WNT ligand biogenesis and trafficking (Homo sapiens)

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2, 4, 17, 18, 20...42, 483, 6, 14, 22, 32...8, 16, 214, 17, 2318, 19, 27, 385, 10, 33, 36, 37, 4718, 389, 12, 15, 25, 29...42, 483, 6, 24, 261, 7, 11, 13, 411, 2, 7, 9, 12...4, 17, 21, 23, 41Golgi lumenextracellular exosomeendoplasmic reticulum lumencytosolearly endosome lumenmultivesicular body, internal vesiclemultivesicular body lumenN4GlycoAsn-PalmS WNT9B WNTsN4GlycoAsn-WNT4 WNT4 N4GlycoAsn-PalmS WNT1 N4GlycoAsn-PalmS WNT2B(1-391) N4GlycoAsn-PalmS WNT9A N4GlycoAsn-PalmS WNT2B(1-391) N4GlycoAsn-PalmS WNT16 N4GlycoAsn-WNT7A VPS29 WNT9B N4GlycoAsn-PalmS WNT8B N4GlycoAsn-PalmS WNT9A WNT3 TMED5N4GlycoAsn-PalmS WNT7A N4GlycoAsn-PalmS WNT5B N4GlycoAsn-PalmS WNT8B N4GlycoAsn-PalmS WNT6 N4GlycoAsn-PalmS WNT8A WNT7B palmitoleyl-N-glycosylated WNTsN4GlycoAsn-PalmS WNT10A N4GlycoAsn-PalmS WNT1 WNT2B(1-391) N4GlycoAsn-PalmS WNT9B N4GlycoAsn-PalmS WNT1 N-glycosylated WNTsN4GlycoAsn-WNT9B N4GlycoAsn-PalmS WNT9B N4GlycoAsn-PalmS WNT6 N4GlycoAsn-PalmS WNT2 N4GlycoAsn-WNT8B N4GlycoAsn-PalmS WNT4 N4GlycoAsn-PalmS WNT7B VPS26A N4GlycoAsn-PalmS WNT11 N4GlycoAsn-PalmS WNT3 SNX3 N4GlycoAsn-PalmS WNT8A WLSN4GlycoAsn-PalmS WNT4 N4GlycoAsn-WNT2 N4GlycoAsn-PalmS WNT2B(1-391) N4GlycoAsn-PalmS WNT7A N4GlycoAsn-PalmS WNT7A N4GlycoAsn-PalmS WNT9A N4GlycoAsn-PalmS WNT2 N4GlycoAsn-PalmS WNT10B N4GlycoAsn-PalmS WNT8A N4GlycoAsn-PalmS WNT1 PORCN N4GlycoAsn-WNT9A WLS:WNTWLS:WNTN4GlycoAsn-PalmS WNT7A WNT10B N4GlycoAsn-PalmS WNT4 N4GlycoAsn-PalmS WNT11 N4GlycoAsn-PalmS WNT2 N4GlycoAsn-PalmS WNT9B N4GlycoAsn-PalmS WNT11 N4GlycoAsn-WNT11 N4GlycoAsn-WNT10B WNT5B WNT2 N4GlycoAsn-PalmS WNT3 N4GlycoAsn-PalmS WNT9A N4GlycoAsn-PalmS WNT2 WNT8A LGK974N4GlycoAsn-PalmS WNT9B N4GlycoAsn-WNT10A N4GlycoAsn-WNT5A(36-380) N4GlycoAsn-PalmS WNT2 VPS35 N4GlycoAsn-PalmS WNT6 N4GlycoAsn-PalmS WNT6 N4GlycoAsn-PalmS WNT2 N4GlycoAsn-PalmS WNT2B(1-391) N4GlycoAsn-PalmS WNT3A N4GlycoAsn-PalmS WNT5A(36-380) N4GlycoAsn-PalmS WNT3A N4GlycoAsn-PalmS WNT2B(1-391) N4GlycoAsn-WNT2B(1-391) N4GlycoAsn-WNT8A N4GlycoAsn-PalmS WNT5A(36-380) N4GlycoAsn-PalmS WNT5A(36-380) N4GlycoAsn-PalmS WNT8B N4GlycoAsn-PalmS WNT10A N4GlycoAsn-PalmS WNT1 