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Extracellular WNTs: Trafficking, Exosomes, and Ligand–Receptor Interaction

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Pharmacology of the WNT Signaling System

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 269))

Abstract

WNT signaling is a key developmental pathway in tissue organization. A recent focus of research is the secretion of WNT proteins from source cells. Research over the past decade on how WNTs are produced and released into the extracellular space has unravelled very specific control mechanisms in the early secretory pathway, specialized trafficking routes, and redundant forms of packaging for delivery to target cells. In this review I discuss the findings that WNT proteins have been found on extracellular vesicles (EVs) such as exosomes and possible functional implications. There is an ongoing debate in the WNT signaling field whether EV are relevant in vivo and can fulfill specific functions, also fueled by the general preconception of EV secretion as cellular garbage disposal. As part of the EV research community, I want to give an overview of what we know and don’t know about WNT secretion on EVs and offer a more unifying model that can explain current discrepancies in observations regarding WNT secretion.

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References

  • Acebron SP, Karaulanov E, Berger BS, Huang YL, Niehrs C (2014) Mitotic Wnt signaling promotes protein stabilization and regulates cell size. Mol Cell 54:663–674

    CAS  PubMed  Google Scholar 

  • Albrecht LV, Tejeda-Munoz N, Bui MH, Cicchetto AC, Di Biagio D, Colozza G, Schmid E, Piccolo S, Christofk HR, De Robertis EM (2020) GSK3 inhibits macropinocytosis and lysosomal activity through the Wnt destruction complex machinery. Cell Rep 32:107973

    CAS  PubMed  PubMed Central  Google Scholar 

  • Alexandre C, Baena-Lopez A, Vincent JP (2014) Patterning and growth control by membrane-tethered wingless. Nature 505:180–185

    CAS  PubMed  Google Scholar 

  • Baietti MF, Zhang Z, Mortier E, Melchior A, Degeest G, Geeraerts A, Ivarsson Y, Depoortere F, Coomans C, Vermeiren E, Zimmermann P, David G (2012) Syndecan-syntenin-ALIX regulates the biogenesis of exosomes. Nat Cell Biol 14:677–685

    CAS  PubMed  Google Scholar 

  • Banfer S, Schneider D, Dewes J, Strauss MT, Freibert SA, Heimerl T, Maier UG, Elsasser HP, Jungmann R, Jacob R (2018) Molecular mechanism to recruit galectin-3 into multivesicular bodies for polarized exosomal secretion. Proc Natl Acad Sci U S A 115:E4396–E4405

    PubMed  PubMed Central  Google Scholar 

  • Beckett K, Monier S, Palmer L, Alexandre C, Green H, Bonneil E, Raposo G, Thibault P, Le Borgne R, Vincent JP (2013) Drosophila S2 cells secrete wingless on exosome-like vesicles but the wingless gradient forms independently of exosomes. Traffic 14:82–96

    CAS  PubMed  Google Scholar 

  • Belenkaya TY, Wu Y, Tang X, Zhou B, Cheng L, Sharma YV, Yan D, Selva EM, Lin X (2008) The retromer complex influences Wnt secretion by recycling wntless from endosomes to the trans-Golgi network. Dev Cell 14:120–131

    CAS  PubMed  Google Scholar 

  • Bischoff M, Gradilla AC, Seijo I, Andres G, Rodriguez-Navas C, Gonzalez-Mendez L, Guerrero I (2013) Cytonemes are required for the establishment of a normal Hedgehog morphogen gradient in Drosophila epithelia. Nat Cell Biol 15:1269–1281

    CAS  PubMed  Google Scholar 

  • Buechling T, Chaudhary V, Spirohn K, Weiss M, Boutros M (2011) p24 proteins are required for secretion of Wnt ligands. EMBO Rep 12:1265–1272

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chaudhary V, Boutros M (2019) Exocyst-mediated apical Wg secretion activates signaling in the Drosophila wing epithelium. PLoS Genet 15:e1008351

