Int J Stem Cells.  2023 Nov;16(4):376-384. 10.15283/ijsc23070.

RNF43 and ZNRF3 in Wnt Signaling - A Master Regulator at the Membrane

• Farnhammer F
• Colozza G
• Kim J

• KMID: 2548001
• DOI: http://doi.org/10.15283/ijsc23070

Abstract

The Wnt β-catenin signaling pathway is a highly conserved mechanism that plays a critical role from embryonic development and adult stem cell homeostasis. However, dysregulation of the Wnt pathway has been implicated in various diseases, including cancer. Therefore, multiple layers of regulatory mechanisms tightly control the activation and suppression of the Wnt signal. The E3 ubiquitin ligases RNF43 and ZNRF3, which are known negative regulators of the Wnt pathway, are critical component of Wnt signaling regulation. These E3 ubiquitin ligases control Wnt signaling by targeting the Wnt receptor Frizzled to induce ubiquitination-mediated endo-lysosomal degradation, thus controlling the activation of the Wnt signaling pathway. We also discuss the regulatory mechanisms, interactors, and evolution of RNF43 and ZNRF3. This review article summarizes recent findings on RNF43 and ZNRF3 and their potential implications for the development of therapeutic strategies to target the Wnt signaling pathway in various diseases, including cancer.

Keyword

Wnt signaling; RNF43; ZNRF3; Stem cell

Figure

• 

  Fig. 1 Overview of Wnt/βcatenin signaling pathway. The absence of Wnt ligands induces the phosphorylation of β-catenin by the destruction complex. The complex comprises the scaffold protein AXIN, APC, and the GSK3β and CK1α. Without Wnt ligands, β-catenin undergoes GSK3β mediated phosphorylation, followed by ubiquitination facilitated by β-TrCP for proteasomal degradation. Therefore, target genes of Wnt signaling are not activated. Activation of the canonical pathway ensues upon the binding of secreted canonical Wnt ligands to FZD receptors and LRP co-receptors. Subsequently, CK1α and GSK3β phosphorylate LRP receptors, facilitating the recruitment of DVL proteins to the plasma membrane. As a result, β-catenin experiences stabilization and accumulation, and subsequently translocates into the nucleus. Within the nucleus, β-catenin forms an active complex with LEF/TCF proteins by displacing TLE/Gaucho complexes and recruiting co-activators involved in histone modification. This transcriptional switch triggers a multitude of alterations in cellular processes.

• 

  Fig. 2 PA-TM-RING family genes. (a) Domain architecture of PA-TM-RING family genes. (b) Amino acid sequence alignment of human PA-TM-RING family.

Reference

References

1. Holstein TW. 2012; The evolution of the Wnt pathway. Cold Spring Harb Perspect Biol. 4:a007922. DOI: 10.1101/cshperspect.a007922. PMID: 22751150. PMCID: PMC3385961.

2. Nüsslein-Volhard C, Wieschaus E. 1980; Mutations affecting segment number and polarity in Drosophila. Nature. 287:795–801. DOI: 10.1038/287795a0. PMID: 6776413.

3. Sharma RP, Chopra VL. 1976; Effect of the wingless (wg1) mutation on wing and haltere development in Drosophila mela-nogaster. Dev Biol. 48:461–465. DOI: 10.1016/0012-1606(76)90108-1. PMID: 815114.

4. Noordermeer J, Klingensmith J, Perrimon N, Nusse R. 1994; Dishevelled and armadillo act in the Wingless signalling pathway in Drosophila. Nature. 367:80–83. DOI: 10.1038/367080a0. PMID: 7906389.

5. Peifer M, Sweeton D, Casey M, Wieschaus E. 1994; Wingless signal and zeste-white 3 kinase trigger opposing changes in the intracellular distribution of armadillo. Development. 120:369–380. DOI: 10.1242/dev.120.2.369. PMID: 8149915.

6. Siegfried E, Chou TB, Perrimon N. 1992; Wingless signaling acts through zeste-white 3, the Drosophila homolog of glycogen synthase kinase-3, to regulate engrailed and establish cell fate. Cell. 71:1167–1179. DOI: 10.1016/S0092-8674(05)80065-0. PMID: 1335365.