CoA-SHN4GlycoAsn-PalmS WNT11 WLS N4GlycoAsn-PalmS WNT16 N4GlycoAsn-PalmS WNT5A(36-380) PORCN:LGK974N4GlycoAsn-PalmS WNT8B N4GlycoAsn-WNT3A N4GlycoAsn-PalmS WNT3A N4GlycoAsn-PalmS WNT10B N4GlycoAsn-PalmS WNT9A N4GlycoAsn-PalmS WNT7A N4GlycoAsn-PalmS WNT10A N4GlycoAsn-PalmS WNT3A N4GlycoAsn-PalmS WNT3 N4GlycoAsn-PalmS WNT16 VPS26A N4GlycoAsn-PalmS WNT7B N4GlycoAsn-PalmS WNT4 palmitoleyl-N-glycosylated WNTsN4GlycoAsn-PalmS WNT3 N4GlycoAsn-WNT1 N4GlycoAsn-PalmS WNT5B N4GlycoAsn-PalmS WNT7B VPS35 N4GlycoAsn-PalmS WNT10A N4GlycoAsn-PalmS WNT8B N4GlycoAsn-PalmS WNT7B N4GlycoAsn-PalmS WNT6 N4GlycoAsn-PalmS WNT6 WLS N4GlycoAsn-PalmS WNT9B N4GlycoAsn-PalmS WNT10B N4GlycoAsn-PalmS WNT10A N4GlycoAsn-PalmS WNT3A N4GlycoAsn-PalmS WNT11 WNT6 N4GlycoAsn-PalmS WNT5A(36-380) WLS:WNTWNT10A unglycosylated WNTsN4GlycoAsn-PalmS WNT3 SNX3 N4GlycoAsn-WNT3 WNT3A N4GlycoAsn-PalmS WNT7A WNT5A(36-380) WLS:retromerN4GlycoAsn-PalmS WNT10B N4GlycoAsn-PalmS WNT7B N4GlycoAsn-PalmS WNT7B N4GlycoAsn-WNT16 WNT9A N4GlycoAsn-PalmS WNT3 WLSN4GlycoAsn-PalmS WNT2 N4GlycoAsn-PalmS WNT8B N4GlycoAsn-PalmS WNT8A SNX3N4GlycoAsn-PalmS WNT8A N4GlycoAsn-WNT7B N4GlycoAsn-PalmS WNT4 VPS35 N4GlycoAsn-PalmS WNT8A N4GlycoAsn-WNT5B WLS N4GlycoAsn-PalmS WNT11 WNT7A N4GlycoAsn-PalmS WNT5A(36-380) N4GlycoAsn-PalmS WNT7B WLS WLSWNT1 N4GlycoAsn-PalmS WNT10A WLS:retromerN4GlycoAsn-PalmS WNT3A N4GlycoAsn-PalmS WNT9A N4GlycoAsn-PalmS WNT3 VPS35:VPS29:VPS26WNT8B N4GlycoAsn-PalmS WNT16 N4GlycoAsn-PalmS WNT5B N4GlycoAsn-PalmS WNT1 N4GlycoAsn-PalmS WNT8B N4GlycoAsn-PalmS WNT5B N4GlycoAsn-PalmS WNT16 N4GlycoAsn-PalmS WNT5A(36-380) N4GlycoAsn-PalmS WNT10B N4GlycoAsn-PalmS WNT9A N4GlycoAsn-PalmS WNT9B N4GlycoAsn-PalmS WNT5B N4GlycoAsn-PalmS WNT2B(1-391) palmitoleoyl-CoAVPS26A N4GlycoAsn-PalmS WNT1 N4GlycoAsn-PalmS WNT10B N4GlycoAsn-PalmS WNT2B(1-391) N4GlycoAsn-PalmS WNT6 N4GlycoAsn-PalmS WNT10B N4GlycoAsn-PalmS WNT5B N4GlycoAsn-PalmS WNT3A WLS:WNTWLS N4GlycoAsn-PalmS WNT7A WNT16 N4GlycoAsn-PalmS WNT8A N4GlycoAsn-PalmS WNT5B PORCNWLS N4GlycoAsn-PalmS WNT16 VPS29 VPS29 N4GlycoAsn-PalmS WNT16 N4GlycoAsn-PalmS WNT4 N4GlycoAsn-PalmS WNT11 N4GlycoAsn-PalmS WNT10A WNT11 N4GlycoAsn-PalmS WNT4 N4GlycoAsn-WNT6 4646


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).