    PubMed  PubMed Central  Google Scholar 

  • Chaudhary V, Hingole S, Frei J, Port F, Strutt D, Boutros M (2019) Robust Wnt signaling is maintained by a Wg protein gradient and Fz2 receptor activity in the developing Drosophila wing. Development 146(15):dev174789

    CAS  PubMed  PubMed Central  Google Scholar 

  • Christianson HC, Svensson KJ, van Kuppevelt TH, Li JP, Belting M (2013) Cancer cell exosomes depend on cell-surface heparan sulfate proteoglycans for their internalization and functional activity. Proc Natl Acad Sci U S A 110:17380–17385

    CAS  PubMed  PubMed Central  Google Scholar 

  • Coombs GS, Yu J, Canning CA, Veltri CA, Covey TM, Cheong JK, Utomo V, Banerjee N, Zhang ZH, Jadulco RC, Concepcion GP, Bugni TS, Harper MK, Mihalek I, Jones CM, Ireland CM, Virshup DM (2010) WLS-dependent secretion of WNT3A requires Ser209 acylation and vacuolar acidification. J Cell Sci 123:3357–3367

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cruciat CM, Ohkawara B, Acebron SP, Karaulanov E, Reinhard C, Ingelfinger D, Boutros M, Niehrs C (2010) Requirement of prorenin receptor and vacuolar H+-ATPase-mediated acidification for Wnt signaling. Science 327:459–463

    CAS  PubMed  Google Scholar 

  • D'Angelo G, Matusek T, Pizette S, Therond PP (2015) Endocytosis of Hedgehog through dispatched regulates long-range signaling. Dev Cell 32:290–303

    CAS  PubMed  Google Scholar 

  • Dhamdhere GR, Fang MY, Jiang J, Lee K, Cheng D, Olveda RC, Liu B, Mulligan KA, Carlson JC, Ransom RC, Weis WI, Helms JA (2014) Drugging a stem cell compartment using Wnt3a protein as a therapeutic. PLoS One 9:e83650

    PubMed  PubMed Central  Google Scholar 

  • Dubois L, Lecourtois M, Alexandre C, Hirst E, Vincent JP (2001) Regulated endocytic routing modulates wingless signaling in Drosophila embryos. Cell 105:613–624

    CAS  PubMed  Google Scholar 

  • Farin HF, Jordens I, Mosa MH, Basak O, Korving J, Tauriello DV, de Punder K, Angers S, Peters PJ, Maurice MM, Clevers H (2016) Visualization of a short-range Wnt gradient in the intestinal stem-cell niche. Nature 530(7590):340–343. https://doi.org/10.1038/nature16937. Epub 2016 Feb 10. PMID: 26863187

    Article  CAS  PubMed  Google Scholar 

  • Gasnereau I, Herr P, Chia PZ, Basler K, Gleeson PA (2011) Identification of an endocytosis motif in an intracellular loop of Wntless protein, essential for its recycling and the control of Wnt protein signaling. J Biol Chem 286:43324–43333

    CAS  PubMed  PubMed Central  Google Scholar 

  • Glaeser K, Urban M, Fenech E, Voloshanenko O, Kranz D, Lari F, Christianson JC, Boutros M (2018) ERAD-dependent control of the Wnt secretory factor Evi. EMBO J 37(4):e97311

    PubMed  PubMed Central  Google Scholar 

  • Gonzalez-Mendez L, Seijo-Barandiaran I, Guerrero I (2017) Cytoneme-mediated cell-cell contacts for Hedgehog reception. elife 6:e24045

    PubMed  PubMed Central  Google Scholar 

  • Gradilla AC, Gonzalez E, Seijo I, Andres G, Bischoff M, Gonzalez-Mendez L, Sanchez V, Callejo A, Ibanez C, Guerra M, Ortigao-Farias JR, Sutherland JD, Gonzalez M, Barrio R, Falcon-Perez JM, Guerrero I (2014) Exosomes as Hedgehog carriers in cytoneme-mediated transport and secretion. Nat Commun 5:5649

