma Z, Fan CW, Wei S, Hao W, Kilgore J, Williams NS, Roth MG, Amatruda JF, Chen C, Lum L.; ''Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer.''; PubMedEurope PMCScholia
Levanon D, Goldstein RE, Bernstein Y, Tang H, Goldenberg D, Stifani S, Paroush Z, Groner Y.; ''Transcriptional repression by AML1 and LEF-1 is mediated by the TLE/Groucho corepressors.''; PubMedEurope PMCScholia
Hecht A, Vleminckx K, Stemmler MP, van Roy F, Kemler R.; ''The p300/CBP acetyltransferases function as transcriptional coactivators of beta-catenin in vertebrates.''; PubMedEurope PMCScholia
Iguchi H, Urashima Y, Inagaki Y, Ikeda Y, Okamura M, Tanaka T, Uchida A, Yamamoto TT, Kodama T, Sakai J.; ''SOX6 suppresses cyclin D1 promoter activity by interacting with beta-catenin and histone deacetylase 1, and its down-regulation induces pancreatic beta-cell proliferation.''; PubMedEurope PMCScholia
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Rothbächer U, Laurent MN, Deardorff MA, Klein PS, Cho KW, Fraser SE.; ''Dishevelled phosphorylation, subcellular localization and multimerization regulate its role in early embryogenesis.''; PubMedEurope PMCScholia
Wei Q, Yokota C, Semenov MV, Doble B, Woodgett J, He X.; ''R-spondin1 is a high affinity ligand for LRP6 and induces LRP6 phosphorylation and beta-catenin signaling.''; PubMedEurope PMCScholia
Daniels DL, Weis WI.; ''Beta-catenin directly displaces Groucho/TLE repressors from Tcf/Lef in Wnt-mediated transcription activation.''; PubMedEurope PMCScholia
Semënov MV, Snyder M.; ''Human dishevelled genes constitute a DHR-containing multigene family.''; PubMedEurope PMCScholia
Bányai L, Kerekes K, Patthy L.; ''Characterization of a Wnt-binding site of the WIF-domain of Wnt inhibitory factor-1.''; PubMedEurope PMCScholia
Moumen M, Chiche A, Decraene C, Petit V, Gandarillas A, Deugnier MA, Glukhova MA, Faraldo MM.; ''Myc is required for β-catenin-mediated mammary stem cell amplification and tumorigenesis.''; PubMedEurope PMCScholia
Song N, Schwab KR, Patterson LT, Yamaguchi T, Lin X, Potter SS, Lang RA.; ''pygopus 2 has a crucial, Wnt pathway-independent function in lens induction.''; PubMedEurope PMCScholia
Pan W, Choi SC, Wang H, Qin Y, Volpicelli-Daley L, Swan L, Lucast L, Khoo C, Zhang X, Li L, Abrams CS, Sokol SY, Wu D.; ''Wnt3a-mediated formation of phosphatidylinositol 4,5-bisphosphate regulates LRP6 phosphorylation.''; PubMedEurope PMCScholia
Huang H, He X.; ''Wnt/beta-catenin signaling: new (and old) players and new insights.''; PubMedEurope PMCScholia
Bafico A, Liu G, Yaniv A, Gazit A, Aaronson SA.; ''Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow.''; PubMedEurope PMCScholia
Liu G, Bafico A, Harris VK, Aaronson SA.; ''A novel mechanism for Wnt activation of canonical signaling through the LRP6 receptor.''; PubMedEurope PMCScholia
Kishida M, Hino Si, Michiue T, Yamamoto H, Kishida S, Fukui A, Asashima M, Kikuchi A.; ''Synergistic activation of the Wnt signaling pathway by Dvl and casein kinase Iepsilon.''; PubMedEurope PMCScholia
Sinner D, Kordich JJ, Spence JR, Opoka R, Rankin S, Lin SC, Jonatan D, Zorn AM, Wells JM.; ''Sox17 and Sox4 differentially regulate beta-catenin/T-cell factor activity and proliferation of colon carcinoma cells.''; PubMedEurope PMCScholia
Jho EH, Zhang T, Domon C, Joo CK, Freund JN, Costantini F.; ''Wnt/beta-catenin/Tcf signaling induces the transcription of Axin2, a negative regulator of the signaling pathway.''; PubMedEurope PMCScholia
Bourhis E, Tam C, Franke Y, Bazan JF, Ernst J, Hwang J, Costa M, Cochran AG, Hannoush RN.; ''Reconstitution of a frizzled8.Wnt3a.LRP6 signaling complex reveals multiple Wnt and Dkk1 binding sites on LRP6.''; PubMedEurope PMCScholia
Su Y, Fu C, Ishikawa S, Stella A, Kojima M, Shitoh K, Schreiber EM, Day BW, Liu B.; ''APC is essential for targeting phosphorylated beta-catenin to the SCFbeta-TrCP ubiquitin ligase.''; PubMedEurope PMCScholia
Goodman RM, Thombre S, Firtina Z, Gray D, Betts D, Roebuck J, Spana EP, Selva EM.; ''Sprinter: a novel transmembrane protein required for Wg secretion and signaling.''; PubMedEurope PMCScholia
Binnerts ME, Kim KA, Bright JM, Patel SM, Tran K, Zhou M, Leung JM, Liu Y, Lomas WE, Dixon M, Hazell SA, Wagle M, Nie WS, Tomasevic N, Williams J, Zhan X, Levy MD, Funk WD, Abo A.; ''R-Spondin1 regulates Wnt signaling by inhibiting internalization of LRP6.''; PubMedEurope PMCScholia
Shilatifard A.; ''Chromatin modifications by methylation and ubiquitination: implications in the regulation of gene expression.''; PubMedEurope PMCScholia
Belenkaya TY, Han C, Standley HJ, Lin X, Houston DW, Heasman J, Lin X.; ''pygopus Encodes a nuclear protein essential for wingless/Wnt signaling.''; PubMedEurope PMCScholia
Wolf D, Rodova M, Miska EA, Calvet JP, Kouzarides T.; ''Acetylation of beta-catenin by CREB-binding protein (CBP).''; PubMedEurope PMCScholia
Feng Y, Lee N, Fearon ER.; ''TIP49 regulates beta-catenin-mediated neoplastic transformation and T-cell factor target gene induction via effects on chromatin remodeling.''; PubMedEurope PMCScholia
Semënov MV, Tamai K, Brott BK, Kühl M, Sokol S, He X.; ''Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6.''; PubMedEurope PMCScholia
Cong F, Varmus H.; ''Nuclear-cytoplasmic shuttling of Axin regulates subcellular localization of beta-catenin.''; PubMedEurope PMCScholia
Tomson BN, Arndt KM.; ''The many roles of the conserved eukaryotic Paf1 complex in regulating transcription, histone modifications, and disease states.''; PubMedEurope PMCScholia
Behrens J, von Kries JP, Kühl M, Bruhn L, Wedlich D, Grosschedl R, Birchmeier W.; ''Functional interaction of beta-catenin with the transcription factor LEF-1.''; PubMedEurope PMCScholia
Fraser E, Young N, Dajani R, Franca-Koh J, Ryves J, Williams RS, Yeo M, Webster MT, Richardson C, Smalley MJ, Pearl LH, Harwood A, Dale TC.; ''Identification of the Axin and Frat binding region of glycogen synthase kinase-3.''; PubMedEurope PMCScholia
Veverka V, Henry AJ, Slocombe PM, Ventom A, Mulloy B, Muskett FW, Muzylak M, Greenslade K, Moore A, Zhang L, Gong J, Qian X, Paszty C, Taylor RJ, Robinson MK, Carr MD.; ''Characterization of the structural features and interactions of sclerostin: molecular insight into a key regulator of Wnt-mediated bone formation.''; PubMedEurope PMCScholia
Mao B, Wu W, Li Y, Hoppe D, Stannek P, Glinka A, Niehrs C.; ''LDL-receptor-related protein 6 is a receptor for Dickkopf proteins.''; PubMedEurope PMCScholia
Thomas GM, Frame S, Goedert M, Nathke I, Polakis P, Cohen P.; ''A GSK3-binding peptide from FRAT1 selectively inhibits the GSK3-catalysed phosphorylation of axin and beta-catenin.''; PubMedEurope PMCScholia
Tago K, Nakamura T, Nishita M, Hyodo J, Nagai S, Murata Y, Adachi S, Ohwada S, Morishita Y, Shibuya H, Akiyama T.; ''Inhibition of Wnt signaling by ICAT, a novel beta-catenin-interacting protein.''; PubMedEurope PMCScholia
Brantjes H, Barker N, van Es J, Clevers H.; ''TCF: Lady Justice casting the final verdict on the outcome of Wnt signalling.''; PubMedEurope PMCScholia
Valenta T, Gay M, Steiner S, Draganova K, Zemke M, Hoffmans R, Cinelli P, Aguet M, Sommer L, Basler K.; ''Probing transcription-specific outputs of β-catenin in vivo.''; PubMedEurope PMCScholia
Bao R, Christova T, Song S, Angers S, Yan X, Attisano L.; ''Inhibition of tankyrases induces Axin stabilization and blocks Wnt signalling in breast cancer cells.''; PubMedEurope PMCScholia
Li FQ, Mofunanya A, Harris K, Takemaru K.; ''Chibby cooperates with 14-3-3 to regulate beta-catenin subcellular distribution and signaling activity.''; PubMedEurope PMCScholia
Chen G, Nguyen PH, Courey AJ.; ''A role for Groucho tetramerization in transcriptional repression.''; PubMedEurope PMCScholia
Ishida-Takagishi M, Enomoto A, Asai N, Ushida K, Watanabe T, Hashimoto T, Kato T, Weng L, Matsumoto S, Asai M, Murakumo Y, Kaibuchi K, Kikuchi A, Takahashi M.; ''The Dishevelled-associating protein Daple controls the non-canonical Wnt/Rac pathway and cell motility.''; PubMedEurope PMCScholia
Städeli R, Basler K.; ''Dissecting nuclear Wingless signalling: recruitment of the transcriptional co-activator Pygopus by a chain of adaptor proteins.''; PubMedEurope PMCScholia
Wöhrle S, Wallmen B, Hecht A.; ''Differential control of Wnt target genes involves epigenetic mechanisms and selective promoter occupancy by T-cell factors.''; PubMedEurope PMCScholia
Sakamoto I, Kishida S, Fukui A, Kishida M, Yamamoto H, Hino S, Michiue T, Takada S, Asashima M, Kikuchi A.; ''A novel beta-catenin-binding protein inhibits beta-catenin-dependent Tcf activation and axis formation.''; PubMedEurope PMCScholia
Henderson BR, Fagotto F.; ''The ins and outs of APC and beta-catenin nuclear transport.''; PubMedEurope PMCScholia
Brantjes H, Roose J, van De Wetering M, Clevers H.; ''All Tcf HMG box transcription factors interact with Groucho-related co-repressors.''; PubMedEurope PMCScholia
Waaler J, Machon O, Tumova L, Dinh H, Korinek V, Wilson SR, Paulsen JE, Pedersen NM, Eide TJ, Machonova O, Gradl D, Voronkov A, von Kries JP, Krauss S.; ''A novel tankyrase inhibitor decreases canonical Wnt signaling in colon carcinoma cells and reduces tumor growth in conditional APC mutant mice.''; PubMedEurope PMCScholia
Janda CY, Waghray D, Levin AM, Thomas C, Garcia KC.; ''Structural basis of Wnt recognition by Frizzled.''; PubMedEurope PMCScholia
Ferkey DM, Kimelman D.; ''Glycogen synthase kinase-3 beta mutagenesis identifies a common binding domain for GBP and Axin.''; PubMedEurope PMCScholia
Sakane H, Yamamoto H, Kikuchi A.; ''LRP6 is internalized by Dkk1 to suppress its phosphorylation in the lipid raft and is recycled for reuse.''; PubMedEurope PMCScholia
Farr GH, Ferkey DM, Yost C, Pierce SB, Weaver C, Kimelman D.; ''Interaction among GSK-3, GBP, axin, and APC in Xenopus axis specification.''; PubMedEurope PMCScholia
Mazieres J, He B, You L, Xu Z, Lee AY, Mikami I, Reguart N, Rosell R, McCormick F, Jablons DM.; ''Wnt inhibitory factor-1 is silenced by promoter hypermethylation in human lung cancer.''; PubMedEurope PMCScholia
Hoffmans R, Basler K.; ''Identification and in vivo role of the Armadillo-Legless interaction.''; PubMedEurope PMCScholia
Dajani R, Fraser E, Roe SM, Yeo M, Good VM, Thompson V, Dale TC, Pearl LH.; ''Structural basis for recruitment of glycogen synthase kinase 3beta to the axin-APC scaffold complex.''; PubMedEurope PMCScholia
Davidson G, Wu W, Shen J, Bilic J, Fenger U, Stannek P, Glinka A, Niehrs C.; ''Casein kinase 1 gamma couples Wnt receptor activation to cytoplasmic signal transduction.''; PubMedEurope PMCScholia
Cairo S, Armengol C, Buendia MA.; ''Activation of Wnt and Myc signaling in hepatoblastoma.''; PubMedEurope PMCScholia