7. Sokol S, Christian JL, Moon RT, Melton DA. 1991; Injected Wnt RNA induces a complete body axis in Xenopus embryos. Cell. 67:741–752. DOI: 10.1016/0092-8674(91)90069-B. PMID: 1834344.

8. Steinhart Z, Angers S. 2018; Wnt signaling in development and tissue homeostasis. Development. 145:dev146589. DOI: 10.1242/dev.146589. PMID: 29884654.

9. Zhan T, Rindtorff N, Boutros M. 2017; Wnt signaling in cancer. Oncogene. 36:1461–1473. DOI: 10.1038/onc.2016.304. PMID: 27617575. PMCID: PMC5357762.

10. Markowitz SD, Bertagnolli MM. 2009; Molecular origins of cancer: molecular basis of colorectal cancer. N Engl J Med. 361:2449–2460. DOI: 10.1056/NEJMra0804588. PMID: 20018966. PMCID: PMC2843693.

11. Groenewald W, Lund AH, Gay DM. 2023; The role of WNT pathway mutations in cancer development and an overview of therapeutic options. Cells. 12:990. DOI: 10.3390/cells12070990. PMID: 37048063. PMCID: PMC10093220. PMID: dd978339ad6840da8e56975c0c3f4072.

12. Jung YS, Park JI. 2020; Wnt signaling in cancer: therapeutic targeting of Wnt signaling beyond β-catenin and the destruction complex. Exp Mol Med. 52:183–191. DOI: 10.1038/s12276-020-0380-6. PMID: 32037398. PMCID: PMC7062731. PMID: bb77a696695b4d39b07898608c7fce6f.

13. ClinicalTrials.gov. Year. Mon. date. A study of LGK974 in patients with malignancies dependent on Wnt ligands [Internet]. U.S. National Library of Medicine;Bethesda: Available from: https://clinicaltrials.gov/ct2/show/NCT01351103. cited 2023 May 22.

14. Krishnamurthy N, Kurzrock R. 2018; Targeting the Wnt/beta-catenin pathway in cancer: update on effectors and inhi-bitors. Cancer Treat Rev. 62:50–60. DOI: 10.1016/j.ctrv.2017.11.002. PMID: 29169144. PMCID: PMC5745276.

15. Koo BK, Spit M, Jordens I, Low TY, Stange DE, van de Wetering M, van Es JH, Mohammed S, Heck AJ, Maurice MM, Clevers H. 2012; Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors. Nature. 488:665–669. DOI: 10.1038/nature11308. PMID: 22895187.

16. Hao HX, Jiang X, Cong F. 2016; Control of Wnt receptor turnover by R-spondin-ZNRF3/RNF43 signaling module and its dysregulation in cancer. Cancers (Basel). 8:54. DOI: 10.3390/cancers8060054. PMID: 27338477. PMCID: PMC4931619. PMID: b6ec445406544552a7bfe71eb7239ab0.

17. Qin K, Yu M, Fan J, Wang H, Zhao P, Zhao G, Zeng W, Chen C, Wang Y, Wang A, Schwartz Z, Hong J, Song L, Wagstaff W, Haydon RC, Luu HH, Ho SH, Strelzow J, Reid RR, He TC, Shi LL. 2023; Canonical and noncanonical Wnt signaling: multilayered mediators, signaling mechanisms and major signaling crosstalk. Genes Dis. doi: 10.1016/j.gendis.2023.01.030 [Epub ahead of print]. DOI: 10.1016/j.gendis.2023.01.030.

18. Chae WJ, Bothwell ALM. 2018; Canonical and non-canonical Wnt signaling in immune cells. Trends Immunol. 39:830–847. DOI: 10.1016/j.it.2018.08.006. PMID: 30213499. PMCID: PMC7367500.

19. Bugter JM, Fenderico N, Maurice MM. 2021; Mutations and mechanisms of Wnt pathway tumour suppressors in cancer. Nat Rev Cancer. 21:5–21. DOI: 10.1038/s41568-020-00307-z. PMID: 33097916.