    CAS  PubMed  Google Scholar 

  • Greco V, Hannus M, Eaton S (2001) Argosomes: a potential vehicle for the spread of morphogens through epithelia. Cell 106:633–645

    CAS  PubMed  Google Scholar 

  • Gross JC, Chaudhary V, Bartscherer K, Boutros M (2012) Active Wnt proteins are secreted on exosomes. Nat Cell Biol 14:1036–1045

    CAS  PubMed  Google Scholar 

  • Guo H, Chitiprolu M, Roncevic L, Javalet C, Hemming FJ, Trung MT, Meng L, Latreille E, Tanese de Souza C, McCulloch D, Baldwin RM, Auer R, Cote J, Russell RC, Sadoul R, Gibbings D (2017) Atg5 disassociates the V1V0-ATPase to promote exosome production and tumor metastasis independent of canonical macroautophagy. Dev Cell 43:716–730.e717

    CAS  PubMed  Google Scholar 

  • Hammond GL (2016) Plasma steroid-binding proteins: primary gatekeepers of steroid hormone action. J Endocrinol 230:R13–R25

    CAS  PubMed  PubMed Central  Google Scholar 

  • Harterink M, Port F, Lorenowicz MJ, McGough IJ, Silhankova M, Betist MC, van Weering JRT, van Heesbeen R, Middelkoop TC, Basler K, Cullen PJ, Korswagen HC (2011) A SNX3-dependent retromer pathway mediates retrograde transport of the Wnt sorting receptor Wntless and is required for Wnt secretion. Nat Cell Biol 13:914–923

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hatori RK, Kornberg TB (2020) Regulated delivery controls drosophila hedgehog, wingless and decapentaplegic signaling. bioRxiv. https://doi.org/10.1101/2020.08.12.247759

  • Hatori R, Wood BM, Oliveira Barbosa G, Kornberg TB (2021) Regulated delivery controls Drosophila Hedgehog Wingless and decapentaplegic signaling. Elife 10:e71744. 57554/eLife.71744. Online ahead of print. PMID: 34292155

    Google Scholar 

  • Hemalatha A, Prabhakara C, Mayor S (2016) Endocytosis of wingless via a dynamin-independent pathway is necessary for signaling in Drosophila wing discs. Proc Natl Acad Sci U S A 113:E6993–E7002

    CAS  PubMed  PubMed Central  Google Scholar 

  • Herr P, Hausmann G, Basler K (2012) WNT secretion and signalling in human disease. Trends Mol Med 18:483–493

    CAS  PubMed  Google Scholar 

  • Huang H, Kornberg TB (2015) Myoblast cytonemes mediate Wg signaling from the wing imaginal disc and Delta-notch signaling to the air sac primordium. elife 4:e06114

    PubMed  PubMed Central  Google Scholar 

  • Humphries AC, Mlodzik M (2018) From instruction to output: Wnt/PCP signaling in development and cancer. Curr Opin Cell Biol 51:110–116

    CAS  PubMed  Google Scholar 

  • Janda CY, Waghray D, Levin AM, Thomas C, Garcia KC (2012) Structural basis of Wnt recognition by frizzled. Science 337:59–64

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kaiser K, Gyllborg D, Prochazka J, Salasova A, Kompanikova P, Molina FL, Laguna-Goya R, Radaszkiewicz T, Harnos J, Prochazkova M, Potesil D, Barker RA, Casado AG, Zdrahal Z, Sedlacek R, Arenas E, Villaescusa JC, Bryja V (2019) WNT5A is transported via lipoprotein particles in the cerebrospinal fluid to regulate hindbrain morphogenesis. Nat Commun 10:1498

