RNF43 is an E3 ubiquitin ligase and known negative regulator of WNT/β-catenin signaling. We demonstrate that RNF43 is also a regulator of noncanonical WNT5A-induced signaling in human cells. Analysis of the RNF43 interactome using BioID and immunoprecipitation showed that RNF43 can interact with the core receptor complex components dedicated to the noncanonical Wnt pathway such as ROR1, ROR2, VANGL1, and VANGL2. RNF43 triggers VANGL2 ubiquitination and proteasomal degradation and clathrin-dependent internalization of ROR1 receptor and inhibits ROR2 activation. These activities of RNF43 are physiologically relevant and block pro-metastatic WNT5A signaling in melanoma. RNF43 inhibits responses to WNT5A, which results in the suppression of invasive properties of melanoma cells. Furthermore, RNF43 prevented WNT5A-assisted development of resistance to BRAF V600E and MEK inhibitors. Next, RNF43 acted as melanoma suppressor and improved response to targeted therapies in vivo. In line with these findings, RNF43 expression decreases during melanoma progression and RNF43-low patients have a worse prognosis. We conclude that RNF43 is a newly discovered negative regulator of WNT5A-mediated biological responses that desensitizes cells to WNT5A.

Central European Institute of Technology Masaryk University Brno Czech Republic

Department of Cytokinetics Institute of Biophysics CAS Brno Czech Republic

Department of Experimental Biology Faculty of Science Masaryk University Brno Czech Republic

Department of Histology and Embryology Faculty of Medicine Masaryk University Brno Czech Republic

International Clinical Research Center FNUSA ICRC Brno Czech Republic

Laboratory of Molecular Oncology Cancer Research Institute Biomedical Research Center of the Slovak Academy of Sciences Bratislava Slovakia

See more in PubMed

Ahn A, Chatterjee A, Eccles MR. The Slow Cycling Phenotype: A Growing Problem for Treatment Resistance in Melanoma. Molecular Cancer Therapeutics. 2017;16:1002–1009. doi: 10.1158/1535-7163.MCT-16-0535. PubMed DOI

Akbani R, Akdemir KC KC, Aksoy BA BA, Albert M N. Genomic classification of cutaneous melanoma. Cell. 2015;161:1681–1696. doi: 10.1016/J.CELL.2015.05.044. PubMed DOI PMC

Anastas JN, Kulikauskas RM, Tamir T, Rizos H, Long GV, von Euw EM, Yang PT, Chen HW, Haydu L, Toroni RA, Lucero OM, Chien AJ, Moon RT. WNT5A enhances resistance of melanoma cells to targeted BRAF inhibitors. The Journal of Clinical Investigation. 2014;124:2877–2890. doi: 10.1172/JCI70156. PubMed DOI PMC

Anaya J. OncoLnc: linking TCGA survival data to mRNAs, miRNAs, and lncRNAs. PeerJ Computer Science. 2016;2:e67. doi: 10.7717/peerj-cs.67. DOI

Andre P, Song H, Kim W, Kispert A, Yang Y. Wnt5a and Wnt11 regulate mammalian anterior-posterior axis elongation. Development. 2015;142:1516–1527. doi: 10.1242/dev.119065. PubMed DOI PMC

Angers S, Thorpe CJ, Biechele TL, Goldenberg SJ, Zheng N, MacCoss MJ, Moon RT. The KLHL12–Cullin-3 ubiquitin ligase negatively regulates the Wnt–β-catenin pathway by targeting Dishevelled for degradation. Nature Cell Biology. 2006;8:348–357. doi: 10.1038/ncb1381. PubMed DOI

Arozarena I, Bischof H, Gilby D, Belloni B, Dummer R, Wellbrock C. In melanoma, beta-catenin is a suppressor of invasion. Oncogene. 2011;30:4531–4543. doi: 10.1038/onc.2011.162. PubMed DOI PMC

Arozarena I, Wellbrock C. Overcoming resistance to BRAF inhibitors. Annals of Translational Medicine. 2017a;5:387. doi: 10.21037/atm.2017.06.09. PubMed DOI PMC

Arozarena I, Wellbrock C. Targeting invasive properties of melanoma cells. The FEBS Journal. 2017b;284:2148–2162. doi: 10.1111/febs.14040. PubMed DOI

Arozarena I, Wellbrock C. Phenotype plasticity as enabler of melanoma progression and therapy resistance. Nature Reviews. Cancer. 2019;19:377–391. doi: 10.1038/s41568-019-0154-4. PubMed DOI

Ascierto PA, McArthur GA, Dréno B, Atkinson V, Liszkay G, Di Giacomo AM, Mandalà M, Demidov L, Stroyakovskiy D, Thomas L, de la Cruz-Merino L, Dutriaux C, Garbe C, Yan Y, Wongchenko M, Chang I, Hsu JJ, Koralek DO, Rooney I, Ribas A, Larkin J. Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. The Lancet. Oncology. 2016;17:1248–1260. doi: 10.1016/S1470-2045(16)30122-X. PubMed DOI

Asem MS, Buechler S, Wates RB, Miller DL, Stack MS. WNT5A signaling in cancer. Cancers. 2016;8:E79. doi: 10.3390/cancers8090079. PubMed DOI PMC

Astudillo P. WNT5A signaling in gastric cancer. Frontiers in Cell and Developmental Biology. 2020;8:110. doi: 10.3389/fcell.2020.00110. PubMed DOI PMC

Bache KG, Raiborg C, Mehlum A, Stenmark H. Stam and hrs are subunits of a multivalent ubiquitin-binding complex on early endosomes. The Journal of Biological Chemistry. 2003;278:12513–12521. doi: 10.1074/jbc.M210843200. PubMed DOI

Bai X, Fisher DE, Flaherty KT. Cell-state dynamics and therapeutic resistance in melanoma from the perspective of MITF and IFNΓ pathways. Nature Reviews. Clinical Oncology. 2019;16:549–562. doi: 10.1038/S41571-019-0204-6. PubMed DOI PMC

Barta T, Peskova L, Hampl A. Mirnasong: A web-based tool for generation and testing of mirna sponge constructs in silico. Scientific Reports. 2016;6:36625. doi: 10.1038/srep36625. PubMed DOI PMC

Belotti E, Puvirajesinghe TM, Audebert S, Baudelet E, Camoin L, Pierres M, Lasvaux L, Ferracci G, Montcouquiol M, Borg JP. Molecular characterisation of endogenous Vangl2/vangl1 heteromeric protein complexes. PLOS ONE. 2012;7:e46213. doi: 10.1371/journal.pone.0046213. PubMed DOI PMC

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. PNAS. 2007;104:14700–14705. doi: 10.1073/pnas.0702305104. PubMed DOI PMC

Birkeland E, Zhang S, Poduval D, Geisler J, Nakken S, Vodak D, Meza-Zepeda LA, Hovig E, Myklebost O, Knappskog S, Lønning PE. Patterns of genomic evolution in advanced melanoma. Nature Communications. 2018;9:2665. doi: 10.1038/s41467-018-05063-1. PubMed DOI PMC

Blitzer JT, Nusse R. A critical role for endocytosis in Wnt signaling. BMC Cell Biology. 2006;7:28. doi: 10.1186/1471-2121-7-28. PubMed DOI PMC

Bollag G, Tsai J, Zhang J, Zhang C, Ibrahim P, Nolop K, Hirth P. VEMURAFENIB: The first drug approved for braf-mutant cancer. Nature Reviews. Drug Discovery. 2012;11:873–886. doi: 10.1038/nrd3847. PubMed DOI

Bond CE, McKeone DM, Kalimutho M, Bettington ML, Pearson SA, Dumenil TD, Wockner LF, Burge M, Leggett BA, Whitehall VLJ. RNF43 and znrf3 are commonly altered in serrated pathway colorectal tumorigenesis. Oncotarget. 2016;7:70589–70600. doi: 10.18632/oncotarget.12130. PubMed DOI PMC

Bryja V, Schulte G, Arenas E. Wnt-3a utilizes a novel low dose and rapid pathway that does not require casein kinase 1-mediated phosphorylation of Dvl to activate beta-catenin. Cellular Signalling. 2007a;19:610–616. doi: 10.1016/j.cellsig.2006.08.011. PubMed DOI

Bryja V, Schulte G, Rawal N, Grahn A, Arenas E. Wnt-5a induces dishevelled phosphorylation and dopaminergic differentiation via a ck1-dependent mechanism. Journal of Cell Science. 2007b;120:586–595. doi: 10.1242/jcs.03368. PubMed DOI