Walf-Vorderwülbecke V, de Boer J, Horton SJ, van Amerongen R, Proost N, Berns A, Williams O.; ''Frat2 mediates the oncogenic activation of Rac by MLL fusions.''; PubMedEurope PMCScholia
Arce L, Pate KT, Waterman ML.; ''Groucho binds two conserved regions of LEF-1 for HDAC-dependent repression.''; PubMedEurope PMCScholia
Melichar HJ, Narayan K, Der SD, Hiraoka Y, Gardiol N, Jeannet G, Held W, Chambers CA, Kang J.; ''Regulation of gammadelta versus alphabeta T lymphocyte differentiation by the transcription factor SOX13.''; PubMedEurope PMCScholia
Akiyama H, Lyons JP, Mori-Akiyama Y, Yang X, Zhang R, Zhang Z, Deng JM, Taketo MM, Nakamura T, Behringer RR, McCrea PD, de Crombrugghe B.; ''Interactions between Sox9 and beta-catenin control chondrocyte differentiation.''; PubMedEurope PMCScholia
Kim S, Jho EH.; ''The protein stability of Axin, a negative regulator of Wnt signaling, is regulated by Smad ubiquitination regulatory factor 2 (Smurf2).''; PubMedEurope PMCScholia
Miyazaki K, Fujita T, Ozaki T, Kato C, Kurose Y, Sakamoto M, Kato S, Goto T, Itoyama Y, Aoki M, Nakagawara A.; ''NEDL1, a novel ubiquitin-protein isopeptide ligase for dishevelled-1, targets mutant superoxide dismutase-1.''; PubMedEurope PMCScholia
Cheyette BN, Waxman JS, Miller JR, Takemaru K, Sheldahl LC, Khlebtsova N, Fox EP, Earnest T, Moon RT.; ''Dapper, a Dishevelled-associated antagonist of beta-catenin and JNK signaling, is required for notochord formation.''; PubMedEurope PMCScholia
Huang SM, Mishina YM, Liu S, Cheung A, Stegmeier F, Michaud GA, Charlat O, Wiellette E, Zhang Y, Wiessner S, Hild M, Shi X, Wilson CJ, Mickanin C, Myer V, Fazal A, Tomlinson R, Serluca F, Shao W, Cheng H, Shultz M, Rau C, Schirle M, Schlegl J, Ghidelli S, Fawell S, Lu C, Curtis D, Kirschner MW, Lengauer C, Finan PM, Tallarico JA, Bouwmeester T, Porter JA, Bauer A, Cong F.; ''Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling.''; PubMedEurope PMCScholia
Chen G, Fernandez J, Mische S, Courey AJ.; ''A functional interaction between the histone deacetylase Rpd3 and the corepressor groucho in Drosophila development.''; PubMedEurope PMCScholia
Kim JH, Kim B, Cai L, Choi HJ, Ohgi KA, Tran C, Chen C, Chung CH, Huber O, Rose DW, Sawyers CL, Rosenfeld MG, Baek SH.; ''Transcriptional regulation of a metastasis suppressor gene by Tip60 and beta-catenin complexes.''; PubMedEurope PMCScholia
Herr P, Hausmann G, Basler K.; ''WNT secretion and signalling in human disease.''; PubMedEurope PMCScholia
Surmann-Schmitt C, Widmann N, Dietz U, Saeger B, Eitzinger N, Nakamura Y, Rattel M, Latham R, Hartmann C, von der Mark H, Schett G, von der Mark K, Stock M.; ''Wif-1 is expressed at cartilage-mesenchyme interfaces and impedes Wnt3a-mediated inhibition of chondrogenesis.''; PubMedEurope PMCScholia
Kansara M, Tsang M, Tsang M, Kodjabachian L, Sims NA, Trivett MK, Ehrich M, Dobrovic A, Slavin J, Choong PF, Choong PF, Simmons PJ, Dawid IB, Thomas DM.; ''Wnt inhibitory factor 1 is epigenetically silenced in human osteosarcoma, and targeted disruption accelerates osteosarcomagenesis in mice.''; PubMedEurope PMCScholia
Schmitt AM, Shi J, Wolf AM, Lu CC, King LA, Zou Y.; ''Wnt-Ryk signalling mediates medial-lateral retinotectal topographic mapping.''; PubMedEurope PMCScholia
van Amerongen R, Nawijn M, Franca-Koh J, Zevenhoven J, van der Gulden H, Jonkers J, Berns A.; ''Frat is dispensable for canonical Wnt signaling in mammals.''; PubMedEurope PMCScholia
Hino S, Michiue T, Asashima M, Kikuchi A.; ''Casein kinase I epsilon enhances the binding of Dvl-1 to Frat-1 and is essential for Wnt-3a-induced accumulation of beta-catenin.''; PubMedEurope PMCScholia
Willert K, Shibamoto S, Nusse R.; ''Wnt-induced dephosphorylation of axin releases beta-catenin from the axin complex.''; PubMedEurope PMCScholia
Galbán S, Duckett CS.; ''XIAP as a ubiquitin ligase in cellular signaling.''; PubMedEurope PMCScholia
Xing Y, Clements WK, Kimelman D, Xu W.; ''Crystal structure of a beta-catenin/axin complex suggests a mechanism for the beta-catenin destruction complex.''; PubMedEurope PMCScholia
Hoffmans R, Städeli R, Basler K.; ''Pygopus and legless provide essential transcriptional coactivator functions to armadillo/beta-catenin.''; PubMedEurope PMCScholia
Tamai K, Semenov M, Kato Y, Spokony R, Liu C, Katsuyama Y, Hess F, Saint-Jeannet JP, He X.; ''LDL-receptor-related proteins in Wnt signal transduction.''; PubMedEurope PMCScholia
Mosimann C, Hausmann G, Basler K.; ''Parafibromin/Hyrax activates Wnt/Wg target gene transcription by direct association with beta-catenin/Armadillo.''; PubMedEurope PMCScholia
Barrott JJ, Cash GM, Smith AP, Barrow JR, Murtaugh LC.; ''Deletion of mouse Porcn blocks Wnt ligand secretion and reveals an ectodermal etiology of human focal dermal hypoplasia/Goltz syndrome.''; PubMedEurope PMCScholia
Kim KA, Zhao J, Andarmani S, Kakitani M, Oshima T, Binnerts ME, Abo A, Tomizuka K, Funk WD.; ''R-Spondin proteins: a novel link to beta-catenin activation.''; PubMedEurope PMCScholia
Wu W, Glinka A, Delius H, Niehrs C.; ''Mutual antagonism between dickkopf1 and dickkopf2 regulates Wnt/beta-catenin signalling.''; PubMedEurope PMCScholia
Lui TT, Lacroix C, Ahmed SM, Goldenberg SJ, Leach CA, Daulat AM, Angers S.; ''The ubiquitin-specific protease USP34 regulates axin stability and Wnt/β-catenin signaling.''; PubMedEurope PMCScholia
Liu Y, Shi J, Lu CC, Wang ZB, Lyuksyutova AI, Song XJ, Zou Y.; ''Ryk-mediated Wnt repulsion regulates posterior-directed growth of corticospinal tract.''; PubMedEurope PMCScholia
Thompson B, Townsley F, Rosin-Arbesfeld R, Musisi H, Bienz M.; ''A new nuclear component of the Wnt signalling pathway.''; PubMedEurope PMCScholia
Sustmann C, Flach H, Ebert H, Eastman Q, Grosschedl R.; ''Cell-type-specific function of BCL9 involves a transcriptional activation domain that synergizes with beta-catenin.''; PubMedEurope PMCScholia
van de Wetering M, Cavallo R, Dooijes D, van Beest M, van Es J, Loureiro J, Ypma A, Hursh D, Jones T, Bejsovec A, Peifer M, Mortin M, Clevers H.; ''Armadillo coactivates transcription driven by the product of the Drosophila segment polarity gene dTCF.''; PubMedEurope PMCScholia
Malik HS, Eickbush TH, Goldfarb DS.; ''Evolutionary specialization of the nuclear targeting apparatus.''; PubMedEurope PMCScholia
Bänziger C, Soldini D, Schütt C, Zipperlen P, Hausmann G, Basler K.; ''Wntless, a conserved membrane protein dedicated to the secretion of Wnt proteins from signaling cells.''; PubMedEurope PMCScholia
Wong HC, Bourdelas A, Krauss A, Lee HJ, Shao Y, Wu D, Mlodzik M, Shi DL, Zheng J.; ''Direct binding of the PDZ domain of Dishevelled to a conserved internal sequence in the C-terminal region of Frizzled.''; PubMedEurope PMCScholia
Li L, Mao J, Sun L, Liu W, Wu D.; ''Second cysteine-rich domain of Dickkopf-2 activates canonical Wnt signaling pathway via LRP-6 independently of dishevelled.''; PubMedEurope PMCScholia
Zorn AM, Barish GD, Williams BO, Lavender P, Klymkowsky MW, Varmus HE.; ''Regulation of Wnt signaling by Sox proteins: XSox17 alpha/beta and XSox3 physically interact with beta-catenin.''; PubMedEurope PMCScholia
Cong F, Schweizer L, Varmus H.; ''Wnt signals across the plasma membrane to activate the beta-catenin pathway by forming oligomers containing its receptors, Frizzled and LRP.''; PubMedEurope PMCScholia
Niehrs C.; ''Function and biological roles of the Dickkopf family of Wnt modulators.''; PubMedEurope PMCScholia
Yost C, Farr GH, Pierce SB, Ferkey DM, Chen MM, Kimelman D.; ''GBP, an inhibitor of GSK-3, is implicated in Xenopus development and oncogenesis.''; PubMedEurope PMCScholia
Fiedler M, Sánchez-Barrena MJ, Nekrasov M, Mieszczanek J, Rybin V, Müller J, Evans P, Bienz M.; ''Decoding of methylated histone H3 tail by the Pygo-BCL9 Wnt signaling complex.''; PubMedEurope PMCScholia
Thompson BA, Tremblay V, Lin G, Bochar DA.; ''CHD8 is an ATP-dependent chromatin remodeling factor that regulates beta-catenin target genes.''; PubMedEurope PMCScholia
Omer CA, Miller PJ, Diehl RE, Kral AM.; ''Identification of Tcf4 residues involved in high-affinity beta-catenin binding.''; PubMedEurope PMCScholia
Mao B, Wu W, Davidson G, Marhold J, Li M, Mechler BM, Delius H, Hoppe D, Stannek P, Walter C, Glinka A, Niehrs C.; ''Kremen proteins are Dickkopf receptors that regulate Wnt/beta-catenin signalling.''; PubMedEurope PMCScholia
Parker DS, Ni YY, Chang JL, Li J, Cadigan KM.; ''Wingless signaling induces widespread chromatin remodeling of target loci.''; PubMedEurope PMCScholia
Luo W, Peterson A, Garcia BA, Coombs G, Kofahl B, Heinrich R, Shabanowitz J, Hunt DF, Yost HJ, Virshup DM.; ''Protein phosphatase 1 regulates assembly and function of the beta-catenin degradation complex.''; PubMedEurope PMCScholia
Lin YC, You L, Xu Z, He B, Mikami I, Thung E, Chou J, Kuchenbecker K, Kim J, Raz D, Yang CT, Chen JK, Jablons DM.; ''Wnt signaling activation and WIF-1 silencing in nasopharyngeal cancer cell lines.''; PubMedEurope PMCScholia
Bernard P, Sim H, Knower K, Vilain E, Harley V.; ''Human SRY inhibits beta-catenin-mediated transcription.''; PubMedEurope PMCScholia
Chen S, Bubeck D, MacDonald BT, Liang WX, Mao JH, Malinauskas T, Llorca O, Aricescu AR, Siebold C, He X, Jones EY.; ''Structural and functional studies of LRP6 ectodomain reveal a platform for Wnt signaling.''; PubMedEurope PMCScholia
Jessen S, Gu B, Dai X.; ''Pygopus and the Wnt signaling pathway: a diverse set of connections.''; PubMedEurope PMCScholia
Song H, Hasson P, Paroush Z, Courey AJ.; ''Groucho oligomerization is required for repression in vivo.''; PubMedEurope PMCScholia
Barker N, Hurlstone A, Musisi H, Miles A, Bienz M, Clevers H.; ''The chromatin remodelling factor Brg-1 interacts with beta-catenin to promote target gene activation.''; PubMedEurope PMCScholia
Willis TG, Zalcberg IR, Coignet LJ, Wlodarska I, Stul M, Jadayel DM, Bastard C, Treleaven JG, Catovsky D, Silva ML, Dyer MJ.; ''Molecular cloning of translocation t(1;14)(q21;q32) defines a novel gene (BCL9) at chromosome 1q21.''; PubMedEurope PMCScholia
Gu B, Watanabe K, Dai X.; ''Pygo2 regulates histone gene expression and H3 K56 acetylation in human mammary epithelial cells.''; PubMedEurope PMCScholia
The beta-catenin destruction complex plays a key role in the canonical Wnt signaling pathway. In the absence of Wnt signaling, this complex controls the levels of cytoplamic beta-catenin. Beta-catenin associates with and is phosphorylated by the destruction complex. Phosphorylated beta-catenin is recognized and ubiquitinated by the SCF-beta TrCP ubiquitin ligase complex and is subsequently degraded by the proteasome (reviewed in Kimelman and Xu, 2006).