20. Munemitsu S, Albert I, Souza B, Rubinfeld B, Polakis P. 1995; Regulation of intracellular beta-catenin levels by the adenomatous polyposis coli (APC) tumor-suppressor protein. Proc Natl Acad Sci U S A. 92:3046–50. DOI: 10.1073/pnas.92.7.3046. PMID: 7708772. PMCID: PMC42356.

21. Rubinfeld B, Albert I, Porfiri E, Fiol C, Munemitsu S, Polakis P. 1996; Binding of GSK3β to the APC-β-catenin complex and regulation of complex assembly. Science. 272:1023–1026. DOI: 10.1126/science.272.5264.1023. PMID: 8638126.

22. Rubinfeld B, Souza B, Albert I, Müller O, Chamberlain SH, Masiarz FR, Munemitsu S, Polakis P. 1993; Association of the APC gene product with β-catenin. Science. 262:1731–1734. DOI: 10.1126/science.8259518. PMID: 8259518.

23. Liu C, Li Y, Semenov M, Han C, Baeg GH, Tan Y, Zhang Z, Lin X, He X. 2002; Control of β-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell. 108:837–847. DOI: 10.1016/S0092-8674(02)00685-2. PMID: 11955436.

24. Hart M, Concordet JP, Lassot I, Albert I, del los Santos R, Durand H, Perret C, Rubinfeld B, Margottin F, Bena-rous R, Polakis P. 1999; The F-box protein β-TrCP associates with phosphorylated β-catenin and regulates its activity in the cell. Curr Biol. 9:207–210. DOI: 10.1016/S0960-9822(99)80091-8. PMID: 10074433.

25. Amit S, Hatzubai A, Birman Y, Andersen JS, Ben-Shushan E, Mann M, Ben-Neriah Y, Alkalay I. 2002; Axin-mediated CKI phosphorylation of β-catenin at Ser 45: a molecular switch for the Wnt pathway. Genes Dev. 16:1066–1076. DOI: 10.1101/gad.230302. PMID: 12000790. PMCID: PMC186245.

26. Tamai K, Semenov M, Kato Y, Spokony R, Liu C, Katsuyama Y, Hess F, Saint-Jeannet JP, He X. 2000; LDL-receptor-related proteins in Wnt signal transduction. Nature. 407:530–535. DOI: 10.1038/35035117. PMID: 11029007.

27. Nusse R, Clevers H. 2017; Wnt/β-catenin signaling, disease, and emerging therapeutic modalities. Cell. 169:985–999. DOI: 10.1016/j.cell.2017.05.016. PMID: 28575679.

28. 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. 2014; RNF43 is frequently mutated in colorectal and endometrial cancers. Nat Genet. 46:1264–1266. DOI: 10.1038/ng.3127. PMID: 25344691. PMCID: PMC4283570.

29. Sugiura T, Yamaguchi A, Miyamoto K. 2008; A cancer-associated RING finger protein, RNF43, is a ubiquitin ligase that interacts with a nuclear protein, HAP95. Exp Cell Res. 314:1519–1528. DOI: 10.1016/j.yexcr.2008.01.013. PMID: 18313049.

30. 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. 2012; ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner. Nature. 485:195–200. DOI: 10.1038/nature11019. PMID: 22575959.

31. Bian J, Dannappel M, Wan C, Firestein R. 2020; Transcriptional regulation of Wnt/β-catenin pathway in colorectal cancer. Cells. 9:2125. DOI: 10.3390/cells9092125. PMID: 32961708. PMCID: PMC7564852. PMID: 05ef0cbb6381439a9ba331ca3fa598a5.

32. Tsukiyama T, Koo BK, Hatakeyama S. 2021; Post-translational Wnt receptor regulation: is the fog slowly clearing?: the molecular mechanism of RNF43/ZNRF3 ubiquitin ligases is not yet fully elucidated and still controversial. Bioessays. 43:e2000297. DOI: 10.1002/bies.202000297. PMID: 33569855.