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Pathway is converted from Reactome ID: 3238698
Reactome version: 65
Reactome Author 
Reactome Author: Rothfels, Karen

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  1. Komekado H, Yamamoto H, Chiba T, Kikuchi A.; ''Glycosylation and palmitoylation of Wnt-3a are coupled to produce an active form of Wnt-3a.''; PubMed Europe PMC
  2. 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.''; PubMed Europe PMC
  3. Belenkaya TY, Wu Y, Tang X, Zhou B, Cheng L, Sharma YV, Yan D, Selva EM, Lin X.; ''The retromer complex influences Wnt secretion by recycling wntless from endosomes to the trans-Golgi network.''; PubMed Europe PMC
  4. Bartscherer K, Pelte N, Ingelfinger D, Boutros M.; ''Secretion of Wnt ligands requires Evi, a conserved transmembrane protein.''; PubMed Europe PMC
  5. Port F, Hausmann G, Basler K.; ''A genome-wide RNA interference screen uncovers two p24 proteins as regulators of Wingless secretion.''; PubMed Europe PMC
  6. Port F, Kuster M, Herr P, Furger E, Bänziger C, Hausmann G, Basler K.; ''Wingless secretion promotes and requires retromer-dependent cycling of Wntless.''; PubMed Europe PMC
  7. Willert K, Brown JD, Danenberg E, Duncan AW, Weissman IL, Reya T, Yates JR, Nusse R.; ''Wnt proteins are lipid-modified and can act as stem cell growth factors.''; PubMed Europe PMC
  8. Eaton S.; ''Release and trafficking of lipid-linked morphogens.''; PubMed Europe PMC
  9. Najdi R, Proffitt K, Sprowl S, Kaur S, Yu J, Covey TM, Virshup DM, Waterman ML.; ''A uniform human Wnt expression library reveals a shared secretory pathway and unique signaling activities.''; PubMed Europe PMC
  10. Buechling T, Chaudhary V, Spirohn K, Weiss M, Boutros M.; ''p24 proteins are required for secretion of Wnt ligands.''; PubMed Europe PMC
  11. Smolich BD, McMahon JA, McMahon AP, Papkoff J.; ''Wnt family proteins are secreted and associated with the cell surface.''; PubMed Europe PMC
  12. Kadowaki T, Wilder E, Klingensmith J, Zachary K, Perrimon N.; ''The segment polarity gene porcupine encodes a putative multitransmembrane protein involved in Wingless processing.''; PubMed Europe PMC
  13. Kurayoshi M, Yamamoto H, Izumi S, Kikuchi A.; ''Post-translational palmitoylation and glycosylation of Wnt-5a are necessary for its signalling.''; PubMed Europe PMC
  14. Coudreuse DY, Roël G, Betist MC, Destrée O, Korswagen HC.; ''Wnt gradient formation requires retromer function in Wnt-producing cells.''; PubMed Europe PMC
  15. MacDonald BT, Tamai K, He X.; ''Wnt/beta-catenin signaling: components, mechanisms, and diseases.''; PubMed Europe PMC
  16. Port F, Basler K.; ''Wnt trafficking: new insights into Wnt maturation, secretion and spreading.''; PubMed Europe PMC
  17. 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.''; PubMed Europe PMC
  18. Korkut C, Ataman B, Ramachandran P, Ashley J, Barria R, Gherbesi N, Budnik V.; ''Trans-synaptic transmission of vesicular Wnt signals through Evi/Wntless.''; PubMed Europe PMC
  19. Simons M, Raposo G.; ''Exosomes--vesicular carriers for intercellular communication.''; PubMed Europe PMC
  20. Herr P, Hausmann G, Basler K.; ''WNT secretion and signalling in human disease.''; PubMed Europe PMC
  21. 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.; ''WLS-dependent secretion of WNT3A requires Ser209 acylation and vacuolar acidification.''; PubMed Europe PMC
  22. Franch-Marro X, Wendler F, Guidato S, Griffith J, Baena-Lopez A, Itasaki N, Maurice MM, Vincent JP.; ''Wingless secretion requires endosome-to-Golgi retrieval of Wntless/Evi/Sprinter by the retromer complex.''; PubMed Europe PMC
  23. 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.''; PubMed Europe PMC
  24. Yang PT, Lorenowicz MJ, Silhankova M, Coudreuse DY, Betist MC, Korswagen HC.; ''Wnt signaling requires retromer-dependent recycling of MIG-14/Wntless in Wnt-producing cells.''; PubMed Europe PMC
  25. Janda CY, Waghray D, Levin AM, Thomas C, Garcia KC.; ''Structural basis of Wnt recognition by Frizzled.''; PubMed Europe PMC
  26. Gasnereau I, Herr P, Chia PZ, Basler K, Gleeson PA.; ''Identification of an endocytosis motif in an intracellular loop of Wntless protein, essential for its recycling and the control of Wnt protein signaling.''; PubMed Europe PMC
  27. 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.''; PubMed Europe PMC