    PubMed  PubMed Central  Google Scholar 

  • Kim H, Vick P, Hedtke J, Ploper D, De Robertis EM (2015) Wnt signaling translocates Lys48-linked polyubiquitinated proteins to the lysosomal pathway. Cell Rep 11:1151–1159

    CAS  PubMed  Google Scholar 

  • Koch S, Acebron SP, Herbst J, Hatiboglu G, Niehrs C (2015) Post-transcriptional Wnt signaling governs epididymal sperm maturation. Cell 163:1225–1236

    CAS  PubMed  Google Scholar 

  • Koles K, Nunnari J, Korkut C, Barria R, Brewer C, Li Y, Leszyk J, Zhang B, Budnik V (2012) Mechanism of evenness interrupted (Evi)-exosome release at synaptic boutons. J Biol Chem 287:16820–16834

    CAS  PubMed  PubMed Central  Google Scholar 

  • Korkut C, Ataman B, Ramachandran P, Ashley J, Barria R, Gherbesi N, Budnik V (2009) Trans-synaptic transmission of vesicular Wnt signals through Evi/Wntless. Cell 139:393–404

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kramer-Albers EM, Bretz N, Tenzer S, Winterstein C, Mobius W, Berger H, Nave KA, Schild H, Trotter J (2007) Oligodendrocytes secrete exosomes containing major myelin and stress-protective proteins: trophic support for axons? Proteomics Clin Appl 1:1446–1461

    PubMed  Google Scholar 

  • Lin YC, Haas A, Bufe A, Parbin S, Hennecke M, Voloshanenko O, Gross J, Boutros M, Acebron SP, Bastians H (2021) Wnt10b-GSK3beta-dependent Wnt/STOP signaling prevents aneuploidy in human somatic cells. Life Sci Alliance 4:e202000855

    CAS  PubMed  Google Scholar 

  • Linnemannstons K, Witte L, Karuna MP, Kittel JC, Danieli A, Muller D, Nitsch L, Honemann-Capito M, Grawe F, Wodarz A, Gross JC (2020) Ykt6-dependent endosomal recycling is required for Wnt secretion in the Drosophila wing epithelium. Development 147(15):dev185421

    PubMed  PubMed Central  Google Scholar 

  • Luga V, Zhang L, Viloria-Petit AM, Ogunjimi AA, Inanlou MR, Chiu E, Buchanan M, Hosein AN, Basik M, Wrana JL (2012) Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration. Cell 151:1542–1556

    CAS  PubMed  Google Scholar 

  • Marois E, Mahmoud A, Eaton S (2006) The endocytic pathway and formation of the wingless morphogen gradient. Development 133:307–317

    CAS  PubMed  Google Scholar 

  • Matsu-Ura T, Dovzhenok A, Aihara E, Rood J, Le H, Ren Y, Rosselot AE, Zhang T, Lee C, Obrietan K, Montrose MH, Lim S, Moore SR, Hong CI (2016) Intercellular coupling of the cell cycle and circadian clock in adult stem cell culture. Mol Cell 64:900–912

    CAS  PubMed  PubMed Central  Google Scholar 

  • McGough IJ, Vecchia L, Bishop B, Malinauskas T, Beckett K, Joshi D, O'Reilly N, Siebold C, Jones EY, Vincent JP (2020) Glypicans shield the Wnt lipid moiety to enable signalling at a distance. Nature 585:85–90

    CAS  PubMed  PubMed Central  Google Scholar 

  • Melo SA, Luecke LB, Kahlert C, Fernandez AF, Gammon ST, Kaye J, LeBleu VS, Mittendorf EA, Weitz J, Rahbari N, Reissfelder C, Pilarsky C, Fraga MF, Piwnica-Worms D, Kalluri R (2015) Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature 523:177–182

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mihara E, Hirai H, Yamamoto H, Tamura-Kawakami K, Matano M, Kikuchi A, Sato T, Takagi J (2016) Active and water-soluble form of lipidated Wnt protein is maintained by a serum glycoprotein afamin/alpha-albumin. elife 5:e11621