Bucci C, Parton RG, Mather IH, Stunnenberg H, Simons K, Hoflack B, Zerial M. The small gtpase rab5 functions as a regulatory factor in the early endocytic pathway. Cell. 1992;70:715–728. doi: 10.1016/0092-8674(92)90306-W. PubMed DOI

Carmon KS, Gong X, Lin Q, Thomas A, Liu Q. R-spondins function as ligands of the orphan receptors LGR4 and LGR5 to regulate Wnt/beta-catenin signaling. PNAS. 2011;108:11452–11457. doi: 10.1073/pnas.1106083108. PubMed DOI PMC

Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, Hogg D, Lorigan P, Lebbe C, Jouary T, Schadendorf D, Ribas A, O’Day SJ, Sosman JA, Kirkwood JM, Eggermont AMM, Dreno B, Nolop K, Li J, Nelson B, Hou J, Lee RJ, Flaherty KT, McArthur GA, BRIM-3 Study Group Improved survival with Vemurafenib in melanoma with BRAF V600E mutation. The New England Journal of Medicine. 2011;364:2507–2516. doi: 10.1056/NEJMoa1103782. PubMed DOI PMC

Chen PI, Kong C, Su X, Stahl PD. RAB5 isoforms differentially regulate the trafficking and degradation of epidermal growth factor receptors. The Journal of Biological Chemistry. 2009;284:30328–30338. doi: 10.1074/jbc.M109.034546. PubMed DOI PMC

Chisholm RH, Lorenzi T, Lorz A, Larsen AK, de Almeida LN, Escargueil A, Clairambault J. Emergence of drug tolerance in cancer cell populations: An evolutionary outcome of selection, nongenetic instability, and stress-induced adaptation. Cancer Research. 2015;75:930–939. doi: 10.1158/0008-5472.CAN-14-2103. PubMed DOI

Choudhury A, Dominguez M, Puri V, Sharma DK, Narita K, Wheatley CL, Marks DL, Pagano RE. Rab proteins mediate golgi transport of caveola-internalized glycosphingolipids and correct lipid trafficking in Niemann-pick C cells. The Journal of Clinical Investigation. 2002;109:1541–1550. doi: 10.1172/jci15420. PubMed DOI PMC

Chu VT, Weber T, Wefers B, Wurst W, Sander S, Rajewsky K, Kühn R. Increasing the efficiency of homology-directed repair for crispr-cas9-induced precise gene editing in mammalian cells. Nature Biotechnology. 2015;33:543–548. doi: 10.1038/nbt.3198. PubMed DOI

Connacher MK, Tay JW, Ahn NG. Rear-polarized Wnt5a-receptor-actin-myosin-polarity (WRAMP) structures promote the speed and persistence of directional cell migration. Molecular Biology of the Cell. 2017;28:1924–1936. doi: 10.1091/mbc.E16-12-0875. PubMed DOI PMC

Coyaud E, Mis M, Laurent EMN, Dunham WH, Couzens AL, Robitaille M, Gingras AC, Angers S, Raught B. BioID-based identification of skp cullin F-box (SCF)β-TrCP1/2 E3 ligase substrates. Molecular & Cellular Proteomics. 2015;14:1781–1795. doi: 10.1074/mcp.M114.045658. PubMed DOI PMC

Cullis DN, Philip B, Baleja JD, Feig LA. Rab11-fip2, an adaptor protein connecting cellular components involved in internalization and recycling of epidermal growth factor receptors. The Journal of Biological Chemistry. 2002;277:49158–49166. doi: 10.1074/jbc.M206316200. PubMed DOI

Da Forno PD, Pringle JH, Hutchinson P, Osborn J, Huang Q, Potter L, Hancox RA, Fletcher A, Saldanha GS. WNT5A expression increases during melanoma progression and correlates with outcome. Clinical Cancer Research. 2008;14:5825–5832. doi: 10.1158/1078-0432.CCR-07-5104. PubMed DOI

Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JWC, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–954. doi: 10.1038/nature00766. PubMed DOI

de Lau W, Barker N, Low TY, Koo B-K, Li VSW, Teunissen H, Kujala P, Haegebarth A, Peters PJ, van de Wetering M, Stange DE, van Es JE, Guardavaccaro D, Schasfoort RBM, Mohri Y, Nishimori K, Mohammed S, Heck AJR, Clevers H. Lgr5 homologues associate with Wnt receptors and mediate r-spondin signalling. Nature. 2011;476:293–297. doi: 10.1038/nature10337. PubMed DOI

Deshar R, Moon S, Yoo W, Cho EB, Yoon SK, Yoon JB. RNF167 targets ARL8B for degradation to regulate lysosome positioning and endocytic trafficking. The FEBS Journal. 2016;283:4583–4599. doi: 10.1111/febs.13947. PubMed DOI

Deutsch EW, Bandeira N, Sharma V, Perez-Riverol Y, Carver JJ, Kundu DJ, García-Seisdedos D, Jarnuczak AF, Hewapathirana S, Pullman BS, Wertz J, Sun Z, Kawano S, Okuda S, Watanabe Y, Hermjakob H, MacLean B, MacCoss MJ, Zhu Y, Ishihama Y, Vizcaíno JA. The ProteomeXchange consortium in 2020: enabling “big data” approaches in proteomics. Nucleic Acids Research. 2020;48:D1145–D1152. doi: 10.1093/nar/gkz984. PubMed DOI PMC

Dissanayake SK, Wade M, Johnson CE, O’Connell MP, Leotlela PD, French AD, Shah KV, Hewitt KJ, Rosenthal DT, Indig FE, Jiang Y, Nickoloff BJ, Taub DD, Trent JM, Moon RT, Bittner M, Weeraratna AT. The Wnt5a/protein kinase C pathway mediates motility in melanoma cells via the inhibition of metastasis suppressors and initiation of an epithelial to mesenchymal transition. The Journal of Biological Chemistry. 2007;282:17259–17271. doi: 10.1074/jbc.M700075200. PubMed DOI PMC

Dissanayake SK, Olkhanud PB, O’Connell MP, Carter A, French AD, Camilli TC, Emeche CD, Hewitt KJ, Rosenthal DT, Leotlela PD, Wade MS, Yang SW, Brant L, Nickoloff BJ, Messina JL, Biragyn A, Hoek KS, Taub DD, Longo DL, Sondak VK, Hewitt SM, Weeraratna AT. WNT5A regulates expression of tumor-associated antigens in melanoma via changes in signal transducers and activators of transcription 3 phosphorylation. Cancer Research. 2008;68:10205–10214. doi: 10.1158/0008-5472.CAN-08-2149. PubMed DOI PMC

Eddy RJ, Weidmann MD, Sharma VP, Condeelis JS. Tumor cell invadopodia: Invasive protrusions that orchestrate metastasis. Trends in Cell Biology. 2017;27:595–607. doi: 10.1016/j.tcb.2017.03.003. PubMed DOI PMC

Ekström EJ, Bergenfelz C, von Bülow V, Serifler F, Carlemalm E, Jönsson G, Andersson T, Leandersson K. WNT5A induces release of exosomes containing pro-angiogenic and immunosuppressive factors from malignant melanoma cells. Molecular Cancer. 2014;13:88. doi: 10.1186/1476-4598-13-88. PubMed DOI PMC

Eto T, Miyake K, Nosho K, Ohmuraya M, Imamura Y, Arima K, Kanno S, Fu L, Kiyozumi Y, Izumi D, Sugihara H, Hiyoshi Y, Miyamoto Y, Sawayama H, Iwatsuki M, Baba Y, Yoshida N, Furukawa T, Araki K, Baba H, Ishimoto T. Impact of loss-of-function mutations at the RNF43 locus on colorectal cancer development and progression. The Journal of Pathology. 2018;245:445–455. doi: 10.1002/path.5098. PubMed DOI

Feng D, Wang J, Yang W, Li J, Lin X, Zha F, Wang X, Ma L, Choi NT, Mii Y, Takada S, Huen MSY, Guo Y, Zhang L, Gao B. Regulation of Wnt/PCP signaling through p97/VCP-KBTBD7-mediated Vangl ubiquitination and endoplasmic reticulum-associated degradation. Science Advances. 2021;7:eabg2099. doi: 10.1126/sciadv.abg2099. PubMed DOI PMC

Fernández NB, Lorenzo D, Picco ME, Barbero G, Dergan-Dylon LS, Marks MP, García-Rivello H, Gimenez L, Labovsky V, Grumolato L, Lopez-Bergami P. ROR1 contributes to melanoma cell growth and migration by regulating n-cadherin expression via the PI3K/AKT pathway. Molecular Carcinogenesis. 2016;55:1772–1785. doi: 10.1002/mc.22426. PubMed DOI

Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, O’Dwyer PJ, Lee RJ, Grippo JF, Nolop K, Chapman PB. Inhibition of mutated, activated BRAF in metastatic melanoma. The New England Journal of Medicine. 2010;363:809–819. doi: 10.1056/NEJMoa1002011. PubMed DOI PMC

Gao B, Song H, Bishop K, Elliot G, Garrett L, English MA, Andre P, Robinson J, Sood R, Minami Y, Economides AN, Yang Y. Wnt signaling gradients establish planar cell polarity by inducing vangl2 phosphorylation through ror2. Developmental Cell. 2011;20:163–176. doi: 10.1016/J.DEVCEL.2011.01.001. PubMed DOI PMC

Gao Y, Cai A, Xi H, Li J, Xu W, Zhang Y, Zhang K, Cui J, Wu X, Wei B, Chen L. Ring finger protein 43 associates with gastric cancer progression and attenuates the stemness of gastric cancer stem-like cells via the wnt-β/catenin signaling pathway. Stem Cell Research & Therapy. 2017;8:98. doi: 10.1186/s13287-017-0548-8. PubMed DOI PMC

Gentile A, Lazzari L, Benvenuti S, Trusolino L, Comoglio PM. Ror1 is a pseudokinase that is crucial for met-driven tumorigenesis. Cancer Research. 2011;71:3132–3141. doi: 10.1158/0008-5472.CAN-10-2662. PubMed DOI

Giannakis M, Hodis E, Jasmine Mu X, Yamauchi M, Rosenbluh J, Cibulskis K, Saksena G, Lawrence MS, Qian ZR, Nishihara R, Van Allen EM, Hahn WC, Gabriel SB, Lander ES, Getz G, Ogino S, Fuchs CS, Garraway LA. RNF43 is frequently mutated in colorectal and endometrial cancers. Nature Genetics. 2014;46:1264–1266. doi: 10.1038/ng.3127. PubMed DOI PMC

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. EMBO Reports. 2011;12:1055–1061. doi: 10.1038/embor.2011.175. PubMed DOI PMC

Guo Y, Zanetti G, Schekman R. A novel gtp-binding protein-adaptor protein complex responsible for export of vangl2 from the trans GOLGI network. eLife. 2013;2:e00160. doi: 10.7554/eLife.00160. PubMed DOI PMC

Hanaki H, Yamamoto H, Sakane H, Matsumoto S, Ohdan H, Sato A, Kikuchi A. An anti-wnt5A antibody suppresses metastasis of gastric cancer cells in vivo by inhibiting receptor-mediated endocytosis. Molecular Cancer Therapeutics. 2012;11:298–307. doi: 10.1158/1535-7163.MCT-11-0682. PubMed DOI

Hanáková K, Bernatík O, Kravec M, Micka M, Kumar J, Harnoš J, Ovesná P, Paclíková P, Rádsetoulal M, Potěšil D, Tripsianes K, Čajánek L, Zdráhal Z, Bryja V. Comparative phosphorylation map of Dishevelled 3 links phospho-signatures to biological outputs. Cell Communication and Signaling. 2019;17:170. doi: 10.1186/s12964-019-0470-z. PubMed DOI PMC

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. Nature. 2012;485:195–200. doi: 10.1038/nature11019. PubMed DOI

Hao HX, Jiang X, Cong F. Control of wnt receptor turnover by r-spondin-znrf3/rnf43 signaling module and its dysregulation in cancer. Cancers. 2016;8:E54. doi: 10.3390/cancers8060054. PubMed DOI PMC

Haqq C, Nosrati M, Sudilovsky D, Crothers J, Khodabakhsh D, Pulliam BL, Federman S, Miller JR, Allen RE, Singer MI, Leong SPL, Ljung BM, Sagebiel RW, Kashani-Sabet M. The gene expression signatures of melanoma progression. PNAS. 2005;102:6092–6097. doi: 10.1073/pnas.0501564102. PubMed DOI PMC

Harnoš J, Cañizal MCA, Jurásek M, Kumar J, Holler C, Schambony A, Hanáková K, Bernatík O, Zdráhal Z, Gömöryová K, Gybeľ T, Radaszkiewicz TW, Kravec M, Trantírek L, Ryneš J, Dave Z, Fernández-Llamazares AI, Vácha R, Tripsianes K, Hoffmann C, Bryja V. Dishevelled-3 conformation dynamics analyzed by fret-based biosensors reveals a key role of casein kinase 1. Nature Communications. 2019;10:1804. doi: 10.1038/s41467-019-09651-7. PubMed DOI PMC

Harris A, Siggers P, Corrochano S, Warr N, Sagar D, Grimes DT, Suzuki M, Burdine RD, Cong F, Koo B-K, Clevers H, Stévant I, Nef S, Wells S, Brauner R, Ben Rhouma B, Belguith N, Eozenou C, Bignon-Topalovic J, Bashamboo A, McElreavey K, Greenfield A. ZNRF3 functions in mammalian sex determination by inhibiting canonical WNT signaling. PNAS. 2018;115:5474–5479. doi: 10.1073/pnas.1801223115. PubMed DOI PMC

Hershko A, Ciechanover A. The UBIQUITIN SYSTEM. Annual Review of Biochemistry. 1998;67:425–479. doi: 10.1146/annurev.biochem.67.1.425. PubMed DOI

Hirst J, Irving C, Borner GHH. Adaptor Protein Complexes AP-4 and AP-5: New Players in Endosomal Trafficking and Progressive Spastic Paraplegia. Traffic. 2013;14:153–164. doi: 10.1111/tra.12028. PubMed DOI

Ho HYH, Susman MW, Bikoff JB, Ryu YK, Jonas AM, Hu L, Kuruvilla R, Greenberg ME. Wnt5a-Ror-Dishevelled signaling constitutes a core developmental pathway that controls tissue morphogenesis. PNAS. 2012;109:4044–4051. doi: 10.1073/pnas.1200421109. PubMed DOI PMC

Hodis E, Watson IR, Kryukov G, Arold ST, Imielinski M, Theurillat JP, Nickerson E, Auclair D, Li L, Place C, Dicara D, Ramos AH, Lawrence MS, Cibulskis K, Sivachenko A, Voet D, Saksena G, Stransky N, Onofrio RC, Winckler W, Ardlie K, Wagle N, Wargo J, Chong K, Morton DL, Stemke-Hale K, Chen G, Noble M, Meyerson M, Ladbury JE, Davies MA, Gershenwald JE, Wagner SN, Hoon DSB, Schadendorf D, Lander ES, Gabriel SB, Getz G, Garraway LA, Chin L. A landscape of driver mutations in melanoma. Cell. 2012;150:251–263. doi: 10.1016/j.cell.2012.06.024. PubMed DOI PMC

Hoek KS, Schlegel NC, Brafford P, Sucker A, Ugurel S, Kumar R, Weber BL, Nathanson KL, Phillips DJ, Herlyn M, Schadendorf D, Dummer R. Metastatic potential of melanomas defined by specific gene expression profiles with no BRAF signature. Pigment Cell Research. 2006;19:290–302. doi: 10.1111/j.1600-0749.2006.00322.x. PubMed DOI

Hoek KS, Goding CR. Cancer stem cells versus phenotype-switching in melanoma. Pigment Cell & Melanoma Research. 2010;23:746–759. doi: 10.1111/J.1755-148X.2010.00757.X. PubMed DOI

Humphries AC, Mlodzik M. From instruction to output: Wnt/pcp signaling in development and cancer. Current Opinion in Cell Biology. 2018;51:110–116. doi: 10.1016/J.CEB.2017.12.005. PubMed DOI PMC

Jacquelot N, Duong CPM, Belz GT, Zitvogel L. Targeting Chemokines and Chemokine Receptors in Melanoma and Other Cancers. Frontiers in Immunology. 2018;9:2480. doi: 10.3389/fimmu.2018.02480. PubMed DOI PMC

Janovská P, Bryja V. Wnt signalling pathways in chronic lymphocytic leukaemia and B-cell lymphomas. British Journal of Pharmacology. 2017;174:4701–4715. doi: 10.1111/bph.13949. PubMed DOI PMC

Ji Z, Erin Chen Y, Kumar R, Taylor M, Jenny Njauw CN, Miao B, Frederick DT, Wargo JA, Flaherty KT, Jönsson G, Tsao H. MITF Modulates Therapeutic Resistance through EGFR Signaling. The Journal of Investigative Dermatology. 2015;135:1863–1872. doi: 10.1038/JID.2015.105. PubMed DOI PMC