  28. Biechele S, Cox BJ, Rossant J.; ''Porcupine homolog is required for canonical Wnt signaling and gastrulation in mouse embryos.''; PubMed Europe PMC
  29. Proffitt KD, Virshup DM.; ''Precise regulation of porcupine activity is required for physiological Wnt signaling.''; PubMed Europe PMC
  30. 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.''; PubMed Europe PMC
  31. Hofmann K.; ''A superfamily of membrane-bound O-acyltransferases with implications for wnt signaling.''; PubMed Europe PMC
  32. Pfeffer SR.; ''Membrane transport: retromer to the rescue.''; PubMed Europe PMC
  33. Strating JR, Martens GJ.; ''The p24 family and selective transport processes at the ER-Golgi interface.''; PubMed Europe PMC
  34. Zhang P, Wu Y, Belenkaya TY, Lin X.; ''SNX3 controls Wingless/Wnt secretion through regulating retromer-dependent recycling of Wntless.''; PubMed Europe PMC
  35. Xu Y, Hortsman H, Seet L, Wong SH, Hong W.; ''SNX3 regulates endosomal function through its PX-domain-mediated interaction with PtdIns(3)P.''; PubMed Europe PMC
  36. Dancourt J, Barlowe C.; ''Protein sorting receptors in the early secretory pathway.''; PubMed Europe PMC
  37. Palmer L, Vincent JP, Beckett K.; ''Wnts need a p(assport)24 to leave the ER.''; PubMed Europe PMC
  38. Gross JC, Chaudhary V, Bartscherer K, Boutros M.; ''Active Wnt proteins are secreted on exosomes.''; PubMed Europe PMC
  39. Ching W, Hang HC, Nusse R.; ''Lipid-independent secretion of a Drosophila Wnt protein.''; PubMed Europe PMC
  40. Galli LM, Burrus LW.; ''Differential palmit(e)oylation of Wnt1 on C93 and S224 residues has overlapping and distinct consequences.''; PubMed Europe PMC
  41. Herr P, Basler K.; ''Porcupine-mediated lipidation is required for Wnt recognition by Wls.''; PubMed Europe PMC
  42. Willert K, Nusse R.; ''Wnt proteins.''; PubMed Europe PMC
  43. Harterink M, Port F, Lorenowicz MJ, McGough IJ, Silhankova M, Betist MC, van Weering JRT, van Heesbeen RGHP, Middelkoop TC, Basler K, Cullen PJ, Korswagen HC.; ''A SNX3-dependent retromer pathway mediates retrograde transport of the Wnt sorting receptor Wntless and is required for Wnt secretion.''; PubMed Europe PMC
  44. van den Heuvel M, Harryman-Samos C, Klingensmith J, Perrimon N, Nusse R.; ''Mutations in the segment polarity genes wingless and porcupine impair secretion of the wingless protein.''; PubMed Europe PMC
  45. Seaman MN.; ''The retromer complex - endosomal protein recycling and beyond.''; PubMed Europe PMC
  46. Liu J, Pan S, Hsieh MH, Ng N, Sun F, Wang T, Kasibhatla S, Schuller AG, Li AG, Cheng D, Li J, Tompkins C, Pferdekamper A, Steffy A, Cheng J, Kowal C, Phung V, Guo G, Wang Y, Graham MP, Flynn S, Brenner JC, Li C, Villarroel MC, Schultz PG, Wu X, McNamara P, Sellers WR, Petruzzelli L, Boral AL, Seidel HM, McLaughlin ME, Che J, Carey TE, Vanasse G, Harris JL.; ''Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974.''; PubMed Europe PMC
  47. Lippincott-Schwartz J, Roberts TH, Hirschberg K.; ''Secretory protein trafficking and organelle dynamics in living cells.''; PubMed Europe PMC
  48. Johannes L, Wunder C.; ''The SNXy flavours of endosomal sorting.''; PubMed Europe PMC
  49. Saito-Diaz K, Chen TW, Wang X, Thorne CA, Wallace HA, Page-McCaw A, Lee E.; ''The way Wnt works: components and mechanism.''; PubMed Europe PMC


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100772view20:40, 31 October 2018ReactomeTeamreactome version 65
100316view19:17, 31 October 2018ReactomeTeamreactome version 64
99861view16:00, 31 October 2018ReactomeTeamreactome version 63
99418view14:36, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99102view12:39, 31 October 2018ReactomeTeamreactome version 62
93992view13:50, 16 August 2017ReactomeTeamreactome version 61
93600view11:28, 9 August 2017ReactomeTeamreactome version 61
88351view16:19, 1 August 2016FehrhartOntology Term : 'Wnt signaling pathway' added !
86707view09:24, 11 July 2016ReactomeTeamreactome version 56
83226view10:25, 18 November 2015ReactomeTeamVersion54
81621view13:10, 21 August 2015ReactomeTeamVersion53
77081view08:37, 17 July 2014ReactomeTeamFixed remaining interactions
76786view12:15, 16 July 2014ReactomeTeamFixed remaining interactions
76109view10:17, 11 June 2014ReactomeTeamRe-fixing comment source
75821view11:37, 10 June 2014ReactomeTeamReactome 48 Update
75171view14:12, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74818view08:55, 30 April 2014ReactomeTeamNew pathway

External references


View all...