19 WNT proteins have been identified in human cells. The WNTs are members of a conserved metazoan family of secreted morphogens that activate several signaling pathways in the responding cell: the canonical (beta-catenin) WNT signaling cascade and several non-canonical pathways, including the planar cell polarity (PCP), the regulation of intracellular calcium signaling and activation of JNK kinases. WNT proteins exist in a gradient outside the secreting cell and are able to act over both short and long ranges to promote proliferation, changes in cell migration and polarity and tissue homeostasis, among others (reviewed in Saito-Diaz et al, 2012; Willert and Nusse, 2012).
The WNTs are ~40kDa proteins with 23 conserved cysteine residues in the N-terminal that may form intramolecular disulphide bonds. They also contain an N-terminal signal sequence and a number of N-linked glycosylation sites (Janda et al, 2012). In addition to being glycosylated, WNTs are also lipid-modified in the endoplasmic reticulum by a WNT-specific O-acyl-transferase, Porcupine (PORCN), contributing to their characteristic hydrophobicity. PORCN-dependent palmitoylation is required for the secretion of WNT as well as its signaling activity, as either depletion of PORCN or mutation of the conserved serine acylation site results in the intracellular accumulation of WNT ligand (Takada et al, 2006; Barrott et al, 2011; Biechele et al, 2011; reviewed in Willert and Nusse, 2012).
Secretion of WNT requires a number of other dedicated factors including the sorting receptor Wntless (WLS) (also knownas Evi, Sprinter, and GPR177), which binds WNT and escorts it to the cell surface (Banziger et al, 2006; Bartscherer et al, 2006; Goodman et al, 2006). A WNT-specific retromer containing SNX3 is subsequently required for the recycling of WLS back to the Golgi (reviewed in Herr et al, 2012; Johannes and Wunder, 2011). Once at the cell surface, WNT makes extensive contacts with components of the extracellular matrix such as heparan sulphate proteoglycans (HSPGs) and may be bound by any of a number of regulatory proteins, including WIFs and SFRPs. The diffusion of the WNT ligand may be aided by its packing either into WNT multimers, exosomes or onto lipoprotein particles to shield the hydrophobic lipid adducts from the aqueous extracellular environment (Gross et al, 2012; Luga et al, 2012, Korkut et al, 2009; reviewed in Willert and Nusse, 2012).
The canonical WNT signaling pathway is initiated when WNT ligands bind to the 7 pass transmembrane receptor Frizzled (FZD) proteins (reviewed in Saito-Diaz et al, 2013). The single pass low-density lipoprotein receptor-related protein (LRP) 5/6 membrane proteins are thought to act as co-receptors with FZD proteins for WNTs, although the details are not fully worked out and a FZD:LRP interaction has not been demonstrated with endogenous proteins in vivo (reviewed in He et al, 2004). LRP5/6 have also been shown to bind directly to a subset of WNT proteins, although the data is conflicting (see for instance Tamai et al, 2000; Semenov et al, 2001; Cong et al, 2004; Wu and Nusse, 2002; Mao et al, 2001). Recent crystal structures have demonstrated direct binding of purified WNT proteins to LRP6 and FZD8 in vitro (Ahn et al, 2011; Janda et al, 2012; Chu et al, 2013), but it is not clear whether the LRP and FZD receptors bind WNTs independently, sequentially or cooperatively in vivo (reviewed in He et al, 2004; Saito-Diaz et al, 2013).
The DIX domains of DVL and AXIN interact and this interaction brings GSK3beta:AXIN1 to the receptor complex (Schwarz-Romond et al, 2007). Subsequently, sequential phosphorylation of LRP5/6 by GSK3beta and CSNK1 generates high affinity AXIN binding sites and functions to amplify recruitment to the membrane (Mao et al, 2001; Zeng et al, 2008). In some models, this recruitment of AXIN to the membrane is facilitated by clustering of DVL and/or LRP5/6 into a 'signalosome' (Bilic et al, 2007).
DVL is recruited to the plasma membrane through a direct interaction between its PDZ domain and a conserved motif of FZD located after the seventh transmembrane region. Recruitment of DVL to the receptor complex is thought to initiate recruitment of AXIN and GSK3beta (Fujii et al, 2007; Wong et al, 2003; Zeng et al, 2008; Tauriello et al, 2012).
In response to WNT signaling, DVL is recruited to the CUL3:KLHL12:RBX1 ubiquitin ligase complex and is subsequently polyubiquitinated and degraded. The BTB domains of the adaptor protein KLHL12 bind constitutively to CUL3 while its Kelch domains mediate a WNT-dependent interaction with the C-terminus of DVL (Angers et al, 2006).
Although it is well established that stabilized beta-catenin is translocated to the nucleus upon WNT pathway activation, the mechanisms that control beta-catenin localization are not fully elucidated. Beta-catenin has neither an NLS nor an NES, and its localization likely arises as the result of a complicated balance between shuttling and retention in both the nucleus and the cytoplasm (reviewed in MacDonald et al, 2009, Saito-Diaz et al, 2013). Nuclear entry of beta-catenin is independent of importins and RanGTPase (Fagotto et al, 1998; Yokoya et al, 1999) and beta-catenin has been suggested to interact directly with the nuclear pore complex by virtue of the structural similarity of its ARM domains to the importin-beta HEAT repeats (Kutay et al, 1997; Malik et al, 1997). Beta-catenin may also 'piggy-back' into the nucleus in complex with other proteins such as FOXM1 (Zhang et al, 2011 ) or BCL9 (Townsley et al, 2004). Once in the nucleus, interaction with TCF, BCL9 and Pygopus may function as an anchor for beta-catenin (Tolwinski and Wieschaus, 2001; Townsley et al, 2004; Krieghoff et al, 2006). Many of the components of the destruction complex, including APC and AXIN are also found in the nucleus and are thought to contribute to beta-catenin localization (Henderson and Fagotto, 2002; Cong and Varmus, 2004). Finally, recent work has revealed a role for Rac1 GTPase and Jun N-terminal kinase 2 (JNK2) in the nuclear localization of beta-catenin upon WNT pathway activation, although the mechanism for this remains to be elucidated (Wu et al, 2008).
LRP5/6 contains 5 PPP(S/T)PxS motifs in its intracellular domain which have been shown to be phosphorylated by a membrane-associated pool of GSK3beta. Individual phosphorylation of each of these motifs promotes interaction with AXIN and stimulates WNT signaling as assessed by activation of a TCF/beta-catenin responsive reporter (Tamai et al, 2004; Zeng et al, 2005; MacDonald et al, 2008). In the context of full length LRP6, phosphorylation of the five motifs shows cooperative stimulation of AXIN binding and WNT signaling. GSK3beta-mediated phosphorylation of LRP6 is thought to prime the receptor for subsequent phosphorylation by CSNK1 (Zeng et al, 2005; reviewed in He et al, 2004).
Stimulation of the WNT pathway results in the recruitment of the GSK3beta:AXIN complex to the membrane (Willert et al, 1999; Schwarz Romond et al, 2007; Bilic et al, 2007; reviewed in Saito-Diaz et al, 2013). Activation of WNT signaling is believed to transiently inhibit GSK3beta kinase activity preventing its phosphorylation of beta-catenin (described in detail in the pathway "Degradation of beta-catenin by the destruction complex"; Piao et al, 2008; reviewed in Saito-Diaz et al, 2013). Inhibition of GSK3beta activity also prevents phosphorylation of AXIN allowing the constitutive dephosphorylation of AXIN at GSK3beta-dependent phosphorylation sites by PP2A predominate. This is believed to weaken the interaction between AXIN and beta-catenin (Willert et al, 1999). AXIN has also been shown to be dephosphorylated by PP1 at several serinve residues initially phosphorylated by CSNK1. The dephosphorylation by PP1 weakens the interaction between AXIN-GSK3beta and inhibits beta-catenin phosphorylation/degradation (Luo et al, 2007; reviewed in Huang et al, 2008). A recent study suggests that sustained inactivation of GSK3beta may result from its sequestration in multivesicular bodies (Taelman et al, 2010; reviewed in Niehrs and Acebon, 2010; Schuldt, 2011). Together, these changes destabilize the destruction complex and allow beta-catenin to accumulate.