Jiang X, Hao HX, Growney JD, Woolfenden S, Bottiglio C, Ng N, Lu B, Hsieh MH, Bagdasarian L, Meyer R, Smith TR, Avello M, Charlat O, Xie Y, Porter JA, Pan S, Liu J, McLaughlin ME, Cong F. Inactivating mutations of RNF43 confer Wnt dependency in pancreatic ductal adenocarcinoma. PNAS. 2013;110:12649–12654. doi: 10.1073/PNAS.1307218110. PubMed DOI PMC

Jiang X, Charlat O, Zamponi R, Yang Y, Cong F. Dishevelled Promotes Wnt Receptor Degradation through Recruitment of ZNRF3/RNF43 E3 Ubiquitin Ligases. Molecular Cell. 2015;58:522–533. doi: 10.1016/J.MOLCEL.2015.03.015. PubMed DOI

Jo YS, Kim MS, Lee JH, Lee SH, An CH, Yoo NJ. Frequent frameshift mutations in 2 mononucleotide repeats of rnf43 gene and its regional heterogeneity in gastric and colorectal cancers. Human Pathology. 2015;46:1640–1646. doi: 10.1016/J.HUMPATH.2015.07.004. PubMed DOI

Johnson DB, Menzies AM, Zimmer L, Eroglu Z, Ye F, Zhao S, Rizos H, Sucker A, Scolyer RA, Gutzmer R, Gogas H, Kefford RF, Thompson JF, Becker JC, Berking C, Egberts F, Loquai C, Goldinger SM, Pupo GM, Hugo W, Kong X, Garraway LA, Sosman JA, Ribas A, Lo RS, Long G, Schadendorf D. Acquired BRAF inhibitor resistance: A multicenter meta-analysis of the spectrum and frequencies, clinical behaviour, and phenotypic associations of resistance mechanisms. European Journal of Cancer. 2015;51:2792–2799. doi: 10.1016/J.EJCA.2015.08.022. PubMed DOI PMC

Joseph EW, Pratilas CA, Poulikakos PI, Tadi M, Wang W, Taylor BS, Halilovic E, Persaud Y, Xing F, Viale A, Tsai J, Chapman PB, Bollag G, Solit DB, Rosen N. The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in a V600E BRAF-selective manner. PNAS. 2010;107:14903–14908. doi: 10.1073/pnas.1008990107. PubMed DOI PMC

Kageshita T, Hamby CV, Ishihara T, Matsumoto K, Saida T, Ono T. Loss of beta-catenin expression associated with disease progression in malignant melanoma. The British Journal of Dermatology. 2001;145:210–216. doi: 10.1046/j.1365-2133.2001.04336.x. PubMed DOI

Kaiser K, Gyllborg D, Procházka J, Salašová A, Kompaníková P, Molina FL, Laguna-Goya R, Radaszkiewicz T, Harnoš J, Procházková M, Potěšil D, Barker RA, Casado ÁG, Zdráhal Z, Sedláček R, Arenas E, Villaescusa JC, Bryja V. WNT5A is transported via lipoprotein particles in the cerebrospinal fluid to regulate hindbrain morphogenesis. Nature Communications. 2019;10:1498. doi: 10.1038/s41467-019-09298-4. PubMed DOI PMC

Kaiser K, Jang A, Lun MP, Procházka J, Machon O, Procházková M, Laurent B, Gyllborg D, van Amerongen R, Kompaníková P, Wu F, Barker RA, Uramová I, Sedláček R, Kozmík Z, Arenas E, Lehtinen MK, Bryja V. 2020. MEIS-WNT5A Axis Regulates Development of 4th Ventricle Choroid Plexus. bioRxiv. 2020 doi: 10.1101/2020.05.07.082370. PubMed DOI PMC

Kanzawa M, Semba S, Hara S, Itoh T, Yokozaki H. WNT5A is a key regulator of the epithelial-mesenchymal transition and cancer stem cell properties in human gastric carcinoma cells. Pathobiology. 2013;80:235–244. doi: 10.1159/000346843. PubMed DOI

Katoh M. Networking of WNT, FGF, notch, BMP, and hedgehog signaling pathways during carcinogenesis. Stem Cell Reviews. 2007;3:30–38. doi: 10.1007/s12015-007-0006-6. PubMed DOI

Kaucká M, Petersen J, Janovská P, Radaszkiewicz T, Smyčková L, Daulat AM, Borg J-P, Schulte G, Bryja V. Asymmetry of VANGL2 in migrating lymphocytes as a tool to monitor activity of the mammalian wnt/planar cell polarity pathway. Cell Communication and Signaling. 2015;13:2. doi: 10.1186/s12964-014-0079-1. PubMed DOI PMC

Kazanskaya O, Glinka A, del Barco Barrantes I, Stannek P, Niehrs C, Wu W. R-Spondin2 is a secreted activator of Wnt/beta-catenin signaling and is required for Xenopus myogenesis. Developmental Cell. 2004;7:525–534. doi: 10.1016/j.devcel.2004.07.019. PubMed DOI

Kemper K, de Goeje PL, Peeper DS, van Amerongen R. Phenotype switching: Tumor cell plasticity as a resistance mechanism and target for therapy. Cancer Research. 2014;74:5937–5941. doi: 10.1158/0008-5472.CAN-14-1174. PubMed DOI

Kim KA, Kakitani M, Zhao J, Oshima T, Tang T, Binnerts M, Liu Y, Boyle B, Park E, Emtage P, Funk WD, Tomizuka K. Mitogenic influence of human R-spondin1 on the intestinal epithelium. Science. 2005;309:1256–1259. doi: 10.1126/science.1112521. PubMed DOI

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. Cell Cycle. 2006;5:23–26. doi: 10.4161/cc.5.1.2305. PubMed DOI

Kim KA, Wagle M, Tran K, Zhan X, Dixon MA, Liu S, Gros D, Korver W, Yonkovich S, Tomasevic N, Binnerts M, Abo A. R-spondin family members regulate the WNT pathway by a common mechanism. Molecular Biology of the Cell. 2008;19:2588–2596. doi: 10.1091/mbc.e08-02-0187. PubMed DOI PMC

Kim IS, Heilmann S, Kansler ER, Zhang Y, Zimmer M, Ratnakumar K, Bowman RL, Simon-Vermot T, Fennell M, Garippa R, Lu L, Lee W, Hollmann T, Xavier JB, White RM. Microenvironment-derived factors driving metastatic plasticity in melanoma. Nature Communications. 2017;8:14343. doi: 10.1038/ncomms14343. PubMed DOI PMC

Koo BK, Spit M, Jordens I, Low TY, Stange DE, van de Wetering M, van Es JH, Mohammed S, Heck AJR, Maurice MM, Clevers H. Tumour suppressor rnf43 is a stem-cell e3 ligase that induces endocytosis of WNT receptors. Nature. 2012;488:665–669. doi: 10.1038/nature11308. PubMed DOI

Kotašková J, Pavlová Š, Greif I, Stehlíková O, Plevová K, Janovská P, Brychtová Y, Doubek M, Pospíšilová Š, Bryja V. Ror1-based immunomagnetic protocol allows efficient separation of CLL and healthy B cells. British Journal of Haematology. 2016;175:339–342. doi: 10.1111/bjh.13848. PubMed DOI

Kotrbová A, Ovesná P, Gybel’ T, Radaszkiewicz T, Bednaříková M, Hausnerová J, Jandáková E, Minář L, Crha I, Weinberger V, Záveský L, Bryja V, Pospíchalová V. WNT signaling inducing activity in ascites predicts poor outcome in ovarian cancer. Theranostics. 2020;10:537–552. doi: 10.7150/thno.37423. PubMed DOI PMC

Kristina G. OmicsWorkflows. GitHub. 2021 https://github.com/OmicsWorkflows

Kucerova L, Skolekova S, Demkova L, Bohovic R, Matuskova M. Long-term efficiency of mesenchymal stromal cell-mediated CD-MSC/5FC therapy in human melanoma xenograft model. Gene Therapy. 2014;21:874–887. doi: 10.1038/gt.2014.66. PubMed DOI

Kurayoshi M, Oue N, Yamamoto H, Kishida M, Inoue A, Asahara T, Yasui W, Kikuchi A. Expression of Wnt-5a is correlated with aggressiveness of gastric cancer by stimulating cell migration and invasion. Cancer Research. 2006;66:10439–10448. doi: 10.1158/0008-5472.CAN-06-2359. PubMed DOI