NameTypeDatabase referenceComment
CHEBI:78030 (ChEBI)
CoA-SHMetaboliteCHEBI:15346 (ChEBI)
LGK974MetaboliteCHEBI:78030 (ChEBI)
N-glycosylated WNTsComplexR-HSA-3238268 (Reactome)
N4GlycoAsn-PalmS WNT1 ProteinP04628 (Uniprot-TrEMBL)
N4GlycoAsn-PalmS WNT10A ProteinQ9GZT5 (Uniprot-TrEMBL)
N4GlycoAsn-PalmS WNT10B ProteinO00744 (Uniprot-TrEMBL)
N4GlycoAsn-PalmS WNT11 ProteinO96014 (Uniprot-TrEMBL)
N4GlycoAsn-PalmS WNT16 ProteinQ9UBV4 (Uniprot-TrEMBL)
N4GlycoAsn-PalmS WNT2 ProteinP09544 (Uniprot-TrEMBL)
N4GlycoAsn-PalmS WNT2B(1-391) ProteinQ93097 (Uniprot-TrEMBL)
N4GlycoAsn-PalmS WNT3 ProteinP56703 (Uniprot-TrEMBL)
N4GlycoAsn-PalmS WNT3A ProteinP56704 (Uniprot-TrEMBL)
N4GlycoAsn-PalmS WNT4 ProteinP56705 (Uniprot-TrEMBL)
N4GlycoAsn-PalmS WNT5A(36-380) ProteinP41221 (Uniprot-TrEMBL)
N4GlycoAsn-PalmS WNT5B ProteinQ9H1J7 (Uniprot-TrEMBL)
N4GlycoAsn-PalmS WNT6 ProteinQ9Y6F9 (Uniprot-TrEMBL)
N4GlycoAsn-PalmS WNT7A ProteinO00755 (Uniprot-TrEMBL)
N4GlycoAsn-PalmS WNT7B ProteinP56706 (Uniprot-TrEMBL)
N4GlycoAsn-PalmS WNT8A ProteinQ9H1J5 (Uniprot-TrEMBL)
N4GlycoAsn-PalmS WNT8B ProteinQ93098 (Uniprot-TrEMBL)
N4GlycoAsn-PalmS WNT9A ProteinO14904 (Uniprot-TrEMBL)
N4GlycoAsn-PalmS WNT9B ProteinO14905 (Uniprot-TrEMBL)
N4GlycoAsn-WNT1 ProteinP04628 (Uniprot-TrEMBL)
N4GlycoAsn-WNT10A ProteinQ9GZT5 (Uniprot-TrEMBL)
N4GlycoAsn-WNT10B ProteinO00744 (Uniprot-TrEMBL)
N4GlycoAsn-WNT11 ProteinO96014 (Uniprot-TrEMBL)
N4GlycoAsn-WNT16 ProteinQ9UBV4 (Uniprot-TrEMBL)
N4GlycoAsn-WNT2 ProteinP09544 (Uniprot-TrEMBL)
N4GlycoAsn-WNT2B(1-391) ProteinQ93097 (Uniprot-TrEMBL)
N4GlycoAsn-WNT3 ProteinP56703 (Uniprot-TrEMBL)
N4GlycoAsn-WNT3A ProteinP56704 (Uniprot-TrEMBL)
N4GlycoAsn-WNT4 ProteinP56705 (Uniprot-TrEMBL)
N4GlycoAsn-WNT5A(36-380) ProteinP41221 (Uniprot-TrEMBL)
N4GlycoAsn-WNT5B ProteinQ9H1J7 (Uniprot-TrEMBL)
N4GlycoAsn-WNT6 ProteinQ9Y6F9 (Uniprot-TrEMBL)
N4GlycoAsn-WNT7A ProteinO00755 (Uniprot-TrEMBL)
N4GlycoAsn-WNT7B ProteinP56706 (Uniprot-TrEMBL)
N4GlycoAsn-WNT8A ProteinQ9H1J5 (Uniprot-TrEMBL)
N4GlycoAsn-WNT8B ProteinQ93098 (Uniprot-TrEMBL)
N4GlycoAsn-WNT9A ProteinO14904 (Uniprot-TrEMBL)
N4GlycoAsn-WNT9B ProteinO14905 (Uniprot-TrEMBL)
PORCN ProteinQ9H237 (Uniprot-TrEMBL)
PORCN:LGK974ComplexR-HSA-5340557 (Reactome)
PORCNProteinQ9H237 (Uniprot-TrEMBL)
SNX3 ProteinO60493 (Uniprot-TrEMBL)
SNX3ProteinO60493 (Uniprot-TrEMBL)
TMED5ProteinQ9Y3A6 (Uniprot-TrEMBL)
VPS26A ProteinO75436 (Uniprot-TrEMBL)
VPS29 ProteinQ9UBQ0 (Uniprot-TrEMBL)
VPS35 ProteinQ96QK1 (Uniprot-TrEMBL)
VPS35:VPS29:VPS26ComplexR-HSA-3247737 (Reactome)
WLS ProteinQ5T9L3 (Uniprot-TrEMBL)
WLS:WNTComplexR-HSA-3247838 (Reactome)
WLS:WNTComplexR-HSA-3247841 (Reactome)
WLS:WNTComplexR-HSA-3781970 (Reactome)
WLS:WNTComplexR-HSA-3781975 (Reactome)
WLS:retromerComplexR-HSA-3247842 (Reactome)
WLS:retromerComplexR-HSA-3247845 (Reactome)
WLSProteinQ5T9L3 (Uniprot-TrEMBL)
WNT1 ProteinP04628 (Uniprot-TrEMBL)
WNT10A ProteinQ9GZT5 (Uniprot-TrEMBL)
WNT10B ProteinO00744 (Uniprot-TrEMBL)
WNT11 ProteinO96014 (Uniprot-TrEMBL)
WNT16 ProteinQ9UBV4 (Uniprot-TrEMBL)
WNT2 ProteinP09544 (Uniprot-TrEMBL)
WNT2B(1-391) ProteinQ93097 (Uniprot-TrEMBL)
WNT3 ProteinP56703 (Uniprot-TrEMBL)
WNT3A ProteinP56704 (Uniprot-TrEMBL)
WNT4 ProteinP56705 (Uniprot-TrEMBL)
WNT5A(36-380) ProteinP41221 (Uniprot-TrEMBL)
WNT5B ProteinQ9H1J7 (Uniprot-TrEMBL)
WNT6 ProteinQ9Y6F9 (Uniprot-TrEMBL)
WNT7A ProteinO00755 (Uniprot-TrEMBL)
WNT7B ProteinP56706 (Uniprot-TrEMBL)
WNT8A ProteinQ9H1J5 (Uniprot-TrEMBL)
WNT8B ProteinQ93098 (Uniprot-TrEMBL)
WNT9A ProteinO14904 (Uniprot-TrEMBL)
WNT9B ProteinO14905 (Uniprot-TrEMBL)
WNTsComplexR-HSA-3247835 (Reactome)
palmitoleoyl-CoAMetaboliteCHEBI:53152 (ChEBI)
palmitoleyl-N-glycosylated WNTsComplexR-HSA-3238374 (Reactome)
palmitoleyl-N-glycosylated WNTsComplexR-HSA-3247824 (Reactome)
unglycosylated WNTsComplexR-HSA-3238376 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
CoA-SHArrowR-HSA-3238694 (Reactome)
LGK974R-HSA-5340560 (Reactome)