After being phosphorylated by GSK3beta on the PPPSP motifs, LRP6 (and by extension LRP5) is phosphorylated at up to 5 sites by a member of the CSNK1 family (Davidson et al, 2005). One screen identified CSNK1gamma as a candidate kinase, while another study showed that CSNK1alpha, delta and epsilon contribute to this phosphorylation step (Davidson et al, 2005; Zeng et al, 2005). This sequential phosphorylation of LRP5/6 by GSK3beta and CSNK1 generates a high affinity binding site for AXIN, thereby amplifying the recruitment of AXIN to the membrane. This is thought to promote the disassembly of the destruction complex, and the activation of WNT signaling (Mao et al, 2001; Tamai et al, 2004; Bilic et al, 2007; reviewed in He et al, 2004).
Once tethered at WNT promoters, beta-catenin is a scaffold for the recruitment of a variety of transcriptional activators. The C-terminal end of beta-catenin interacts with a wide range of general transcriptional activators and chromatin remodelers, while the N-terminal region recruits more WNT-specific activators including BCL9 and Pygopus (reviewed in Jessen et al, 2008). BCL9 proteins (2 in vertebrates, BCL9 and BCL9L) interact with both beta-catenin and the putative activator Pygo (also 2 in vertebrates, Pygo1 and Pygo2) and in this way function as a bridging molecule to promote WNT-dependent transcription (reviewed in Valenta et al, 2012). BCL9 was identified as the gene overexpressed in a B cell acute lymphoblastic leukemia cell line (Willis et al, 1998) and was subsequently found to be homologous to Legless (Lgs), a Drosophila gene identified in a number of screens for components of the WNT signalling pathway (Kramps et al, 2002; Belenkaya et al, 2002; Thompson et al, 2002). Lgs and BCL9 have no recognizable protein motifs and share sequence similarity only in three short stretches of 30 amino acids termed homology domains (HD) 1-3 (Kramps et al, 2002; reviewed in Valenta et al, 2012). HD1 mediates the interaction with the N-terminal ARM domain of beta-catenin while HD2 is required for the recruitment of Pygo through its C-terminal plant homology domain (PHD) (Kramps et al, 2002; Sampietro et al, 2006, Sierra et al, 2006). Replacement of the PHD domain of Pygo with the beta-catenin-interacting HD2 domain of Lgs rescues the phenotype of both lgs and pygo deletion in Drosophila suggesting that the primary role of Lgs is the recruitment of Pygo (Kramps et al, 2002). Transcriptional activation by Pygo depends on the conserved tripeptide NPF in the N-terminal homology domain (NHD) (Kramps et al, 2002; Hoffmans and Basler, 2004; Hoffmans et al, 2005; Städeli and Basler, 2005). In Drosophila, Lgs is essential for Wg signalling, and deletion of either Lgs or Pygo phenocopies armadillo (the Drosophila beta-catenin homologue) null mutants (Kramps et al, 2002; Thompson et al, 2002). In mammals, the requirement and roles for BCL9 and Pygo are both less strict and less completely understood. Unlike in Drosophila, disruption of the BCL9/Pygo branch in mammals has less impact on transcriptional activation than abrogation of beta-catenin-dependent signalling through the C-terminal tail (Valenta et al, 2011). Ablation of pygopus genes in mice does not phenocopy with loss of Wnt signaling (Song et al, 2007; Schwab et al, 2007; Li et al, 2007), and disruption of the BCL9/BCL9L beta-catenin interaction results in embryonic lethality three days later than in the case of complete disruption of beta-catenin-dependent transcription (Valenta et al, 2011). Mammalian BCL9 also has Pygo-independent roles in WNT signaling and has been shown to interact directly with other transcriptional co-activators such as CBP/p300 or TRRAP/GCN5 through its C-terminus (Sustmann et al, 2008). Finally, the PHD of Pygo is able to bind methylated histones, which may contribute to context-specific roles of the protein (Gu et al, 2009; Fielder et al, 2008; Kessler et al, 2009; Gu et al, 2012).
DVL proteins from Drosophila, Xenopus, mouse and human cells have been shown to be phosphorylated, however the role of phosphorylation remains incompletely understood (Willert et al, 1997; Semenov and Synder, 1997; Yanagawa et al, 1995; Rothbächer et al, 2000). CSNK2 was identified as a DVL-associated kinase in Drosophila cells, and was shown to mediate the phosphorylation of serine and threonine residues in vitro (Willert et al, 1997). CSNK2-mediated phosphorylation of DVL may be constitutive, as DVL exists as a phosphoprotein even in the absence of WNT signaling (Bernatik et al, 2011). The association between DVL and CSNK2 may be enhanced upon WNT signaling, leading to increased levels of DVL phosphorylation (Willert et al, 2007).
TCF7 (TCF1), LEF1, TCF7L1 (TCF3) and TCF7L2 (TCF4) are HMG box-containing DNA-binding proteins that recognize WNT-responsive elements (WREs) in the promoters of WNT target genes. The WRE consensus sequence is CCTTTGWW, where W represents either T or A (reviewed in Brantjes et al, 2002). In the absence of a WNT signal, promoter-bound TCF/LEF is bound by one of four Groucho homologues, TLE1, 2, 3 or 4 (Levanon et al, 1998; Brantjes et al, 2001; Daniels and Weis, 2005). Groucho/TLE proteins are co-repressors for a variety of DNA-binding transcription factors and mediate repression at least in part through their interaction with histone deacetylases such as RPD3/HDAC1 (Arce et al, 2009; Brantjes et al, 2001; Chen et al, 1999; reviewed in Chen and Courey, 2000). Groucho proteins have been shown to homo-tetramerize through a glutamine rich Q domain at the N-terminus, and this oligomerization is required for repression. The Q domain is also sufficient for interaction with TCF/LEF proteins (Brantjes et al, 2001; Chen et al, 1998; Pinto and Lobe, 1996; Song et al, 2004). Studies with purified proteins have shown that human TLE1 and 2 bind to an amino-terminal truncated form of LEF1(69-397) with an affinity comparable to that for full length LEF1 (Daniels and Weis, 2005) Evidence suggests that upon activation of the WNT pathway, TLE proteins are displaced from TCF/LEF complexes by competition with nuclear beta-catenin. A primary N-terminal beta-catenin binding site has been defined on TCF/LEF. Beta-catenin binds this region of TCF/LEF through ARM domains 3-8; beta-catenin residues D19 and E27 are essential for this interaction (van de Wetering et al, 1997; Graham et al, 2000). The beta-catenin binding site on TCF/LEF does not overlap with the putative TLE binding site and is not required for TLE binding (Daniels and Weis, 2005; Poy et al, 2001; Graham et al, 2000; von Kries et al, 2000; Omer et al, 1999; Korinek et al, 1998; Behrens et al, 1996; Molenaar et al, 1996, van de Wetering et al, 1997). Limited proteolysis and competition studies with purified proteins suggests that TLEs and beta-catenin share a secondary C-terminal binding site on LEF-1; competition for this binding site is proposed to trigger the switch from repressive to activating complexes at the promoters of WNT target genes, though this may not be universally true at all WNT-responsive promoters (Daniels and Weis, 2005).
SMARCA4, one of two ATPase components of SWI/SNF chromatin remodelling complexes, was identified in a two-hybrid screen for beta-catenin interactors that activate TCF/LEF-dependent transcription (Barker et al, 2001; Wilson and Roberts, 2011). SMARCA4 co-immunoprecipitates with beta-catenin when both tagged proteins are expressed in HEK293 cells; likewise, tagged SMARCA4 co-precipitates endogenous beta-catenin from a colon carcinoma cell line. Expression of SMARCA4 enhances the expression of a TCF reporter in a manner that depends on a functional ATPase domain, indicating a probable role for chromatin remodelling at WNT-responsive promoters (Barker et al, 2001). By ChIP, SMARCA4 and beta-catenin are associated with WNT-responsive promoters upon WNT pathway stimulation; this study also identified TERT, a telomerase reverse transcriptase, as SMARCA4-interacting protein that is present at WNT promoters (Park et al, 2009).
The C-terminal region of beta-catenin (ARM repeat 12 through the C-terminal domain) interacts directly with CDC73/Parafibromin, a component of the PAF1 complex (Mosimann et al, 2006). PAF1 is a conserved protein complex that affects aspects of RNA polymerase II transcription including histone modification, transcription elongation and RNA 3' end formation, among others (reviewed in Tomson and Arndt, 2013). In humans, the PAF1 complex consists of CDC73, PAF1, LEO1, CTR9, RTF1 and WDR61. Endogenous beta-catenin from HEK293 and HeLa cells can be co-immunoprecipitated with either CDC73 or LEO1, suggesting that the whole PAF1 complex may be associated with beta-catenin in vivo (Mosimann et al, 2006). The interaction between beta-catenin and CDC73 may be regulated by SHP2-mediated dephosphorylation of CDC73 (Takahashi et al, 2011). Overexpression of CDC73 stimulates expression of a WNT-responsive reporter in HEK293 cells; this enhancement is abrogated when hPYGO2 is depleted or the interaction between beta-catenin and BCL9 is disrupted. These results, which suggest that BCL9-PYGO may act in parallel to CDC73, are supported by the observation that CDC73 and beta-catenin coprecipitate with BCL9 and PYGO2 in HEK293 cells (Mosimann et al, 2006). CDC73 is frequently mutated in parathyroid carcinomas, and these tumors demonstrate aberrant WNT signaling (Juhlin et al, 2009).
CBP (CREB-binding protein) and the closely related p300 are histone acetyltransferases that are recruited to WNT-responsive promoters through interactions with the C-terminal half of beta-catenin (Hecht et al, 2000; Takemura and Moon, 2000; Sun et al, 2000). Although recruitment is WNT-signaling dependent and results in activation of several WNT target genes, the precise role of CBP and p300 is not yet clear. In Drosophila, recruitment of CBP can affect the acetylation of histones H3 and H4 up to 30kb away from WREs, possibly aided by the DNA bending induced by TCFs (Parker et al, 2008); in other instances, the intrinsic HAT activity has been shown to acetylate beta-catenin (Levy et al, 2004; Wolf et al, 2002), or to be dispensable for the transcriptional activation activity of CBP/p300 at WREs (Hecht et al, 2000).
XIAP has been shown to ubiquitinate all human isoforms of TLE in vitro, likely in the conserved Q domain. Ubiquitination does not appear to affect the stability, localization or tetramerization of TLE; rather ubiquitination affects the interaction with TCF/LEF. Ubiquitinated TLE3 is not able to bind TCF7L2 (TCF4) in vitro and addition of XIAP to TLE3-TCF7L2 complexes promotes the dissociation of TLE from TCF7L2. Although XIAP ubiquitinates TLE in a constitutive manner, XIAP only co-immunoprecipitates with TCF7L2 upon activation of the WNT signalling pathway. These data support a model where XIAP regulates the interaction between TLE and TCF/LEF by limiting the pool of free nuclear TLE that is available for binding, and by potentially disrupting existing repression complexes at WNT-responsive promoters. By disrupting the interaction between TLE and TCF/LEF, XIAP may facilitate the recruitment of beta-catenin and the establishment of an activation complex at WNT-responsive promoters (Hanson et al, 2012)
XIAP (X-linked inhibitor of apoptosis) has three BIR domains with known roles in the degradation of caspases and a C-terminal E3 ligase domain with both anti-apoptotic and non-apoptotic roles (Galban and Duckett, 2010; Burstein et al, 2004). The Drosophila homologue DAIP1 was recently identified in a screen in S2 cells for regulators of Wg signalling (Hanson et al, 2012). Knockdown of XIAP in HEK293 cells reduces WNT3a-induced reporter activity and expression of endogenous WNT target genes without affecting beta-catenin levels or localization. In vitro studies show that XIAP can ubiquitinate all human TLE isoforms, including the truncated isoform Amino-terminal enhancer of split (AES). TLE3 co-immunoprecipitates with XIAP from HEK293 cells in both the presence and absence of WNT signalling, consistent with a constitutive role for XIAP in TLE regulation. XIAP may act either by ubiquitinating free nuclear TLE to reduce the amount available to interact with TCF/LEFs or by ubiquitinating TLE in the context of TCF/LEF transcriptional complexes to promote its dissociation, or both. In support of the latter model, XIAP is pulled down with TCF7L2 (TCF4) in a WNT-dependent manner, and knockdown of XIAP reduces the amount of beta-catenin that co-immunoprecipitates with TCF7L2 (TCF4) upon WNT pathway activation (Hanson et al, 2012).