Lai SS, Xue B, Yang Y, Zhao L, Chu CS, Hao JY, Wen CJ. Ror2-src signaling in metastasis of mouse melanoma cells is inhibited by NRAGE. Cancer Genetics. 2012;205:552–562. doi: 10.1016/J.CANCERGEN.2012.09.002. PubMed DOI

Lavelle TJ, Alver TN, Heintz KM, Wernhoff P, Nygaard V, Nakken S, Øy GF, Bøe SL, Urbanucci A, Hovig E. Dysregulation of MITF leads to transformation in mc1r-defective melanocytes. Cancers. 2020;12:1–19. doi: 10.3390/cancers12071719. PubMed DOI PMC

Lebensohn AM, Rohatgi R. R-spondins can potentiate WNT signaling without LGRS. eLife. 2018;7:e33126. doi: 10.7554/eLife.33126. PubMed DOI PMC

Li S, Wang W, Zhang N, Ma T, Zhao C. Il-1β mediates mcp-1 induction by WNT5A in gastric cancer cells. BMC Cancer. 2014;14:480. doi: 10.1186/1471-2407-14-480. PubMed DOI PMC

Lim X, Nusse R. WNT signaling in skin development, homeostasis, and disease. Cold Spring Harbor Perspectives in Biology. 2013;5:a008029. doi: 10.1101/cshperspect.a008029. PubMed DOI PMC

Linnskog R, Mohapatra P, Moradi F, Prasad CP, Andersson T. Demonstration of a wnt5a-il-6 positive feedback loop in melanoma cells: Dual interference of this loop more effectively impairs melanoma cell invasion. Oncotarget. 2016;7:37790–37802. doi: 10.18632/oncotarget.9332. PubMed DOI PMC

Liu Q, Zhu H, Tiruthani K, Shen L, Chen F, Gao K, Zhang X, Hou L, Wang D, Liu R, Huang L. Nanoparticle-mediated trapping of Wnt family member 5A in tumor microenvironments enhances immunotherapy for B-RAF proto-oncogene mutant melanoma. ACS Nano. 2018;12:1250–1261. doi: 10.1021/acsnano.7b07384. PubMed DOI PMC

Luebker SA, Koepsell SA. Diverse mechanisms of BRAF inhibitor resistance in melanoma identified in clinical and preclinical studies. Frontiers in Oncology. 2019;9:268. doi: 10.3389/fonc.2019.00268. PubMed DOI PMC

Luo C, Balsa E, Perry EA, Liang J, Tavares CD, Vazquez F, Widlund HR, Puigserver P. H3k27me3-mediated pgc1α gene silencing promotes melanoma invasion through wnt5a and YAP. The Journal of Clinical Investigation. 2020;130:853–862. doi: 10.1172/JCI130038. PubMed DOI PMC

Makowiecka A, Simiczyjew A, Nowak D, Mazur AJ. Varying effects of EGF, HGF and tgfβ on formation of invadopodia and invasiveness of melanoma cell lines of different origin. European Journal of Histochemistry. 2016;60:2728. doi: 10.4081/ejh.2016.2728. PubMed DOI PMC

Malcikova J, Stano-Kozubik K, Tichy B, Kantorova B, Pavlova S, Tom N, Radova L, Smardova J, Pardy F, Doubek M, Brychtova Y, Mraz M, Plevova K, Diviskova E, Oltova A, Mayer J, Pospisilova S, Trbusek M. Detailed analysis of therapy-driven clonal evolution of tp53 mutations in chronic lymphocytic leukemia. Leukemia. 2015;29:877–885. doi: 10.1038/leu.2014.297. PubMed DOI PMC

Mali P, Yang L, Esvelt KM, Aach J, Guell M, DiCarlo JE, Norville JE, Church GM. RNA-guided human genome engineering via cas9. Science. 2013;339:823–826. doi: 10.1126/science.1232033. PubMed DOI PMC

Masi I, Caprara V, Bagnato A, Rosanò L. Tumor cellular and microenvironmental cues controlling invadopodia formation. Frontiers in Cell and Developmental Biology. 2020;8:584181. doi: 10.3389/fcell.2020.584181. PubMed DOI PMC

Massi D, Mihic-Probst D, Schadendorf D, Dummer R, Mandalà M. Dedifferentiated melanomas: Morpho-phenotypic profile, genetic reprogramming and clinical implications. Cancer Treatment Reviews. 2020;88 doi: 10.1016/j.ctrv.2020.102060. PubMed DOI

Matsumoto A, Shimada Y, Nakano M, Oyanagi H, Tajima Y, Nakano M, Kameyama H, Hirose Y, Ichikawa H, Nagahashi M, Nogami H, Maruyama S, Takii Y, Ling Y, Okuda S, Wakai T. RNF43 mutation is associated with aggressive tumor biology along with BRAF V600E mutation in right-sided colorectal cancer. Oncology Reports. 2020;43:1853–1862. doi: 10.3892/or.2020.7561. PubMed DOI PMC

McArdle TJ, Ogle BM, Noubissi FK. An in vitro inverted vertical invasion assay to avoid manipulation of rare or sensitive cell types. Journal of Cancer. 2016;7:2333–2340. doi: 10.7150/jca.15812. PubMed DOI PMC

Mentink RA, Rella L, Radaszkiewicz TW, Gybel T, Betist MC, Bryja V, Korswagen HC. The planar cell polarity protein Vang-1/vangl negatively regulates wnt/β-catenin signaling through a DVL dependent mechanism. PLOS Genetics. 2018;14:e1007840. doi: 10.1371/journal.pgen.1007840. PubMed DOI PMC

Moffat LL, Robinson RE, Bakoulis A, Clark SG. The conserved transmembrane ring finger protein PLR-1 downregulates wnt signaling by reducing Frizzled, ROR and ryk cell-surface levels in C. elegans. Development. 2014;141:617–628. doi: 10.1242/dev.101600. PubMed DOI PMC

Mohapatra P, Prasad CP, Andersson T. Combination therapy targeting the elevated interleukin-6 level reduces invasive migration of BRAF inhibitor-resistant melanoma cells. Molecular Oncology. 2019;13:480–494. doi: 10.1002/1878-0261.12433. PubMed DOI PMC

Müller J, Krijgsman O, Tsoi J, Robert L, Hugo W, Song C, Kong X, Possik PA, Cornelissen-Steijger PDM, Geukes Foppen MH, Kemper K, Goding CR, McDermott U, Blank C, Haanen J, Graeber TG, Ribas A, Lo RS, Peeper DS. Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma. Nature Communications. 2014;5:1–15. doi: 10.1038/ncomms6712. PubMed DOI PMC

Nam JS, Turcotte TJ, Smith PF, Choi S, Yoon JK. Mouse cristin/R-spondin family proteins are novel ligands for the Frizzled 8 and LRP6 receptors and activate beta-catenin-dependent gene expression. The Journal of Biological Chemistry. 2006;281:13247–13257. doi: 10.1074/jbc.M508324200. PubMed DOI

Nam JS, Turcotte TJ, Yoon JK. Dynamic expression of R-spondin family genes in mouse development. Gene Expression Patterns. 2007;7:306–312. doi: 10.1016/j.modgep.2006.08.006. PubMed DOI

Nam S, Chung JW, Yang JY. WNT5A correlates with clinicopathological characteristics in gastric cancer: A meta-analysis. Cellular Physiology and Biochemistry. 2017;41:33–40. doi: 10.1159/000455934. PubMed DOI

Narimatsu M, Bose R, Pye M, Zhang L, Miller B, Ching P, Sakuma R, Luga V, Roncari L, Attisano L, Wrana JL. Regulation of planar cell polarity by Smurf ubiquitin ligases. Cell. 2009;137:295–307. doi: 10.1016/j.cell.2009.02.025. PubMed DOI

Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, Chen Z, Lee M-K, Attar N, Sazegar H, Chodon T, Nelson SF, McArthur G, Sosman JA, Ribas A, Lo RS. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature. 2010;468:973–977. doi: 10.1038/nature09626. PubMed DOI PMC

Neumeyer V, Grandl M, Dietl A, Brutau-Abia A, Allgäuer M, Kalali B, Zhang Y, Pan KF, Steiger K, Vieth M, Anton M, Mejías-Luque R, Gerhard M. Loss of endogenous RNF43 function enhances proliferation and tumour growth of intestinal and gastric cells. Carcinogenesis. 2019a;40:551–559. doi: 10.1093/carcin/bgy152. PubMed DOI