    PubMed  PubMed Central  Google Scholar 

  • Najdi R, Proffitt K, Sprowl S, Kaur S, Yu J, Covey TM, Virshup DM, Waterman ML (2012) A uniform human Wnt expression library reveals a shared secretory pathway and unique signaling activities. Differentiation 84:203–213

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nakato H, Li JP (2016) Functions of heparan sulfate proteoglycans in development: insights from drosophila models. Int Rev Cell Mol Biol 325:275–293

    CAS  PubMed  Google Scholar 

  • Naschberger A, Orry A, Lechner S, Bowler MW, Nurizzo D, Novokmet M, Keller MA, Oemer G, Seppi D, Haslbeck M, Pansi K, Dieplinger H, Rupp B (2017) Structural evidence for a role of the multi-functional human glycoprotein afamin in Wnt transport. Structure 25:1907–1915.e1905

    CAS  PubMed  Google Scholar 

  • Neumann S, Coudreuse DY, van der Westhuyzen DR, Eckhardt ER, Korswagen HC, Schmitz G, Sprong H (2009) Mammalian Wnt3a is released on lipoprotein particles. Traffic 10:334–343

    CAS  PubMed  Google Scholar 

  • Niehrs C (2012) The complex world of WNT receptor signalling. Nat Rev Mol Cell Biol 13:767–779

    CAS  PubMed  Google Scholar 

  • Nusse R, Clevers H (2017) Wnt/beta-catenin signaling, disease, and emerging therapeutic modalities. Cell 169:985–999

    CAS  PubMed  Google Scholar 

  • Nygaard R, Yu J, Kim J, Ross DR, Parisi G, Clarke OB, Virshup DM, Mancia F (2021) Structural basis of WLS/Evi-mediated Wnt transport and secretion. Cell 184:194–206.e114

    CAS  PubMed  Google Scholar 

  • Panakova D, Sprong H, Marois E, Thiele C, Eaton S (2005) Lipoprotein particles are required for hedgehog and wingless signalling. Nature 435:58–65

    CAS  PubMed  Google Scholar 

  • Pfeiffer S, Ricardo S, Manneville JB, Alexandre C, Vincent JP (2002) Producing cells retain and recycle wingless in drosophila embryos. Curr Biol 12:957–962

    CAS  PubMed  Google Scholar 

  • Port F, Kuster M, Herr P, Furger E, Banziger C, Hausmann G, Basler K (2008) Wingless secretion promotes and requires retromer-dependent cycling of Wntless. Nat Cell Biol 10:178–185

    CAS  PubMed  Google Scholar 

  • Port F, Hausmann G, Basler K (2011) A genome-wide RNA interference screen uncovers two p24 proteins as regulators of wingless secretion. EMBO Rep 12:1144–1152

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rahbari M, Pecqueux M, Aust D, Stephan H, Tiebel O, Chatzigeorgiou A, Tonn T, Baenke F, Rao V, Ziegler N, Greif H, Lin K, Weitz J, Rahbari NN, Kahlert C (2019) Expression of glypican 3 is an independent prognostic biomarker in primary gastro-esophageal adenocarcinoma and corresponding serum exosomes. J Clin Med 8. https://doi.org/10.3390/jcm8050696

  • Saric A, Freeman SA (2020) Endomembrane tension and trafficking. Front Cell Dev Biol 8:611326

    PubMed  Google Scholar 

  • Seto ES, Bellen HJ (2006) Internalization is required for proper wingless signaling in Drosophila melanogaster. J Cell Biol 173:95–106

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sonnen KF, Lauschke VM, Uraji J, Falk HJ, Petersen Y, Funk MC, Beaupeux M, Francois P, Merten CA, Aulehla A (2018) Modulation of phase shift between Wnt and notch signaling oscillations controls mesoderm segmentation. Cell 172:1079–1090.e1012