After ubiquitinating TLE, XIAP presumably dissociates. The model proposed by Hanson et al suggests the existence of an as-yet unidentified deubiquitinase that removes the ubiquitin from TLE to allow it to rebind to TCF/LEF.
Displacement of the APC:CTBP:beta-catenin:betaTrCP complex allows subsequent recruitment of TLE:HDAC1 to TCF/LEF, re-establishing a repression complex (Sierra et al, 2006)
A number of SET1-type complex proteins are pulled down from HeLa and SW480 extracts by a fragment of beta-catenin consisting of ARM repeats 11 and 12 and the adjacent C-terminal activation domain (Sierra et al, 2006). SET1 complexes are histone methyltransferases that promote H3K4 trimethylation in a manner that depends on prior ubiquitination of H2B; H3K4 is a mark associated with active chromatin (reviewed in Shilatifard, 2006). ChIP experiments show that SET1 complex members MLL2, MEN1, RBBP5 and ASH2L cycle on and off the MYC promoter in vivo in a complex with BCL9, PYGO and beta-catenin. Recruitment of the SET proteins correlates with increased H3K4me3 and transcription of the MYC gene, and endogenous mMYC mRNA levels decline somewhat in the presence of MLL2 siRNA. These data suggest that the C-terminal of beta-catenin interacts with a functional histone H3 methyltransferase complex that activates WNT-target gene transcription (Sierra et al, 2006).
The recruitment of SET1-type complexes at the MYC enhancer correlates with increased H3K4 trimethylation in vivo, a mark associated with active chromatin (Sierra et al, 2006). Studies in yeast have shown that H3K4 trimethylation depends on previous H2B ubiquitination by Rad6 and Bre1, which in turn are recruited to DNA by the Paf1 complex (reviewed in Shilatifard, 2006). In this context, the identification of Paf1 components as interactors with the C-terminal activation domain of beta-catenin is intriguing (Sierra et al, 2006)
Studies in mouse myoblast and colorectal cancer cell lines show that APC, beta-TrCP and the CTBP corepressor are present at the MYC enhancer at times when beta-catenin and its associated coactivators are also present. Binding of APC is correlated with dissociation of the activator complex and precedes recruitment of TLE1 and HDAC1, suggesting that APC may promote the exchange between activator and repressor complexes at the enhancer (Sierra et al, 2006). CSNK1gamma phosphorylation of APC strongly increases its affinity for beta-catenin, and a phosphorylated APC fragment disrupts the formation of a DNA:LEF1:beta-catenin complex by EMSA, consistent with previous reports (Xing et al, 2003; Xing et al, 2004; Sierra et al, 2006). Because beta-catenin is unable to simultaneously bind APC and TCF/LEF, however, the mechanism of APC recruitment to the enhancer complex is unclear (Sierra et al, 2006). Full-length APC associates with CTBP in vitro and in vivo (Hamada and Bienz, 2004; Sierra et al, 2006) while Class I and Class II mutant APC proteins, which are commonly found in colorectal cancers, do not (Sierra et al, 2006; reviewed in Neufeld, 2009). CTBP repressor functions may therefore include facilitating the exchange of coactivator and corepressor complexes at WNT target genes.
TIP49, TRRAP, TCF7L2 (TCF4) and KAT5 are present at the ITF-2 promoter in vivo in HEK293 cells as assessed by ChIP. Expression of a dominant negative form of TIP49 in rat epithelial cells is associated with a decrease in both histone H4 acetylation at the ITF-2 promoter and in ITF-2 gene expression. These results suggest that a TIP49-containing HAT complex may play a role in promoting WNT-responsive ITF-2 expression, although more functional studies will be required to elucidate the mechanism (Feng et al, 2003).
Pulldown experiments in colorectal cancer cells show an interaction between the C-terminal region of beta-catenin (ARM domains 11 and 12 through the C terminal) with a number of TRRAP-KAT5 HAT complex members including TRRAP, TIP49, p400 and KAT5 (TIP60), among others (Sierra et al, 2006; Bauer et al, 1998; Bauer et al, 2000; Feng et al, 2003). KAT5 and TIP49 have been shown to directly regulate WNT target genes in vivo and are associated with increased H4 acetylation (Bauer et al, 2000; Feng et al, 2003; Kim et al, 2005).
AXIN is believed to be dephosphorylated upon WNT pathway stimulation, decreasing its affinity for beta-catenin (Willert et al, 1999; Jho et al 1999). AXIN has been shown to be a direct target of GSK3beta in vitro (Ikeda et al, 1998; Jho et al, 1999). In the absence of a WNT signal AXIN is phosphorylated at Thr519 and Ser524 by GSK3beta and at Ser531 by an unknown kinase. Mutation of these sites decreases the binding to beta-catenin and results in increased TCF-dependent signaling (Jho et al, 1999).
The destruction complex phosphatase PP2A has been implicated as both a positive and negative regulator of WNT and is a candidate for the WNT-dependent dephosphorylation of AXIN (Willert et al, 1999; reviewed in Kimelman and Xu, 2006; MacDonald et al, 2009). Stimulation of the WNT pathway leads to changes in AXIN mobility that are reproduced in vitro by dephosphorylation of immunoprecipitated AXIN by PP2A. Consistent with this, treatment of cells with the PP2A inhibitor okadaic acid blocks the dephosphorylation of AXIN upon treatment with WNT3A (Willert et al, 1999). Stimulation of the WNT pathway results in the recovery of less AXIN in a beta-catenin pulldown, and the AXIN that is isolated in this way is exclusively the phosphorylated form (Willert et al, 1999). In addition to dephosphorylating AXIN, PP2A has also been shown to dephosphorylate beta-catenin itself, as well as APC (Su et al, 2008; Ikeda et al, 2000).
Another candidate for the dephosphorylation of AXIN is PP1. PP1 interacts with AXIN and PP1-dependent dephosphorylation of AXIN decreases the AXIN-GSK3beta interaction and inhibits beta-catenin phosphorylation (Luo et al, 2007).
RNF146 is an E3 RING ubiquitin ligase that was identified as a positive regulator of WNT signalling (Callow et al, 2011; Zhang et al, 2011). Depletion of RNF146 increases the levels of AXIN and decreases expression of WNT target genes and WNT-responsive reporters in a WNT-independent manner (Zhang et al, 2011; Callow et al, 2011). RNF146 binds directly to poly-ADP-ribose groups through its WWE domain and ubiquitinates substrates in a tankyrase-dependent manner (Zhang et al, 2011). AXIN, Tankyrase and RNF146 are thought to exist in a complex (Callow et al, 2011) and RNF146 mediates the tankyrase-dependent ubiquitination of all three proteins to promote their degradation (Callow et al, 2011; Zhang et al, 2011). In this reaction, only the targeted degradation of AXIN is depicted.
TNKS1 and 2 function redundantly to control AXIN protein levels through the addition of poly-ADP-ribosyl groups (PARSylation), which may lead to subsequent ubiquitination and degradation by the proteasome. In HEK293, SW480 and breast cancer cell lines, depletion of TNKS1 and 2 increases the protein levels of AXIN1 and AXIN2 resulting in increased beta-catenin phosphorylation, decreased beta-catenin abundance and decreased expression of WNT targets and WNT-responsive reporters (Huang et al, 2009; Callow et al, 2011; Waaler et al, 2012; Bao et al, 2012). In vitro, TNKS2 catalyzes the addition of ADP-ribosyl groups to the TBD fragment of AXIN1, while in vivo, both exogenous GST-AXIN1 and endogenous AXIN1 are PARSylated in a TNKS-dependent manner (Huang et al, 2009; Callow et al, 2011; Zhang et al, 2011). PARSylation is likely required for the subsequent proteasome-mediated degradation of AXIN, as the increase in levels of polyubiquitinated AXIN1 and 2 seen upon treatment of cells with the proteasome inhibitor MG132 is lost if cells are simultaneously treated with an inhibitor of TNKS1 and 2 (Huang et al, 2009). Although in this reaction, TNKS is shown PARSylating unbound AXIN, it is likely that this regulation occurs at the level of the destruction complex. Also not shown in this reaction is the ability of TNKS to catalyze autoPARSylation reactions, which ultimately lead to its own degradation (Yeh et al, 2006; Huang et al, 2009; Zhang et al, 2011).
Several recent chemical screens have identified inhibitors of the poly-ADP ribosylation enzymes tankyrase (TNKS) 1 and 2 as regulators of WNT signalling (Huang et al, 2009; Chen et al, 2009; Waaler et al, 2012). Endogenous TNKS1 and 2 associate with AXIN2 in SW480 cells as assessed by co-immunoprecipitation. Both AXIN1 and AXIN2 interact strongly with TNKS1/2 by two-hybrid, and deletion analysis shows that amino acids 19-30 of AXIN1 are necessary and sufficient for binding to TNKS1. This region, termed the tankyrase-binding-domain (TBD) is necessary and sufficient for the interaction in GST-pulldown and co-immunoprecipitation studies (Huang et al, 2009).
UBP34 (also known as USP34) is a ubiquitin protease that co-precipitates in AXIN-containing complexes. In vitro studies show that the core domain of UBP34 is able to deubiquitinate AXIN purified from HEK293 transfected cells, and knockdown of UBP34 reduces AXIN1 protein levels in vivo. Treatment of UBP34-knockdown cells with the tankyrase inhibitor XAV939 reverses the degradation of AXIN, suggesting that the activity of UBP34 counteracts the tankyrase-dependent ubiquitination and degradation of AXIN. UBP34 plays a not-fully characterized role in the nuclear accumulation of AXIN, where AXIN is thought to positively regulate beta-catenin mediated transcription (Lui et al, 2011).
In the presence of the proteasome inhibitor MG132, polyubiquitinated forms of AXIN accumulate (Huang et al, 2009; Zhang et al, 2011; Callow et al, 2011). This effect is abrogated by co-treatment of cells with both MG132 and inhibitors of tankyrase activity, suggesting that both PARSylation and ubiquitination are required for AXIN degradation (Huang et al, 2009).