Neumeyer V, Vieth M, Gerhard M, Mejías-Luque R. Mutated RNF43 aggravates helicobacter pylori-induced gastric pathology. Cancers. 2019b;11:E372. doi: 10.3390/cancers11030372. PubMed DOI PMC

Niu L, Qin H-Z, Xi H-Q, Wei B, Xia S-Y, Chen L. RNF43 inhibits cancer cell proliferation and could be a potential prognostic factor for human gastric carcinoma. Cellular Physiology and Biochemistry. 2015;36:1835–1846. doi: 10.1159/000430154. PubMed DOI

Ohkawara B, Glinka A, Niehrs C. RSPO3 binds syndecan 4 and induces Wnt/pcp signaling via clathrin-mediated endocytosis to promote morphogenesis. Developmental Cell. 2011;20:303–314. doi: 10.1016/J.DEVCEL.2011.01.006. PubMed DOI

Ozeki N, Mogi M, Hase N, Hiyama T, Yamaguchi H, Kawai R, Kondo A, Nakata K. Wnt16 signaling is required for il-1β-induced matrix metalloproteinase-13-regulated proliferation of human stem cell-derived osteoblastic cells. International Journal of Molecular Sciences. 2016;17:E221. doi: 10.3390/ijms17020221. PubMed DOI PMC

O’Connell MP, French AD, Leotlela PD, Weeraratna AT. Assaying Wnt5a-Mediated Invasion in Melanoma Cells. Methods in Molecular Biology. 2008;468:243. doi: 10.1007/978-1-59745-249-6_19. PubMed DOI PMC

O’Connell MP, Weeraratna AT. Hear the Wnt ROR: How melanoma cells adjust to changes in Wnt. Pigment Cell & Melanoma Research. 2009;22:724–739. doi: 10.1111/j.1755-148X.2009.00627.x. PubMed DOI PMC

O’Connell MP, Fiori JL, Xu M, Carter AD, Frank BP, Camilli TC, French AD, Dissanayake SK, Indig FE, Bernier M, Taub DD, Hewitt SM, Weeraratna AT. The orphan tyrosine kinase receptor, ror2, mediates wnt5a signaling in metastatic melanoma. Oncogene. 2010;29:34–44. doi: 10.1038/onc.2009.305. PubMed DOI PMC

O’Connell MP, Marchbank K, Webster MR, Valiga AA, Kaur A, Vultur A, Li L, Herlyn M, Villanueva J, Liu Q, Yin X, Widura S, Nelson J, Ruiz N, Camilli TC, Indig FE, Flaherty KT, Wargo JA, Frederick DT, Cooper ZA, Nair S, Amaravadi RK, Schuchter LM, Karakousis GC, Xu W, Xu X, Weeraratna AT. Hypoxia induces phenotypic plasticity and therapy resistance in melanoma via the tyrosine kinase receptors ror1 and ror2. Cancer Discovery. 2013;3:1378–1393. doi: 10.1158/2159-8290.CD-13-0005. PubMed DOI PMC

Paclíková P, Bernatík O, Radaszkiewicz TW, Bryja V. The N-terminal part of the Dishevelled DEP domain is required for Wnt/β- catenin signaling in mammalian cells. Molecular and Cellular Biology. 2017;37:e00145-17. doi: 10.1128/MCB.00145-17. PubMed DOI PMC

Pandur P, Maurus D, Kühl M. Increasingly complex: New players enter the Wnt signaling network. BioEssays. 2002;24:881–884. doi: 10.1002/bies.10164. PubMed DOI

Peek RMJ, Crabtree JE. Helicobacter infection and gastric neoplasia. The Journal of Pathology. 2006;208:233–248. doi: 10.1002/path.1868. PubMed DOI

Peng WC, de Lau W, Madoori PK, Forneris F, Granneman JCM, Clevers H, Gros P. Structures of wnt-antagonist ZNRF3 and its complex with R-spondin 1 and implications for signaling. PLOS ONE. 2013;8:e83110. doi: 10.1371/journal.pone.0083110. PubMed DOI PMC

Perez-Riverol Y, Csordas A, Bai J, Bernal-Llinares M, Hewapathirana S, Kundu DJ, Inuganti A, Griss J, Mayer G, Eisenacher M, Pérez E, Uszkoreit J, Pfeuffer J, Sachsenberg T, Yilmaz S, Tiwary S, Cox J, Audain E, Walzer M, Jarnuczak AF, Ternent T, Brazma A, Vizcaíno JA. The PRIDE database and related tools and resources in 2019: improving support for quantification data. Nucleic Acids Research. 2019;47:D442–D450. doi: 10.1093/nar/gky1106. PubMed DOI PMC

Planas-Paz L, Orsini V, Boulter L, Calabrese D, Pikiolek M, Nigsch F, Xie Y, Roma G, Donovan A, Marti P, Beckmann N, Dill MT, Carbone W, Bergling S, Isken A, Mueller M, Kinzel B, Yang Y, Mao X, Nicholson TB, Zamponi R, Capodieci P, Valdez R, Rivera D, Loew A, Ukomadu C, Terracciano LM, Bouwmeester T, Cong F, Heim MH, Forbes SJ, Ruffner H, Tchorz JS. The RSPO-LGR4/5-ZNRF3/RNF43 module controls liver zonation and size. Nature Cell Biology. 2016;18:467–479. doi: 10.1038/ncb3337. PubMed DOI

Prasad C, Mohapatra P, Andersson T. Therapy for BRAFi-Resistant Melanomas: Is WNT5A the Answer. Cancers. 2015;7:1900–1924. doi: 10.3390/cancers7030868. PubMed DOI PMC

Radaszkiewicz KA, Beckerová D, Woloszczuková L, Radaszkiewicz TW, Lesáková P, Blanářová OV, Kubala L, Humpolíček P, Pachernik J. 12-o-tetradecanoylphorbol-13-acetate increases cardiomyogenesis through PKC/ERK signaling. Scientific Reports. 2020;10:1–13. doi: 10.1038/s41598-020-73074-4. PubMed DOI PMC

Radaszkiewicz T, Bryja V. Protease associated domain of RNF43 is not necessary for the suppression of wnt/β-catenin signaling in human cells. Cell Communication and Signaling. 2020;18:91. doi: 10.1186/s12964-020-00559-0. PubMed DOI PMC

Raiborg C, Bache KG, Mehlum A, Stang E, Stenmark H. Hrs recruits clathrin to early endosomes. The EMBO Journal. 2001;20:5008–5021. doi: 10.1093/emboj/20.17.5008. PubMed DOI PMC

Rambow F, Rogiers A, Marin-Bejar O, Aibar S, Femel J, Dewaele M, Karras P, Brown D, Chang YH, Debiec-Rychter M, Adriaens C, Radaelli E, Wolter P, Bechter O, Dummer R, Levesque M, Piris A, Frederick DT, Boland G, Flaherty KT, van den Oord J, Voet T, Aerts S, Lund AW, Marine JC. Toward minimal residual disease-directed therapy in melanoma. Cell. 2018;174:843–855. doi: 10.1016/J.CELL.2018.06.025. PubMed DOI

Ran FA, Hsu PD, Wright J, Agarwala V, Scott DA, Zhang F. Genome engineering using the crispr-cas9 system. Nature Protocols. 2013;8:2281–2308. doi: 10.1038/nprot.2013.143. PubMed DOI PMC

Rape M. Post-translational modifications: Ubiquitylation at the crossroads of development and disease. Nature Reviews Molecular Cell Biology. 2018;7:128. doi: 10.1038/nrm.2017.83. PubMed DOI

Raudvere U, Kolberg L, Kuzmin I, Arak T, Adler P, Peterson H, Vilo J. g:Profiler: a web server for functional enrichment analysis and conversions of gene lists (2019 update. Nucleic Acids Research. 2019;47:W191–W198. doi: 10.1093/nar/gkz369. PubMed DOI PMC

Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D, Barrette T, Pandey A, Chinnaiyan AM. ONCOMINE: A cancer microarray database and integrated data-mining platform. Neoplasia. 2004;6:1–6. doi: 10.1016/s1476-5586(04)80047-2. PubMed DOI PMC

Roux KJ, Kim DI, Raida M, Burke B. A promiscuous biotin ligase fusion protein identifies proximal and interacting proteins in mammalian cells. The Journal of Cell Biology. 2012;196:801–810. doi: 10.1083/jcb.201112098. PubMed DOI PMC

Ryland GL, Hunter SM, Doyle MA, Rowley SM, Christie M, Allan PE, Bowtell DDL, Australian Ovarian Cancer Study Group. Gorringe KL, Campbell IG. RNF43 is a tumour suppressor gene mutated in mucinous tumours of the ovary. The Journal of Pathology. 2013;229:469–476. doi: 10.1002/path.4134. PubMed DOI