    CAS  PubMed  PubMed Central  Google Scholar 

  • Stanganello E, Scholpp S (2016) Role of cytonemes in Wnt transport. J Cell Sci 129:665–672

    CAS  PubMed  Google Scholar 

  • Stanganello E, Hagemann AI, Mattes B, Sinner C, Meyen D, Weber S, Schug A, Raz E, Scholpp S (2015) Filopodia-based Wnt transport during vertebrate tissue patterning. Nat Commun 6:5846

    CAS  PubMed  Google Scholar 

  • Stapornwongkul KS, de Gennes M, Cocconi L, Salbreux G, Vincent JP (2020) Patterning and growth control in vivo by an engineered GFP gradient. Science 370:321–327

    CAS  PubMed  PubMed Central  Google Scholar 

  • Strigini M, Cohen SM (2000) Wingless gradient formation in the Drosophila wing. Curr Biol 10:293–300

    CAS  PubMed  Google Scholar 

  • Sun J, Yu S, Zhang X, Capac C, Aligbe O, Daudelin T, Bonder EM, Gao N (2017) A Wntless-SEC12 complex on the ER membrane regulates early Wnt secretory vesicle assembly and mature ligand export. J Cell Sci 130:2159–2171

    CAS  PubMed  PubMed Central  Google Scholar 

  • Taelman VF, Dobrowolski R, Plouhinec JL, Fuentealba LC, Vorwald PP, Gumper I, Sabatini DD, De Robertis EM (2010) Wnt signaling requires sequestration of glycogen synthase kinase 3 inside multivesicular endosomes. Cell 143:1136–1148

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tanaka K, Okabayashi K, Asashima M, Perrimon N, Kadowaki T (2000) The evolutionarily conserved porcupine gene family is involved in the processing of the Wnt family. Eur J Biochem 267:4300–4311

    CAS  PubMed  Google Scholar 

  • Tassew NG, Charish J, Shabanzadeh AP, Luga V, Harada H, Farhani N, D'Onofrio P, Choi B, Ellabban A, Nickerson PEB, Wallace VA, Koeberle PD, Wrana JL, Monnier PP (2017) Exosomes mediate mobilization of autocrine Wnt10b to promote axonal regeneration in the injured CNS. Cell Rep 20:99–111

    CAS  PubMed  Google Scholar 

  • Tejeda-Munoz N, Albrecht LV, Bui MH, De Robertis EM (2019) Wnt canonical pathway activates macropinocytosis and lysosomal degradation of extracellular proteins. Proc Natl Acad Sci U S A 116:10402–10411

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tian A, Duwadi D, Benchabane H, Ahmed Y (2019) Essential long-range action of wingless/Wnt in adult intestinal compartmentalization. PLoS Genet 15:e1008111

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tsiairis CD, Aulehla A (2016) Self-organization of embryonic genetic oscillators into spatiotemporal wave patterns. Cell 164:656–667

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tuysuz N, van Bloois L, van den Brink S, Begthel H, Verstegen MM, Cruz LJ, Hui L, van der Laan LJ, de Jonge J, Vries R, Braakman E, Mastrobattista E, Cornelissen JJ, Clevers H, Ten Berge D (2017) Lipid-mediated Wnt protein stabilization enables serum-free culture of human organ stem cells. Nat Commun 8:14578

    PubMed  PubMed Central  Google Scholar 

  • van Niel G, Bergam P, Di Cicco A, Hurbain I, Lo Cicero A, Dingli F, Palmulli R, Fort C, Potier MC, Schurgers LJ, Loew D, Levy D, Raposo G (2015) Apolipoprotein E regulates amyloid formation within endosomes of pigment cells. Cell Rep 13:43–51