WNT Inhibitory factor 1 (WIF1) is a secreted antagonist of WNT signaling that acts by binding to WNTs in the extracellular space and inhibiting their interaction with the FZD receptor complex (Hsieh et al, 1999; Surmann-Schmitt et al, 2009; Malinauskas et al, 2011; Banyai et al, 2012). WIF1 consists of a WIF domain (WD; also present in RYK receptors) and 5 EGF domains (Patthy 2000; Hsieh et al, 1999). Functional studies show that the WD contributes most of the WNT-binding activity while the EGF repeats make contact with components of the extracellular matrix such as HSPGs and glypicans (Hsieh et al, 1999; Malinauskas et al, 2011; Sanchez-Hernandez et al, 2012). WIF1 is downregulated in some cancers, and overexpression of human WIF1 has been shown to inhibit growth of lung and bladder cancer cells (Mazieres et al, 2004; Kansara et al, 2009; Lin et al, 2006; Tang et al, 2009)
Chibby (CBY1) is a conserved 126 amino acid protein that acts as an antagonist to the canonical WNT signaling pathway. CBY1 binds to the C-terminal region of beta-catenin and inhibits beta-catenin-dependent signaling by competing for the TCF/LEF binding sites and by promoting beta-catenin nuclear export (Takemaru et al, 2003; Li et al, 2008; Li et al, 2010). Endogenous CBY1 and beta-catenin co-immunoprecipitate from HEK293 cells and overexpression of CBY1 reduces expression of a beta-catenin dependent reporter gene, supporting a functional role for the CBY1-beta-catenin interaction in vivo (Takemaru et al, 2003). Studies with CBY1 knockout mice show only a slight effect on expression of WNT-dependent target genes, however; more work will be required to fully elucidate the role of CBY1 in regulating endogenous WNT signaling (Veronina et al, 2009).
CBY1 contains both NLS and NES sequences and continuously shuttles between the cytoplasm and the nucleus. Treatment of cells with leptomycin B (LMB), an inhibitor of XPO1-mediated nuclear export, results in nuclear accumulation of both CBY1 and 14-3-3/YWHAZ proteins (Li et al, 2008; Li et al, 2010). Consistent with this, CBY1 binds to XPO1 in an NES-dependent manner. 14-3-3/YWHAZ enhances the CBY1-XPO1 interaction, possibly by inducing a conformational change that exposes the adjacent NES sequence. Binding of 14-3-3/YWHAZ also inhibits the interaction of CBY1 with alpha-importin, additionally favouring its cytoplasmic localization. CBY1 NES mutants that are incapable of nuclear export show reduced ability to repress a beta-catenin-dependent reporter, and knockdown of endogenous CBY1 causes an accumulation of beta-catenin in the nucleus. These data support a role for CBY1 in the nuclear export of beta-catenin (Li et al, 2010). Despite growing evidence for a role for CBY1 in regulating WNT signaling, a formal requirement for CBY1 in vivo is still lacking.
14-3-3/YWHAZ and XPO1 both contribute to the CBY1-mediated nuclear export of beta-catenin (Li et al, 2008; Li et al, 2010). The fate of the tripartite beta-catenin:CBY1:14-3-3/YWHAZ complex in the cytoplasm is unknown, although it may represent a reservoir of beta-catenin available for further signaling. CBY1 may remain associated with 14-3-3/YWHAZ in the cytoplasm, as 14-3-3/YWHAZ binding inhibits binding of alpha-importin to CBY1 (Li et al, 2010) . This suggests the presence of a phosphatase that dephosphorylates S20 on CBY1 to allow binding with alpha-importin and reimport into the nucleus.
14-3-3 proteins, represented here as YWHAZ, bind directly to CBY1 after AKT-dependent phosphorylation of CBY1 serine 20. Tagged versions of beta-catenin, CBY1 and 14-3-3/YWHAZ expressed in HEK293 cells co-immunoprecipitate in a CBY1-phosphorylation dependent manner. 14-3-3/YWHAZ binding promotes sequestration of CBY1 and beta-catenin in the cytoplasm, thus antagonizing beta-catenin-dependent transcription (Li et al, 2008).
CBY1 is phosphorylated in vitro at serine 20 by AKT1 and AKT2. In vivo, this phosphorylation is required for the export of beta-catenin from the nucleus, facilitated by the binding of 14-3-3/YWHAZ proteins to the pS20 residue of CBY1 (Li et al, 2008).
SOST is a secreted antagonist of WNT signaling that acts by binding to LRP5/6 (Li et al, 2005; Semenov et al, 2005; Veverka et al, 2005). Binding of SOST requires the first two YWTD EGF repeats of LRP5/6 and appears to inhibit WNT signaling by preventing the formation of the LRP5/6:FZD receptor complex (Li et al, 2005; Semenov et al, 2005).
DKK1, 2 and 4 are secreted antagonists of WNT signaling that act by binding to LRP5/6 and preventing the formation of an LRP:FZD receptor complex (Semenov et al, 2001; Mao et al, 2001; Bafico et al, 2001; reviewed in Niehrs, 2006). LRP6 has multiple independent WNT binding sites on its surface that are bound by different subsets of WNT proteins (Bourhis et al, 2010; Bourhis et al, 2011). Structural studies show that full length DKK1 binds to an LRP6 site that overlaps with both of these regions, suggesting that WNT and DKK proteins compete for receptor binding (Chen et al, 2011; Ahn et al, 2011; Cheng et al, 2011). Binding of DKK1 is postulated to stabilize LRP6 in an autoinhibited conformation that is relieved upon WNT-binding (Liu et al, 2003; Ahn et al, 2011). In some instances, DKK-mediated inhibition of WNT signaling may be enhanced by the concurrent binding of the single pass transmembrane proteins Kremen1 and 2, although their presence is not absolutely required (Mao et al, 2002; Mao and Niehrs, 2003; Wang et al, 2008). In some cases, DKK2 may also function as a WNT agonist (Brott and Sokol, 2002; Wu et al, 2000; Mao and Nierhs, 2003; Li et al, 2007).
CTNNBIP1 (also known as ICAT) is an 81 amino-acid protein that was identified in a two-hybrid screen to identify beta-catenin interacting partners (Tago et al, 2000). CTNNBIP1 binds directly to beta-catenin in vitro and in vivo and interferes with the formation of a TCF/LEF:beta-catenin complex (Tago et al, 2000; Daniels and Weiss et al, 2002; Graham et al, 2002). Expression of CTNNBIP1 abrogates expression of a WNT-dependent reporter gene (Tago et al, 2000).
DVL1 and 3 have been shown to co-immunoprecipitate with PIP5KB in HEK293 cells. This interaction is mediated by the N-terminal half of the kinase and the PDZ and DIX domain of DVL and recruits PIPK5B to the receptor complex. The interaction of DVL and PIP5KB is required for the WNT3A-dependent phosphorylation of LRP6 at serine 1490 and threonine 1479, as well as and the subsequent formation of the signalosome and recruitment of AXIN (Pan et al, 2008).
CSNK1E and DVL physically interact in vivo and CSNK1E phosphorylates DVL in response to WNT signaling (Peters et al, 1999; Sakanaka et al, 1999; Kishida et al, 2001; Gao et al, 2002; Hino et al, 2003; Klimowski et al, 2006; Bernatik et al, 2011). Phosphorylation by CSNK1E in the PDZ domain of DVL appears to be required for the recruitment of AXIN and the subsequent phosphorylation of LRP6 (Bernatik et al, 2011).
Stimulation of the WNT pathway controls the activity of PIP5KB in a FZD- and DVL-dependent manner (Pan et al, 2008; Bilic et al, 2007; Cong et al, 2004; Qin et al, 2009). Activation of PIP5KB results in the formation of PI(4,5)P2 at the plasma membrane, which is required through an unclear mechanism for the phosphorylation of LRP6 at serine 1490, LRP6 aggregation into 'signalosomes' and LRP6 phosphorylation at threonine 1479. These events are required for the recruitment of AXIN to the plasma membrane (Pan et al, 2008; Qin et al, 2009).
Mammalian genomes encode 5 secreted Frizzled related proteins (sFRPs) that are proposed to antagonize WNT signaling by binding directly to WNT ligands. Binding is mediated by a cysteine-rich-domain in the N-terminal that is homologous to the one found in FZD receptors and which is also found in the alternative WNT receptors ROR1 and ROR2 (reviewed in Kawano and Kupta, 2003; Boloventa et al, 2008). Direct binding of sFRP1, 2, 3 and 4 to Wnt3a has been demonstrated by surface plasmon resonance, but only sFRP1 and 2 were shown to inhibit Wtn3a-dependent signaling in mouse ES cells (Wawrzak et al, 2007). In addition to binding to WNT ligands, sFRPs are proposed to antagonize WNT signaling in a number of other ways. sFRPs have been shown to bind directly to FZD proteins by virtue of the CRDs: this interaction is postulated to block WNT signaling by inhibiting the WNT:FZD interaction (Bafico et al, 1999; Rodgriguez et al, 2005).
All four vertebrate TCF/LEF proteins have been demonstrated to bind to the AXIN2 gene in vivo and to mediate beta-catenin dependent transcription (Leung et al, 2002; Jho et al, 2002; Lustig et al, 2002, Wohrle et al, 2007; Park et al, 2009)
TCF7L1 (also known as TCF3), TCF7L3 (also known as LEF1) and TCF7L2 (also known as TCF4) have been demonstrated to bind to the MYC gene in vivo and in vitro and to mediate beta-catenin dependent transcription (Park et al, 2009; He et al, 1998; Sierra et al, 2006). Aberrant beta-catenin dependent activation of the MYC gene contributes to oncogenic signaling and cellular proliferation in colorectal and other cancers (see for instance Sansom et al, 2007; Moumen et al, 2013; reviewed in Wilkins and Sansom, 2008; Cairo et al, 2012). Binding of RUNX3 to the CTNNB1:TCF7L2 and possibly to the CTNNB1:LEF1 and TCF7L1 complexes, prevents binding of CTNNB1 complexes to the MYC promoter, thus negatively regulating MYC transcription (Ito et al. 2008).
TCF7L1 (also known as TCF3), TCF7L3 (also known as LEF1) and TCF7L2 (also known as TCF4) have been demonstrated to bind to the MYC gene in vivo and in vitro and to mediate beta-catenin dependent transcription (Park et al, 2009; He et al, 1998; Sierra et al, 2006). Aberrant beta-catenin dependent activation of the MYC gene contributes to oncogenic signaling and cellular proliferation in colorectal and other cancers (see for instance Sansom et al, 2007; Moumen et al, 2013; reviewed in Wilkins and Sansom, 2008; Cairo et al, 2012). Binding of RUNX3 to the CTNNB1:TCF7L2 and possibly to the CTNNB1:LEF1 and TCF7L1 complexes, prevents binding of CTNNB1 complexes to the MYC promoter, thus negatively regulating MYC transcription (Ito et al. 2008).
Each of the four TCF/LEF transcription factors have been shown to bind to the AXIN2 promoter in conjunction with beta-catenin to activate transcription (Park et al, 2009; Lustig et al, 2002; Jho et al, 2002, Leung et al 2002; Wohrle et al, 2007).
SMURF2 has been shown to ubiquitinate AXIN at lysine 505 both in vitro and in vivo in a manner that depends on the interaction between the two proteins (Kim and Jho, 2012).
SMURF2 is an E3 ubiquitin ligase for AXIN and promotes its ubiquitin-mediated degradation. Ectopic SMURF2 immunoprecipitates both exogenously expressed and endogenous AXIN. AXIN is polyubiquitinated by SMURF2 at lysine 505 both in vitro and in vivo (Kim and Jho, 2012).
DACT1, also known as DAPPER1, was identified in Xenopus as a negative regulator of WNT canonical and non-canonical signaling. In Xenopus, DACT1 has been shown to form a complex with GSK3beta, AXIN, CSNK1 and beta-catenin when co-expressed in HEK293 cells with DVL, and expression of DACT1 negatively regulates expression of beta-catenin target genes (Cheyette et al, 2002). In human cells, DACT1 co-precipitates with DVL2, an interaction mediated by the DIX domain of DVL2 and the C-terminal region of DACT1. siRNA depletion of DACT1 results in higher expression of beta-catenin dependent reporters and increased protein levels of DVL2, suggesting that DACT1 restricts beta-catenin-dependent signaling by promoting the degradation of DVL2. Consistent with this, lysosome inhibitors block DACT1-induced degradation of DVL2 (Zhang et al, 2006).