Sadeghi RS, Kulej K, Kathayat RS, Garcia BA, Dickinson BC, Brady DC, Witze ES. Wnt5a signaling induced phosphorylation increases apt1 activity and promotes melanoma metastatic behavior. eLife. 2018;7:e34362. doi: 10.7554/eLife.34362. PubMed DOI PMC

Saitoh T, Mine T, Katoh M. Frequent up-regulation of WNT5A mrna in primary gastric cancer. International Journal of Molecular Medicine. 2002;9:515–519. doi: 10.3892/ijmm.9.5.515. PubMed DOI

Sammar M, Stricker S, Schwabe GC, Sieber C, Hartung A, Hanke M, Oishi I, Pohl J, Minami Y, Sebald W, Mundlos S, Knaus P. Modulation of GDF5/BRI-B signalling through interaction with the tyrosine kinase receptor ROR2. Genes to Cells. 2004;9:1227–1238. doi: 10.1111/j.1365-2443.2004.00799.x. PubMed DOI

Sandru A, Voinea S, Panaitescu E, Blidaru A. Survival rates of patients with metastatic malignant melanoma. Journal of Medicine and Life. 2014;7:572–576. PubMed PMC

Santolini E, Puri C, Salcini AE, Gagliani MC, Pelicci PG, Tacchetti C, Di Fiore PP. Numb is an endocytic protein. The Journal of Cell Biology. 2000;151:1345–1352. doi: 10.1083/jcb.151.6.1345. PubMed DOI PMC

Schmitt M, Sinnberg T, Nalpas NC, Maass A, Schittek B, Macek B. Quantitative proteomics links the intermediate filament nestin to resistance to targeted braf inhibition in melanoma cells. Molecular & Cellular Proteomics. 2019;18:1096–1109. doi: 10.1074/mcp.RA119.001302. PubMed DOI PMC

Seet LF, Hong W. Endofin recruits clathrin to early endosomes via tom1. Journal of Cell Science. 2005;118:575–587. doi: 10.1242/jcs.01628. PubMed DOI

Sensi M, Catani M, Castellano G, Nicolini G, Alciato F, Tragni G, De Santis G, Bersani I, Avanzi G, Tomassetti A, Canevari S, Anichini A. Human cutaneous melanomas lacking MITF and melanocyte differentiation antigens express a functional AXL receptor kinase. The Journal of Investigative Dermatology. 2011;131:2448–2457. doi: 10.1038/JID.2011.218. PubMed DOI

Seo HS, Habas R, Chang C, Wang J. Bimodal regulation of dishevelled function by vangl2 during morphogenesis. Human Molecular Genetics. 2017;26:2053–2061. doi: 10.1093/hmg/ddx095. PubMed DOI PMC

Shain AH, Yeh I, Kovalyshyn I, Sriharan A, Talevich E, Gagnon A, Dummer R, North J, Pincus L, Ruben B, Rickaby W, D’Arrigo C, Robson A, Bastian BC. The genetic evolution of melanoma from precursor lesions. The New England Journal of Medicine. 2015;373:1926–1936. doi: 10.1056/NEJMoa1502583. PubMed DOI

Signorelli J, Shah Gandhi A. Cobimetinib: A novel MEK inhibitor for metastatic melanoma. The Annals of Pharmacotherapy. 2017;51:146–153. doi: 10.1177/1060028016672037. PubMed DOI

Spit M, Fenderico N, Jordens I, Radaszkiewicz T, Lindeboom RG, Bugter JM, Cristobal A, Ootes L, van Osch M, Janssen E, Boonekamp KE, Hanakova K, Potesil D, Zdrahal Z, Boj SF, Medema JP, Bryja V, Koo B-K, Vermeulen M, Maurice MM. RNF43 truncations trap CK1 to drive niche-independent self-renewal in cancer. The EMBO Journal. 2020;39:e103932. doi: 10.15252/embj.2019103932. PubMed DOI PMC

Štětková M, Growková K, Fojtík P, Valčíková B, Palušová V, Verlande A, Jorda R, Kryštof V, Hejret V, Alexiou P, Rotrekl V, Uldrijan S. Cdk9 activity is critical for maintaining mdm4 overexpression in tumor cells. Cell Death & Disease. 2020;11:754. doi: 10.1038/s41419-020-02971-3. PubMed DOI PMC

Su Y, Wei W, Robert L, Xue M, Tsoi J, Garcia-Diaz A, Homet Moreno B, Kim J, Ng RH, Lee JW, Koya RC, Comin-Anduix B, Graeber TG, Ribas A, Heath JR. Single-cell analysis resolves the cell state transition and signaling dynamics associated with melanoma drug-induced resistance. PNAS. 2017;114:13679–13684. doi: 10.1073/pnas.1712064115. PubMed DOI PMC

Su Y, Ko ME, Cheng H, Zhu R, Xue M, Wang J, Lee JW, Frankiw L, Xu A, Wong S, Robert L, Takata K, Yuan D, Lu Y, Huang S, Ribas A, Levine R, Nolan GP, Wei W, Plevritis SK, Li G, Baltimore D, Heath JR. Multi-omic single-cell snapshots reveal multiple independent trajectories to drug tolerance in a melanoma cell line. Nature Communications. 2020;11:2345. doi: 10.1038/s41467-020-15956-9. PubMed DOI PMC

Szenker-Ravi E, Altunoglu U, Leushacke M, Bosso-Lefèvre C, Khatoo M, Thi Tran H, Naert T, Noelanders R, Hajamohideen A, Beneteau C, de Sousa SB, Karaman B, Latypova X, Başaran S, Yücel EB, Tan TT, Vlaminck L, Nayak SS, Shukla A, Girisha KM, Le Caignec C, Soshnikova N, Uyguner ZO, Vleminckx K, Barker N, Kayserili H, Reversade B. Rspo2 inhibition of RNF43 and znrf3 governs limb development independently of lgr4/5/6. Nature. 2018;557:564–569. doi: 10.1038/s41586-018-0118-y. PubMed DOI

Takahashi N, Yamaguchi K, Ikenoue T, Fujii T, Furukawa Y. Identification of two wnt-responsive elements in the intron of RING finger protein 43 (rnf43) gene. PLOS ONE. 2014;9:e86582. doi: 10.1371/journal.pone.0086582. PubMed DOI PMC

Talantov D, Mazumder A, Yu JX, Briggs T, Jiang Y, Backus J, Atkins D, Wang Y. Novel genes associated with malignant melanoma but not benign melanocytic lesions. Clinical Cancer Research. 2005;11:7234–7242. doi: 10.1158/1078-0432.CCR-05-0683. PubMed DOI

Talebi A, Dehairs J, Rambow F, Rogiers A, Nittner D, Derua R, Vanderhoydonc F, Duarte JAG, Bosisio F, Van den Eynde K, Nys K, Pérez MV, Agostinis P, Waelkens E, Van den Oord J, Fendt S-M, Marine J-C, Swinnen JV. Sustained srebp-1-dependent lipogenesis as a key mediator of resistance to braf-targeted therapy. Nature Communications. 2018;9:2500. doi: 10.1038/s41467-018-04664-0. PubMed DOI PMC

Tauriello DVF, Haegebarth A, Kuper I, Edelmann MJ, Henraat M, Canninga-van Dijk MR, Kessler BM, Clevers H, Maurice MM. Loss of the Tumor Suppressor CYLD Enhances Wnt/β-Catenin Signaling through K63-Linked Ubiquitination of Dvl. Molecular Cell. 2010;37:607–619. doi: 10.1016/J.MOLCEL.2010.01.035. PubMed DOI

Tebar F, Bohlander SK, Sorkin A. Clathrin assembly lymphoid myeloid leukemia (CALM) protein: Localization in endocytic-coated pits, interactions with clathrin, and the impact of overexpression on clathrin-mediated traffic. Molecular Biology of the Cell. 1999;10:2687–2702. doi: 10.1091/mbc.10.8.2687. PubMed DOI PMC

Tirosh I, Izar B, Prakadan SM, Wadsworth MH, Treacy D, Trombetta JJ, Rotem A, Rodman C, Lian C, Murphy G, Fallahi-Sichani M, Dutton-Regester K, Lin JR, Cohen O, Shah P, Lu D, Genshaft AS, Hughes TK, Ziegler CGK, Kazer SW, Gaillard A, Kolb KE, Villani AC, Johannessen CM, Andreev AY, Van Allen EM, Bertagnolli M, Sorger PK, Sullivan RJ, Flaherty KT, Frederick DT, Jane-Valbuena J, Yoon CH, Rozenblatt-Rosen O, Shalek AK, Regev A, Garraway LA. Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. Science. 2016;352:189–196. doi: 10.1126/science.aad0501. PubMed DOI PMC