N-glycosylated WNTsArrowR-HSA-3238691 (Reactome)
N-glycosylated WNTsR-HSA-3238694 (Reactome)
PORCN:LGK974ArrowR-HSA-5340560 (Reactome)
PORCNR-HSA-5340560 (Reactome)
PORCNmim-catalysisR-HSA-3238694 (Reactome)
R-HSA-3238691 (Reactome) All WNT ligands are predicted to be highly glycosylated. By similarity with WNT ligands in mouse, human WNTs are believed to undergo N-linked glycosylation at multiple asparagine residues and this glycosylation is critical for their secretion (Smolich et al, 1993; Willert et al, 2003, Komekado et al, 2006; Kurayoshi et al, 2007). The mechanism of N-linked glycosylation is not shown here. For a more detailed description, please refer to pathway "Asparagine N-linked glycosylation".
R-HSA-3238694 (Reactome) All WNT proteins except Drosophila WntD are lipid modified. Lipid modifications contribute to the hydrophobicity and poor solubility of all known WNT ligands with the exception of Drosophila WntD. Acylation is required for their secretion from the cell and their ability to bind to FRZ receptors (reviewed in MacDonald et al, 2009; Takada et al, 2006; Janda et al, 2012; Herr and Basler, 2012; Ching et al, 2008). Although an initial study suggested that conserved Cys77 in mouse Wnt3a was palmitoylated (Willert et al, 2003), further work showed that mutation of this residue had minimal effect on WNT secretion (Komekado et al, 2007). In contrast, addition of palmitoleic acid to mWnt3a Ser209 is essential for WNT secretion, and mutant S209A is largely retained in the ER (Takada et al, 2006; Galli and Burrus, 2011). This serine residue is conserved at this position in all known WNTs with the exception of Drosophila WntD (Ching et al, 2008; Herr and Basler, 2012). A recent crystal structure of Xenopus WNT8 in complex with a Frizzled cysteine-rich-domain shows a single lipid modification on the conserved serine residue, while the conserved cysteine participates in a disulphide bond (Janda et al, 2012). In addition to being required for secretion, the lipid at S209 also makes direct contact with a groove in the Frizzled receptor and is thus essential for binding (Janda et al, 2012).

Porcupine is a conserved multi-pass transmembrane ER protein that has an O-acyl-transferase domain (van den Heuvel et al, 1993; Kadowaki et al, 1996; Hofmann, 2000). First identified in Drosophila, Porcupine is a WNT-specific modulator that is required for Wingless processing and secretion (Kadowaki et al, 1996). In porcn-deficient cells, Wg and WNT3A have decreased palmitoylation at S209 and accumulate in the ER (Takada et al, 2006), and mutations in PORCN eliminate all WNT signalling and cause embryonic lethality in mice (Barrott et al, 2011; Biechele et al, 2011). Recent studies show that PORCN is required for activity of all human WNT ligands (Proffitt et al, 2012; Najdi et al, 2012).
R-HSA-3247836 (Reactome) Retromer is believed to escort WLS from the early endosome back to the Golgi for subsequent rounds of WNT secretion (reviewed in Johannes and Wunder, 2011; Willert and Nusse, 2012 ).
R-HSA-3247837 (Reactome) This black box event represents the non-WNT-specific ER-to-Golgi trafficking step of protein secretion (reviewed in Dancourt and Barlowe, 2010; Lippincott Schwatz et al, 2000; for more details, please refer to the pathway "ER to Golgi transport"). Two recent screens in Drosophila have identified members of the p24 family as WNT-specific regulators of ER-to-Golgi transport, although the details have not been elucidated (Port et al, 2011; Buechling et al, 2011; reviewed in Strating and Martens, 2009). Depletion of the Drosophila p24 protein Opossum causes accumulation of WNT ligand in the ER, suggesting a role for Opm in ER-to-Golgi transport of WNTs. WNT-dependent reporter activity was reduced in HEK293 cells that were depleted for the human p24 homologue TMED5, supporting a conserved role for these proteins in WNT signaling (Buechling et al, 2011; reviewed in Palmer et al, 2012).