    PubMed  Google Scholar 

  • Wesslowski J, Kozielewicz P, Wang X, Cui H, Schihada H, Kranz D, Karuna MP, Levkin P, Gross JC, Boutros M, Schulte G, Davidson G (2020) eGFP-tagged Wnt-3a enables functional analysis of Wnt trafficking and signaling and kinetic assessment of Wnt binding to full-length frizzled. J Biol Chem 295(26):8759–8774. https://doi.org/10.1074/jbc.RA120.012892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Willert K, Brown JD, Danenberg E, Duncan AW, Weissman IL, Reya T, Yates JR 3rd, Nusse R (2003) Wnt proteins are lipid-modified and can act as stem cell growth factors. Nature 423:448–452

    CAS  PubMed  Google Scholar 

  • Witte L, Linnemannstons K, Schmidt K, Honemann-Capito M, Grawe F, Wodarz A, Gross JC (2020) The kinesin motor Klp98A mediates apical to basal Wg transport. Development 147(15):dev186833

    CAS  PubMed  PubMed Central  Google Scholar 

  • Won JH, Cho KO (2021) Wg secreted by conventional Golgi transport diffuses and forms Wg gradient whereas Wg tethered to extracellular vesicles do not diffuse. Cell Death Differ 28:1013–1025

    CAS  PubMed  Google Scholar 

  • Xie M, Li JP (2019) Heparan sulfate proteoglycan - a common receptor for diverse cytokines. Cell Signal 54:115–121

    CAS  PubMed  Google Scholar 

  • Yamazaki Y, Palmer L, Alexandre C, Kakugawa S, Beckett K, Gaugue I, Palmer RH, Vincent JP (2016) Godzilla-dependent transcytosis promotes wingless signalling in drosophila wing imaginal discs. Nat Cell Biol 18:451–457

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yang PT, Lorenowicz MJ, Silhankova M, Coudreuse DY, Betist MC, Korswagen HC (2008) Wnt signaling requires retromer-dependent recycling of MIG-14/Wntless in Wnt-producing cells. Dev Cell 14:140–147

    CAS  PubMed  Google Scholar 

  • Yu J, Chia J, Canning CA, Jones CM, Bard FA, Virshup DM (2014) WLS retrograde transport to the endoplasmic reticulum during Wnt secretion. Dev Cell 29:277–291

    CAS  PubMed  Google Scholar 

  • Zhang P, Wu Y, Belenkaya TY, Lin X (2011) SNX3 controls wingless/Wnt secretion through regulating retromer-dependent recycling of Wntless. Cell Res 21:1677–1690

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

I thank Pradhipa Karuna M and Karen Linnemannstöns for critical reading of the manuscript as well as Leonie Witte for her support with art drawings. I apologize to the many authors whose work could not be included owing to space constraints and I look forward to discussing matters of Wnt secretion again in the near future with my colleagues of the Wnt research community.

Funding: Research in the laboratory of J.C.G. is supported by the Deutsche Forschungsgemeinschaft-funded Research Center [SFB1324/1 (331351713) and GR4810/2-1].

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Authors and Affiliations

  1. Developmental Biochemistry, University Medical Center Goettingen, Goettingen, Germany

    Julia Christina Gross

  2. Hematology and Oncology, University Medical Center Goettingen, Goettingen, Germany

    Julia Christina Gross

  3. Health and Medical University Potsdam, Potsdam, Germany

    Julia Christina Gross

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Correspondence to Julia Christina Gross .

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  1. Department of Physiology & Pharmacology Section for Receptor Biology & Signaling, Karolinska Institutet Biomedicum 6D, Stockholm, Sweden

    Gunnar Schulte

  2. Department of Physiology & Pharmacology Section for Receptor Biology & Signaling, Karolinska Institutet Biomedicum 6D, Stockholm, Sweden

    Pawel Kozielewicz

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Gross, J.C. (2021). Extracellular WNTs: Trafficking, Exosomes, and Ligand–Receptor Interaction. In: Schulte, G., Kozielewicz, P. (eds) Pharmacology of the WNT Signaling System. Handbook of Experimental Pharmacology, vol 269. Springer, Cham. https://doi.org/10.1007/164_2021_531

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