Tiwary S, Xu L. FRIZZLED7 Is Required for Tumor Initiation and Metastatic Growth of Melanoma Cells. PLOS ONE. 2016;11:e0147638. doi: 10.1371/journal.pone.0147638. PubMed DOI PMC

Tower-Gilchrist C, Zlatic SA, Yu D, Chang Q, Wu H, Lin X, Faundez V, Chen P. Adaptor protein-3 complex is required for vangl2 trafficking and planar cell polarity of the inner ear. Molecular Biology of the Cell. 2019;30:2422–2434. doi: 10.1091/mbc.E16-08-0592. PubMed DOI PMC

Tsukiyama T, Fukui A, Terai S, Fujioka Y, Shinada K, Takahashi H, Yamaguchi TP, Ohba Y, Hatakeyama S. Molecular role of RNF43 in canonical and noncanonical wnt signaling. Molecular and Cellular Biology. 2015;35:2007–2023. doi: 10.1128/MCB.00159-15. PubMed DOI PMC

Tsukiyama T, Zou J, Kim J, Ogamino S, Shino Y, Masuda T, Merenda A, Matsumoto M, Fujioka Y, Hirose T, Terai S, Takahashi H, Ishitani T, Nakayama KI, Ohba Y, Koo BK, Hatakeyama S. A phospho-switch controls rnf43-mediated degradation of WNT receptors to suppress tumorigenesis. Nature Communications. 2020;11:4586. doi: 10.1038/s41467-020-18257-3. PubMed DOI PMC

Uka R, Britschgi C, Krättli A, Matter C, Mihic D, Okoniewski MJ, Gualandi M, Stupp R, Cinelli P, Dummer R, Levesque MP, Shakhova O. Temporal activation of wnt/β-catenin signaling is sufficient to inhibit sox10 expression and block melanoma growth. Oncogene. 2020;39:4132–4154. doi: 10.1038/s41388-020-1267-7. PubMed DOI PMC

Ullrich O, Reinsch S, Urbé S, Zerial M, Parton RG. RAB11 regulates recycling through the pericentriolar recycling endosome. The Journal of Cell Biology. 1996;135:913–924. doi: 10.1083/jcb.135.4.913. PubMed DOI PMC

Van Engelenburg SB, Palmer AE. Imaging type-iii secretion reveals dynamics and spatial segregation of salmonella effectors. Nature Methods. 2010;7:325–330. doi: 10.1038/nmeth.1437. PubMed DOI PMC

van Kappel EC, Maurice MM. Molecular regulation and pharmacological targeting of the β-catenin destruction complex. British Journal of Pharmacology. 2017;174:4575–4588. doi: 10.1111/bph.13922. PubMed DOI PMC

VanderVorst K, Dreyer CA, Konopelski SE, Lee H, Ho HYH, Carraway KL. Wnt/pcp signaling contribution to carcinoma collective cell migration and metastasis. Cancer Research. 2019;79:1719–1729. doi: 10.1158/0008-5472.CAN-18-2757. PubMed DOI PMC

Wan PTC, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D, Good VM, Jones CM, Marshall CJ, Springer CJ, Barford D, Marais R, Cancer Genome Project Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell. 2004;116:855–867. doi: 10.1016/S0092-8674(04)00215-6. PubMed DOI

Wang VE, Xue JY, Frederick DT, Cao Y, Lin E, Wilson C, Urisman A, Carbone DP, Flaherty KT, Bernards R, Lito P, Settleman J, McCormick F. Adaptive resistance to dual BRAF/MEK inhibition in braf-driven tumors through autocrine FGFR pathway activation. Clinical Cancer Research. 2019;25:7202–7217. doi: 10.1158/1078-0432.CCR-18-2779. PubMed DOI PMC

Webster MR, Weeraratna AT. A wnt-er migration: The confusing role of β-catenin in melanoma metastasis. Science Signaling. 2013;6:pe11. doi: 10.1126/scisignal.2004114. PubMed DOI

Webster MR, Xu M, Kinzler KA, Kaur A, Appleton J, O’Connell MP, Marchbank K, Valiga A, Dang VM, Perego M, Zhang G, Slipicevic A, Keeney F, Lehrmann E, Becker KG, Kossenkov AV, Frederick DT, Flaherty KT, Xu X, Herlyn M, Murphy ME, Weeraratna AT. WNT5A promotes an adaptive, senescent-like stress response, while continuing to drive invasion in melanoma cells. Pigment Cell & Melanoma Research. 2015;28:184–195. doi: 10.1111/pcmr.12330. PubMed DOI PMC

Weeber F, Becher A, Seibold T, Seufferlein T, Eiseler T. Concerted regulation of actin polymerization during constitutive secretion by cortactin and pkd2. Journal of Cell Science. 2019;132:jcs232355. doi: 10.1242/jcs.232355. PubMed DOI

Weeraratna AT, Jiang Y, Hostetter G, Rosenblatt K, Duray P, Bittner M, Trent JM. WNT5A signaling directly affects cell motility and invasion of metastatic melanoma. Cancer Cell. 2002;1:279–288. doi: 10.1016/S1535-6108(02)00045-4. PubMed DOI

Wiese KE, Nusse R. Wnt signalling: Conquering complexity. Development. 2018;145:dev165902. doi: 10.1242/dev.165902. PubMed DOI

Witte F, Bernatik O, Kirchner K, Masek J, Mahl A, Krejci P, Mundlos S, Schambony A, Bryja V, Stricker S. Negative regulation of Wnt signaling mediated by CK1-phosphorylated Dishevelled via Ror2. FASEB Journal. 2010;24:2417–2426. doi: 10.1096/fj.09-150615. PubMed DOI

Xie Y, Zamponi R, Charlat O, Ramones M, Swalley S, Jiang X, Rivera D, Tschantz W, Lu B, Quinn L, Dimitri C, Parker J, Jeffery D, Wilcox SK, Watrobka M, LeMotte P, Granda B, Porter JA, Myer VE, Loew A, Cong F. Interaction with both ZNRF3 and LGR4 is required for the signalling activity of r-spondin. EMBO Reports. 2013;14:1120–1126. doi: 10.1038/embor.2013.167. PubMed DOI PMC

Xu L, Shen SS, Hoshida Y, Subramanian A, Ross K, Brunet JP, Wagner SN, Ramaswamy S, Mesirov JP, Hynes RO. Gene expression changes in an animal melanoma model correlate with aggressiveness of human melanoma metastases. Molecular Cancer Research. 2008;6:760–769. doi: 10.1158/1541-7786.MCR-07-0344. PubMed DOI PMC

Yan HHN, Lai JCW, Ho SL, Leung WK, Law WL, Lee JFY, Chan AKW, Tsui WY, Chan ASY, Lee BCH, Yue SSK, Man AHY, Clevers H, Yuen ST, Leung SY. RNF43 germline and somatic mutation in serrated neoplasia pathway and its association with BRAF mutation. Gut. 2017;66:1645–1656. doi: 10.1136/gutjnl-2016-311849. PubMed DOI

Yang W, Garrett L, Feng D, Elliott G, Liu X, Wang N, Wong YM, Choi NT, Yang Y, Gao B. Wnt-induced vangl2 phosphorylation is dose-dependently required for planar cell polarity in mammalian development. Cell Research. 2017;27:1466–1484. doi: 10.1038/cr.2017.127. PubMed DOI PMC

Zebisch M, Xu Y, Krastev C, MacDonald BT, Chen M, Gilbert RJC, He X, Jones EY. Structural and molecular basis of ZNRF3/RNF43 transmembrane ubiquitin ligase inhibition by the WNT agonist R-spondin. Nature Communications. 2013;4:2787. doi: 10.1038/ncomms3787. PubMed DOI PMC

Zebisch M, Jones EY. ZNRF3/RNF43--A direct linkage of extracellular recognition and E3 ligase activity to modulate cell surface signalling. Progress in Biophysics and Molecular Biology. 2015;118:112–118. doi: 10.1016/J.PBIOMOLBIO.2015.04.006. PubMed DOI

Intestinal Paneth cell differentiation relies on asymmetric regulation of Wnt signaling by Daam1/2

Hierarchically Structured Polystyrene-Based Surfaces Amplifying Fluorescence Signals: Cytocompatibility with Human Induced Pluripotent Stem Cell