R-HSA-3247839 (Reactome) Retromer is a conserved multi-protein complex that is required for retrograde transport of transmembrane proteins. It was initially characterized in yeast as a pentameric complex required for the recycling of the transmembrane receptor VPS10 to the trans-Golgi, and was subsequently shown to be conserved in flies, worms and humans. In humans, retromer consists of a cargo-recognition subcomplex made up of VPS35, VPS26 and VPS29 and a membrane-targeting subcomplex containing a heterodimer of SNX proteins (SNX1 or 2 paired with SNX5 or 6). The SNX proteins contain a BAR domain that is believed to promote membrane curvature, and SNX-BAR proteins are thought to aid in the formation of endosomal membrane tubules into which cargo is loaded (reviewed in Pfeffer, 2001; Seaman, 2012).

Retromer is required for the recycling of WLS to the Golgi to allow further rounds of WNT-ligand delivery to the plasma membrane (Coudreuse et al 2006; Belenkaya et al 2008; Port et al, 2008). In the absence of essential retromer component VPS35 or VPS26, WLS is diverted to the MVB and degraded, and WNT ligand accumulates inside the cell; overexpression of WLS is sufficient to rescue the vps35 defect in WNT signaling (Belenkaya et al, 2006; Franch-Marro et al, 2008). WLS and retromer colocalize on endosomal structures and WLS and VPS35 co-precipitate in pull down studies (Belenkaya et al, 2006; Port et al, 2008; Franch-Marro et al, 2008).

Several recent studies have suggested that WLS recycling depends on a WNT-specific retromer in which the SNX-BAR proteins of the classic complex are replaced by SNX3 (Zhang et al, 2011; Harterink et al, 2011; reviewed in Johannes and Wunder, 2011). Unlike SNX1/2/5/6, SNX3 does not contain a BAR domain, and WLS is suggested to accumulate in endocytic vesicles rather than in the tubular structures of the 'classic' retromer (Harterink et al, 2011; Zhang et al, 2011). SNX3 is recruited from the cytosol to the early endosome through the interaction of its PX domain with PIP3 in the membrane. Mutation of critical residues in the PX domain abolish the interaction with PIP3 and ablate endsomal recruitment of SNX3 (Xu et al, 2001; Zhang at al, 2011; Harterink et al, 2011). SNX3 has been shown to co-immunoprecipitate with VPS35 and VPS26, and some studies have also shown a direct interaction between SNX3 and WLS (Zhang et al, 2011; Harterink et al, 2011).
R-HSA-3247840 (Reactome) Wntless (WLS) (Evi/Sprinter/GPR177) is a conserved transmembrane protein that is required for the secretion of WNT ligands from the cell (Bänzinger et al, 2006; Bartscherer et al, 2006; Goodman et al, 2006). Notably, WLS is not required for the secretion of Hedgehog, another acylated signaling molecule, and wls-mutants phenocopy wg/wnt mutants (Bänziger et al, 2006; Bartscherer et al, 2006; Goodman et al, 2006), supporting the notion that WLS is a dedicated WNT pathway member. WLS binds directly to WNT ligands in the Golgi in a WNT-acylation dependent manner, as the interaction is abrogated by mutation of either PORCN or the conserved Ser209 residue (Coombs et al, 2010; Herr and Basler, 2012). WLS is thought to contain a lipocalin-family fold (Coombs et al, 2010), a lipid-interacting domain, which may play a role in binding to the lipid adduct on WNT.
R-HSA-3247843 (Reactome) Vacuolar acidification is required but not sufficient for the release of WNT ligands from WLS at the cell surface. V-ATPase inhibitors cause the accumulation of WLS-WNT complexes both within the cell and at the plasma membrane (Coombs et al, 2010).
Once in the extracellular space, the lipid-modified WNT ligand must be shielded to allow the morphogen to diffuse away from the plasma membrane. Possible mechanisms include interaction with HSPGs, exosomes, multimerization or incorporation into lipoprotein particles (reviewed in Eaton, 2006; Port and Basler, 2010).
R-HSA-3247844 (Reactome) WLS accompanies WNT through the secretory pathway to the cell surface, where the ligand is released into the extracellular space (Bänziger et al, 2006; Bartscherer et al, 2006; Goodman et al, 2006).
R-HSA-3247847 (Reactome) WLS endocytosis is a clathrin-dependent process. In Drosophila cells, internalization of WLS has been shown to depend on clathrin, AP-2, dynamin, Rab5 and HRS (Belenkaya et al, 2006; Port et al, 2008), while in HeLa cells, WLS colocalizes with endogenous AP-2, and depletion of AP-2 increases WLS levels at the cell surface (Yang et al, 2008). A recent study identified a conserved YEGL endocytosis motif in the third intracellular loop of WLS that is required for its clathrin- and dynamin-dependent internalization (Gasnereau et al, 2011).