HECW1, also known as NEDL1, is an HECT E3 ligase that co-immunoprecipitates with DVL1 upon cotransfection in Neuro2 cells and targets it for proteasomal degradation (Miyazaki et al, 2004).
RSPO1-4 increase the levels of FZD and LRP6 receptors and decrease the amount of ZNRF3 at the plasma membrane. RSPO-induced internalization of ZNRF3 depends on LGR and the ubiquitin ligase activity of ZNRF3, and RSPO has been shown to bind directly to the extracellular region of ZNRF3 in an LGR-independent manner. These data are consistent with a model where RSPO promotes an interaction between ZNRF3 and LGR proteins that is required for downregulation of the ubiquitin ligase. In support of this model, artificial dimerization of ZNRF3 and LGR bypasses the requirement for RSPO in ZNRF3 internalization (Hao et al, 2012).
There are four human RSpondin genes in humans whose products are secreted agonists of canonical and non-canonical WNT signaling (Kim et al, 2005; Glinka et al, 2007; reviewed in Kim et al, 2006). RSPO proteins enhance signaling in the presence of WNT ligand and have been shown to bind to the leucine-rich repeat containing G protein coupled receptors (LGR) 4, 5 and 6 (Kim et al, 2005; Binnerts et al, 2007; Carmon et al, 2011; de Lau et al, 2011). RSPO:LGR complexes are postulated to potentiate WNT-dependent signaling in a number of potentially overlapping mechanisms. RSPO proteins enhance WNT-mediated phosphorylation of LRP6 in HEK293 cells (Wei et al, 2007; Binnerts et al, 2007; Carmon et al, 2011). A recent report suggests that this effect may be mediated in part by downregulating the levels of ZNFR3 at the plasma membrane. ZNFR3 is an E3 ubiquitin ligase that has been shown to ubiquitinate FZD and to promote internalization of FZD and LRP6. In the presence of RSPO:LGR, ZNFR3 itself is targeted for internalization, allowing enhanced signaling through the WNT receptor complex (Yao et al, 2012).
USP8 is a deubiquitinase that enhances WNT signaling by deubiquitinating the FZD receptor and promoting its recycling to the cell surface (Mukai et al, 2010).
Mutation of the RING domain of ZNRF3 abrogates membrane clearance of the ubiquitin ligase, suggesting that its internalization depends on auto-ubiquitination (Hao et al, 2012).
ZNFR3 and RNF43 are plasma membrane E3 RING domain ubiquitin ligases that have been shown to ubiquitinate FZD proteins to promote their downregulation (Hao et al, 2012). Inhibition of ZNRF3 or RNF43 increases the protein level of FZD and LRP6 at the plasma membrane, and stably expressed ZNRF3 can be co-immunoprecipitated with endogenous LRP6 and FZD6 (Hao et al, 2012; Jiang et al 2013). Turnover of the LRP6 and FZD receptors appears to be regulated by multiubiquitination and is abrogated upon treatment with lysosomal inhibitors (Mukai et al, 2010).
ZNRF3 has been shown to ubiquitinate FZD4 in vivo, and inhibition of ZNRF3/RNF43 increases the protein levels of LRP6 and FZD8 at the cell surface (Hao et al, 2012; Jiang et al, 2013). Degradation of FZD and LRP is abrogated upon treatment of cells with bafilomycin A1 but not with MG132, suggesting that degradation of the receptors occurs in the lysosome. Consistent with this, mutational analysis suggests that FZD4 is multi-monoubiquitinated (Mukai et al, 2010).
XAV939 binds to the catalytic sites of tankyrase 1 and 2 and inhibits the ADP-ribosylation of AXIN1 and 2. Treatment of cells with XAV939 significantly increases the protein, but not the mRNA levels of AXIN1 and 2 and supports a strong increase in the level of GSK3beta-AXIN complexes. These cells also show increased phosphorylation of beta-catenin, decreased beta-catenin protein levels and a corresponding decrease in beta-catenin dependent transcription. Treatment of DLD-1 cells with XAV939 has also been shown to inhibit proliferation (Huang et al, 2009). XAV939 has not been tested in a clinical setting.
The FRAT genes, which were initially identified as a target of Frequent Rearrangement in Advanced T-cell lymphoma, encode potent activators of canonical WNT signaling and are highly conserved in vertebrates. Xenopus and zebrafish each have one FRAT gene, while the human and mouse genomes contains two and three, respectively (Jonkers et al, 1997; reviewed in van Amerongen and Berns, 2005). Frat proteins activate WNT signaling by binding to GSK3beta and inhibiting its phosphorylation of beta-catenin (Yost et al, 1998; van Amerongen et al, 2004). The interaction with GSK3beta is mediated by a highly conserved IKEA box in the C-terminal domain of FRAT (Yost et al, 1998; van Amerongen et al, 2004; Thomas et al, 1999). This region of FRAT is able to compete with AXIN for binding to GSK3beta, suggesting a model where FRAT is able to destabilize the destruction complex by abrogating the GSK3beta-AXIN interaction (Farr et al, 2000; Thomas et al, 1999; Fraser at el, 2002; Ferkey et al, 2002). This model is supported by structural studies showing that AXIN and FRAT bind to the same region on the surface of GSK3beta (Bax et al, 2001; Dajani et al, 2003). Endogenous FRAT1 has also been shown to interact with DVL3, and this reaction persists in a FRAT1 mutant lacking the GSK3beta-interacting domain (Li et al, 1999). FRAT proteins may thus help bridge between GSK3beta’s role in the destruction complex and its role in activating signaling in response to WNT.
Despite the apparent importance of FRAT proteins in beta-catenin-dependent signaling, a triple FRAT knockout mouse shows no readily evident defects in canonical signaling and, unlike the GBP knockout in Xenopus, no overt phenotypic defects (van Amerongen et al, 2005; Yost et al, 1989). The in vivo role and significance of the FRAT proteins in WNT signaling remains to be resolved; it is worth noting, however, that FRAT proteins have also recently been shown to be involved in non-canonical WNT signaling in a GSK3beta-independent manner. It is possible that it is through this non-canonical role that FRAT proteins contribute to oncogenesis (van Amerongen et al, 2010; Walf-Vorderwülbecke et al, 2012).
RYK is an atypical receptor tyrosine kinase-like receptor that is required for craniofacial and skeletal development, axon guidance and neuronal differentiation. RYK has an extracellular WNT-binding WIF domain, a putative tetrabasic cleavage site, an intracellular PDZ domain and a cytosolic RTK-like catalytic site that is rendered inactive by a number of substitutions at conserved positions (reviewed in Fradkin et al, 2010; Keeble et al, 2006a). The WIF domain of RYK has been shown to interact with WNT1, 3, 3A and 5A and signaling through RYK is believed to contribute to both canonical and non-canonical WNT pathways (Lu et al, 2004; Keeble et al, 2006b; Liu et al, 2005; Macheda et al, 2012; Schmitt et al, 2006; reviewed in Keeble et al, 2006a).
Expression of a beta-catenin-dependent reporter gene has been demonstrated after RYK-binding by WNT1 and WNT3A, however the details of downstream signaling remain to be clarified (Lu et al, 2004; Berndt et al, 2011). Signaling through RYK may occur in the context of a RYK-FZD co-receptor and appears to involve the recruitment of DVL (Lu et al, 2004). The E3 ligase Mindbomb (MIB1) was also identified as a RYK-interacting protein that contributes to canonical WNT signaling, possibly by regulating the levels of RYK at the cell surface (Berndt et al, 2011). Finally, RYK has been shown to be cleaved by gamma-secretase in response to WNT3, liberating a intracellular domain (ICD) that translocates to the nucleus and that is required for neuronal differentitation (Lyu et al, 2008). The significance of these findings is not yet fully clear.
CHD8 is a ATP-dependent chromatin remodeling factor that binds directly to beta-catenin to repress transcription of WNT target genes (Thompson et al, 2008; Sakamoto et al, 2000). ChIP studies show that CHD8 is recruited to the promoters of several beta-catenin-responsive targets, and knockdown of CHD8 results in induction of these target genes in vivo (Thompson et al, 2008). An N-terminal fragment of CHD was independently identified as the rat protein Duplin. Duplin was shown to negatively regulate WNT target gene expression by competing with TCF7L2 for beta-catenin binding (Sakamoto et al, 2000; Kobayashi et al, 2002). A corresponding fragment of CHD8 has not been identified in human cells and its significance is not clear.
CXXC4 binds to DVL to negatively regulate WNT-dependent gene expression. CXXC4 competes with AXIN for DVL binding, and expression of CXXC4 abrogates the expression of a WNT-dependent reporter gene in L cells (Hino et al, 2001). In Xenopus, the CXXC4 homologue is expressed in neural tissue during and after the neurula stage and is required for anterior neural development (Michiue et al, 2004).
Binding of DKK1 to LRP6 induces the clathrin-mediated endocytosis of LRP6, preventing the WNT3-dependent phosphorylation of LRP and thereby attenuating WNT signaling (Sakane et al, 2010; Yamamoto et al, 2008). The DKK:LRP:KRM complex traffics to the early endosome in a RAB5-dependent manner. The LRP receptor can subsequently recycle back to the plasma membrane in a RAB11-dependent manner, while DKK may be degraded in the lysosome (Sakane et al, 2010)
CCDC88C was identified as Dapple in a screen of mouse brain cDNAs for DVL1-interacting proteins (Oshita et al, 2003). CCDC88C binds to the PDZ domain of DVL through the three amino acids Gly-Cys-Val at the C-terminus, and this interaction negatively regulates canonical WNT signaling (Oshita et al, 2003; Ekici et al, 2010). Interaction between DVL and CCDC88C also regulates signaling in the non-canonical WNT pathway, where the interaction is required for aPKC-mediated RAC activation, lamellipodia formation and cell migration (Ishida-Takagisha et al, 2012).
After stimulation by WNT3A, FZD5 and phosphorylated LRP6 are internalized from lipid rafts in a caveolin- and RAB5-dependent manner (Yamamoto et al, 2006; Yamamoto et al, 2008). Recruitment of CAV1 to the activated receptor complex inhibits the binding of beta-catenin to AXIN in the destruction complex, resulting in the accumulation of cytosolic beta-catenin and the induction of WNT-dependent signaling (Yamamoto et al, 2006; Yamamoto et al, 2008).
SOX protein family members are the transcription factors that regulate many different development processes and also control homeostasis in adult tissues. SOX proteins can be either transcriptional activators or repressors depending on the cellular context and their associated interacting proteins (Kormish et al. 2010). There are over twenty SOX proteins encoded in mammalian genome of which many of these can physically interact with beta-catenin and TCF (T-cell factor) transcription factors and modulate the Wnt signaling. Evidences suggest that SOX proteins have widespread role in modulating Wnt signaling in development and disease. In most cases SOX proteins repress WNT transcriptional responses, however some SOX proteins appear to enhance WNT-regulated gene expression. The precise mechanism by which SOX proteins regulate beta-catenin/TCF activity are still unclear. Differential recruitment of transcriptional co-activators or co-repressors is one mechanism by which SOX factors can either enhance or repress Wnt-target gene transcription. Another mechanism by which some SOX proteins repress Wnt signaling is by promoting proteosome-mediated beta-catenin degradation (Kormish et al. 2010). Human SRY binds beta-catenin through a N-terminal domain (Bernard et al. 2008), SOX6 interacts via a centrally located leucine zipper (LZ/Q) element (Iguchi et al. 2007), and mammalian SOX7, SOX9 and SOX17 all bind beta-catenin via their C-terminal regions (Zorn et al., 1999; Takash et al., 2001; Akiyama et al., 2004; Sinner et al., 2007, Kormish et al. 2010). SRY and SOX9 function in part by suppressing canonical Wnt signaling by promoting beta-catenin phosphorylation in the nucleus (Topol et al. 2009). SOX9 and SRY are involved in the regulation of mammalian sex determination and mutation in human SRY and SOX9 results in sex reversal, with female development in XY individuals (Bernard et al. 2008). SOX2 binds beta-catenin and promotes cell proliferation by transcriptionally activating the Wnt target Cyclin D1 gene in breast cancer cells (Chen et al., 2008), whereas SOX6 represses Cyclin D1 transcription in pancreatic cells (Iguchi et al., 2007). SOX7 and SOX17 reduce cyclin-D1 expression and repress proliferation by stimulating beta-catenin degradation (Sinner et al. 2007, Zhang et al. 2008, 2009).
In vitro protein binding experiments have shown that mammalian SOX4, SOX13 and SOX17 can directly interact with TCF (T-cell factor) (Sinner at al. 2007). SOX4 and SOX17 can interact with either TCF or beta-catenin protein. They have opposite effects on Wnt signalling, SOX4 enhances while SOX17 represses Wnt activity (Sinner et al. 2007). SOX13 is known to repress Wnt signaling by interacting and sequestering TCF1 from the Wnt transcriptionally active complex (Melichar et al. 2007). SOX and TCF proteins interact with overlapping armadillo repeats with in beta-catenin and thus might compete for beta-catenin binding (Kormish et al. 2010).
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beta-catenin by the
destruction complexbiogenesis and
traffickingThe WNTs are ~40kDa proteins with 23 conserved cysteine residues in the N-terminal that may form intramolecular disulphide bonds. They also contain an N-terminal signal sequence and a number of N-linked glycosylation sites (Janda et al, 2012). In addition to being glycosylated, WNTs are also lipid-modified in the endoplasmic reticulum by a WNT-specific O-acyl-transferase, Porcupine (PORCN), contributing to their characteristic hydrophobicity. PORCN-dependent palmitoylation is required for the secretion of WNT as well as its signaling activity, as either depletion of PORCN or mutation of the conserved serine acylation site results in the intracellular accumulation of WNT ligand (Takada et al, 2006; Barrott et al, 2011; Biechele et al, 2011; reviewed in Willert and Nusse, 2012).
Secretion of WNT requires a number of other dedicated factors including the sorting receptor Wntless (WLS) (also knownas Evi, Sprinter, and GPR177), which binds WNT and escorts it to the cell surface (Banziger et al, 2006; Bartscherer et al, 2006; Goodman et al, 2006). A WNT-specific retromer containing SNX3 is subsequently required for the recycling of WLS back to the Golgi (reviewed in Herr et al, 2012; Johannes and Wunder, 2011). Once at the cell surface, WNT makes extensive contacts with components of the extracellular matrix such as heparan sulphate proteoglycans (HSPGs) and may be bound by any of a number of regulatory proteins, including WIFs and SFRPs. The diffusion of the WNT ligand may be aided by its packing either into WNT multimers, exosomes or onto lipoprotein particles to shield the hydrophobic lipid adducts from the aqueous extracellular environment (Gross et al, 2012; Luga et al, 2012, Korkut et al, 2009; reviewed in Willert and Nusse, 2012).
Annotated Interactions
BCL9 was identified as the gene overexpressed in a B cell acute lymphoblastic leukemia cell line (Willis et al, 1998) and was subsequently found to be homologous to Legless (Lgs), a Drosophila gene identified in a number of screens for components of the WNT signalling pathway (Kramps et al, 2002; Belenkaya et al, 2002; Thompson et al, 2002). Lgs and BCL9 have no recognizable protein motifs and share sequence similarity only in three short stretches of 30 amino acids termed homology domains (HD) 1-3 (Kramps et al, 2002; reviewed in Valenta et al, 2012). HD1 mediates the interaction with the N-terminal ARM domain of beta-catenin while HD2 is required for the recruitment of Pygo through its C-terminal plant homology domain (PHD) (Kramps et al, 2002; Sampietro et al, 2006, Sierra et al, 2006). Replacement of the PHD domain of Pygo with the beta-catenin-interacting HD2 domain of Lgs rescues the phenotype of both lgs and pygo deletion in Drosophila suggesting that the primary role of Lgs is the recruitment of Pygo (Kramps et al, 2002). Transcriptional activation by Pygo depends on the conserved tripeptide NPF in the N-terminal homology domain (NHD) (Kramps et al, 2002; Hoffmans and Basler, 2004; Hoffmans et al, 2005; Städeli and Basler, 2005).
In Drosophila, Lgs is essential for Wg signalling, and deletion of either Lgs or Pygo phenocopies armadillo (the Drosophila beta-catenin homologue) null mutants (Kramps et al, 2002; Thompson et al, 2002). In mammals, the requirement and roles for BCL9 and Pygo are both less strict and less completely understood. Unlike in Drosophila, disruption of the BCL9/Pygo branch in mammals has less impact on transcriptional activation than abrogation of beta-catenin-dependent signalling through the C-terminal tail (Valenta et al, 2011). Ablation of pygopus genes in mice does not phenocopy with loss of Wnt signaling (Song et al, 2007; Schwab et al, 2007; Li et al, 2007), and disruption of the BCL9/BCL9L beta-catenin interaction results in embryonic lethality three days later than in the case of complete disruption of beta-catenin-dependent transcription (Valenta et al, 2011). Mammalian BCL9 also has Pygo-independent roles in WNT signaling and has been shown to interact directly with other transcriptional co-activators such as CBP/p300 or TRRAP/GCN5 through its C-terminus (Sustmann et al, 2008). Finally, the PHD of Pygo is able to bind methylated histones, which may contribute to context-specific roles of the protein (Gu et al, 2009; Fielder et al, 2008; Kessler et al, 2009; Gu et al, 2012).
Evidence suggests that upon activation of the WNT pathway, TLE proteins are displaced from TCF/LEF complexes by competition with nuclear beta-catenin. A primary N-terminal beta-catenin binding site has been defined on TCF/LEF. Beta-catenin binds this region of TCF/LEF through ARM domains 3-8; beta-catenin residues D19 and E27 are essential for this interaction (van de Wetering et al, 1997; Graham et al, 2000). The beta-catenin binding site on TCF/LEF does not overlap with the putative TLE binding site and is not required for TLE binding (Daniels and Weis, 2005; Poy et al, 2001; Graham et al, 2000; von Kries et al, 2000; Omer et al, 1999; Korinek et al, 1998; Behrens et al, 1996; Molenaar et al, 1996, van de Wetering et al, 1997). Limited proteolysis and competition studies with purified proteins suggests that TLEs and beta-catenin share a secondary C-terminal binding site on LEF-1; competition for this binding site is proposed to trigger the switch from repressive to activating complexes at the promoters of WNT target genes, though this may not be universally true at all WNT-responsive promoters (Daniels and Weis, 2005).
The destruction complex phosphatase PP2A has been implicated as both a positive and negative regulator of WNT and is a candidate for the WNT-dependent dephosphorylation of AXIN (Willert et al, 1999; reviewed in Kimelman and Xu, 2006; MacDonald et al, 2009). Stimulation of the WNT pathway leads to changes in AXIN mobility that are reproduced in vitro by dephosphorylation of immunoprecipitated AXIN by PP2A. Consistent with this, treatment of cells with the PP2A inhibitor okadaic acid blocks the dephosphorylation of AXIN upon treatment with WNT3A (Willert et al, 1999). Stimulation of the WNT pathway results in the recovery of less AXIN in a beta-catenin pulldown, and the AXIN that is isolated in this way is exclusively the phosphorylated form (Willert et al, 1999). In addition to dephosphorylating AXIN, PP2A has also been shown to dephosphorylate beta-catenin itself, as well as APC (Su et al, 2008; Ikeda et al, 2000).
Another candidate for the dephosphorylation of AXIN is PP1. PP1 interacts with AXIN and PP1-dependent dephosphorylation of AXIN decreases the AXIN-GSK3beta interaction and inhibits beta-catenin phosphorylation (Luo et al, 2007).
Binding of RUNX3 to the CTNNB1:TCF7L2 and possibly to the CTNNB1:LEF1 and TCF7L1 complexes, prevents binding of CTNNB1 complexes to the MYC promoter, thus negatively regulating MYC transcription (Ito et al. 2008).
Binding of RUNX3 to the CTNNB1:TCF7L2 and possibly to the CTNNB1:LEF1 and TCF7L1 complexes, prevents binding of CTNNB1 complexes to the MYC promoter, thus negatively regulating MYC transcription (Ito et al. 2008).
Despite the apparent importance of FRAT proteins in beta-catenin-dependent signaling, a triple FRAT knockout mouse shows no readily evident defects in canonical signaling and, unlike the GBP knockout in Xenopus, no overt phenotypic defects (van Amerongen et al, 2005; Yost et al, 1989). The in vivo role and significance of the FRAT proteins in WNT signaling remains to be resolved; it is worth noting, however, that FRAT proteins have also recently been shown to be involved in non-canonical WNT signaling in a GSK3beta-independent manner. It is possible that it is through this non-canonical role that FRAT proteins contribute to oncogenesis (van Amerongen et al, 2010; Walf-Vorderwülbecke et al, 2012).
Expression of a beta-catenin-dependent reporter gene has been demonstrated after RYK-binding by WNT1 and WNT3A, however the details of downstream signaling remain to be clarified (Lu et al, 2004; Berndt et al, 2011). Signaling through RYK may occur in the context of a RYK-FZD co-receptor and appears to involve the recruitment of DVL (Lu et al, 2004). The E3 ligase Mindbomb (MIB1) was also identified as a RYK-interacting protein that contributes to canonical WNT signaling, possibly by regulating the levels of RYK at the cell surface (Berndt et al, 2011). Finally, RYK has been shown to be cleaved by gamma-secretase in response to WNT3, liberating a intracellular domain (ICD) that translocates to the nucleus and that is required for neuronal differentitation (Lyu et al, 2008). The significance of these findings is not yet fully clear.
Human SRY binds beta-catenin through a N-terminal domain (Bernard et al. 2008), SOX6 interacts via a centrally located leucine zipper (LZ/Q) element (Iguchi et al. 2007), and mammalian SOX7, SOX9 and SOX17 all bind beta-catenin via their C-terminal regions (Zorn et al., 1999; Takash et al., 2001; Akiyama et al., 2004; Sinner et al., 2007, Kormish et al. 2010). SRY and SOX9 function in part by suppressing canonical Wnt signaling by promoting beta-catenin phosphorylation in the nucleus (Topol et al. 2009). SOX9 and SRY are involved in the regulation of mammalian sex determination and mutation in human SRY and SOX9 results in sex reversal, with female development in XY individuals (Bernard et al. 2008). SOX2 binds beta-catenin and promotes cell proliferation by transcriptionally activating the Wnt target Cyclin D1 gene in breast cancer cells (Chen et al., 2008), whereas SOX6 represses Cyclin D1 transcription in pancreatic cells (Iguchi et al., 2007). SOX7 and SOX17 reduce cyclin-D1 expression and repress proliferation by stimulating beta-catenin degradation (Sinner et al. 2007, Zhang et al. 2008, 2009).