R-HSA-3247849 (Reactome) Although the role of retromer in delivering WLS back to the Golgi is reasonably well established (reviewed in Johannes and Wunder, 2011; Willert and Nusse, 2012), the details of how the complex is disassembled at the TGN remain to be determined.
R-HSA-3781941 (Reactome) Exsomes have been shown to be involved in secretion of WNTs from HEK293 cells as well as from the human colon cancer cell line Caco2 (Gross et al, 2012). In addition, exosomes from cancer-associated fibroblasts have been shown to promote autocrine PCP signaling and protrusive activity and motility in breast cancer cells (Korkut et al, 2009).
R-HSA-3781943 (Reactome) Fractionation of extracellular WNT activity shows that between 12-40% of secreted WNT ligand is present on exosomal vesicles (Gross et al, 2012; Beckett et al, 2013). Exosomes are 40 - 100 nm microvesicles of endocytic origin with established roles in cell-cell communication. They are produced by multivesicular bodies (MVBs) and directed to the plasma membrane for secretion (reviewed in Simons and Raposo, 2009). WNT secretion in the exosomal fraction is dependent on WLS/EVI/SPR in both human and Drosophila cells (Gross et al, 2012; Beckett et al, 2013). While exosomes have been shown to be required for presynaptic release of EVI and Wg at Drosophila neuromuscular junctions, there is conflicting evidence about whether they play a role in the formation of a Wg gradient at the Drosophila imaginal disc (Korkut et al, 2009; Gross et al, 2012; Beckett et al, 2013). Exosomal WNT fractions co-purify with TSG101 and other components of the ESCRT machinery, and knockdown of ESCRT 0 components reduces the levels of WNT3A and the signaling activity of the exosomal fractions (Gross et al, 2012; Beckett et al, 2013).
R-HSA-5340560 (Reactome) Porcupine (PORCN) is an O-acyl-transferase that catalyzes the palmitoleoylation of WNT ligands at the conserved S209 (van den Heuvel et al, 1993; Kadowaki et al, 1996; Hofmann, 2000). This lipid modification is required for the trafficking of WNT ligands from the ER to the cell surface, and is also required for binding to the FZD receptors. In the absence of PORCN, WNT ligand accumulates in the ER and WNT signaling is abrogated (reviewed in MacDonald et al, 2009; Takada et al, 2006; Janda et al, 2012; Herr and Basler, 2012; Ching et al, 2008). PORCN is required for activity of all human WNT ligands (Proffitt et al, 2012; Najdi et al, 2012).

LGK974 is a small molecule inhibitor of PORCN that was identified in a screen for compounds that block WNT secretion (Liu et al, 2013). LGK974 potently blocks WNT signaling in vitro and in vivo and is in Phase I clinical trials (NCT01351103) for use in the treatment of WNT-dependent cancers.
SNX3ArrowR-HSA-3247849 (Reactome)
SNX3R-HSA-3247839 (Reactome)
TMED5ArrowR-HSA-3247837 (Reactome)
VPS35:VPS29:VPS26ArrowR-HSA-3247849 (Reactome)
VPS35:VPS29:VPS26R-HSA-3247839 (Reactome)
WLS:WNTArrowR-HSA-3247840 (Reactome)
WLS:WNTArrowR-HSA-3247844 (Reactome)
WLS:WNTArrowR-HSA-3781941 (Reactome)
WLS:WNTArrowR-HSA-3781943 (Reactome)
WLS:WNTR-HSA-3247843 (Reactome)
WLS:WNTR-HSA-3247844 (Reactome)
WLS:WNTR-HSA-3781941 (Reactome)
WLS:WNTR-HSA-3781943 (Reactome)
WLS:retromerArrowR-HSA-3247836 (Reactome)
WLS:retromerArrowR-HSA-3247839 (Reactome)
WLS:retromerR-HSA-3247836 (Reactome)
WLS:retromerR-HSA-3247849 (Reactome)
WLSArrowR-HSA-3247843 (Reactome)
WLSArrowR-HSA-3247847 (Reactome)
WLSArrowR-HSA-3247849 (Reactome)
WLSR-HSA-3247839 (Reactome)
WLSR-HSA-3247840 (Reactome)
WLSR-HSA-3247847 (Reactome)
WNTsArrowR-HSA-3247843 (Reactome)
palmitoleoyl-CoAR-HSA-3238694 (Reactome)
palmitoleyl-N-glycosylated WNTsArrowR-HSA-3238694 (Reactome)
palmitoleyl-N-glycosylated WNTsArrowR-HSA-3247837 (Reactome)
palmitoleyl-N-glycosylated WNTsR-HSA-3247837 (Reactome)
palmitoleyl-N-glycosylated WNTsR-HSA-3247840 (Reactome)
unglycosylated WNTsR-HSA-3238691 (Reactome)
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