33. Tsukiyama T, Fukui A, Terai S, Fujioka Y, Shinada K, Takahashi H, Yamaguchi TP, Ohba Y, Hatakeyama S. 2015; Molecular role of RNF43 in canonical and noncanonical Wnt signaling. Mol Cell Biol. 35:2007–2023. DOI: 10.1128/MCB.00159-15. PMID: 25825523. PMCID: PMC4420922.

34. Carmon KS, Gong X, Lin Q, Thomas A, Liu Q. 2011; R-spondins function as ligands of the orphan receptors LGR4 and LGR5 to regulate Wnt/β-catenin signaling. Proc Natl Acad Sci U S A. 108:11452–11457. DOI: 10.1073/pnas.1106083108. PMID: 21693646. PMCID: PMC3136304.

35. de Lau W, Barker N, Low TY, Koo BK, Li VS, Teunissen H, Kujala P, Haegebarth A, Peters PJ, van de Wetering M, Stange DE, van Es JE, Guardavaccaro D, Schasfoort RB, Mohri Y, Nishimori K, Mohammed S, Heck AJ, Clevers H. 2011; Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling. Nature. 476:293–297. DOI: 10.1038/nature10337. PMID: 21727895.

36. Barker N, van Es JH, Kuipers J, Kujala P, van den Born M, Cozijnsen M, Haegebarth A, Korving J, Begthel H, Peters PJ, Clevers H. 2007; Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature. 449:1003–1007. DOI: 10.1038/nature06196. PMID: 17934449.

37. Barker N, Rookmaaker MB, Kujala P, Ng A, Leushacke M, Snippert H, van de Wetering M, Tan S, Van Es JH, Huch M, Poulsom R, Verhaar MC, Peters PJ, Clevers H. 2012; Lgr5(+ve) stem/progenitor cells contribute to nephron formation during kidney development. Cell Rep. 2:540–552. DOI: 10.1016/j.celrep.2012.08.018. PMID: 22999937. PMID: 080bb29615104b7eb96138775e7cda62.

38. de Visser KE, Ciampricotti M, Michalak EM, Tan DW, Speksnijder EN, Hau CS, Clevers H, Barker N, Jonkers J. 2012; Developmental stage-specific contribution of LGR5(+) cells to basal and luminal epithelial lineages in the postnatal mammary gland. J Pathol. 228:300–309. DOI: 10.1002/path.4096. PMID: 22926799.

39. Snippert HJ, Haegebarth A, Kasper M, Jaks V, van Es JH, Barker N, van de Wetering M, van den Born M, Begthel H, Vries RG, Stange DE, Toftgård R, Clevers H. 2010; Lgr6 marks stem cells in the hair follicle that generate all cell lineages of the skin. Science. 327:1385–1389. DOI: 10.1126/science.1184733. PMID: 20223988.

40. Wang Y, Dong J, Li D, Lai L, Siwko S, Li Y, Liu M. 2013; Lgr4 regulates mammary gland development and stem cell activity through the pluripotency transcription factor Sox2. Stem Cells. 31:1921–1931. DOI: 10.1002/stem.1438. PMID: 23712846. PMCID: PMC3934111.

41. 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. 2013; Interaction with both ZNRF3 and LGR4 is required for the signalling activity of R-spondin. EMBO Rep. 14:1120–1126. DOI: 10.1038/embor.2013.167. PMID: 24165923. PMCID: PMC3981092.

42. Kim KA, Kakitani M, Zhao J, Oshima T, Tang T, Binnerts M, Liu Y, Boyle B, Park E, Emtage P, Funk WD, Tomizuka K. 2005; Mitogenic influence of human R-spondin1 on the intestinal epithelium. Science. 309:1256–1259. DOI: 10.1126/science.1112521. PMID: 16109882.

43. Kazanskaya O, Glinka A, del Barco Barrantes I, Stannek P, Niehrs C, Wu W. 2004; R-Spondin2 is a secreted activator of Wnt/β-catenin signaling and is required for Xenopus myogenesis. Dev Cell. 7:525–534. DOI: 10.1016/j.devcel.2004.07.019. PMID: 15469841.

44. de Lau W, Peng WC, Gros P, Clevers H. 2014; The R-spondin/Lgr5/Rnf43 module: regulator of Wnt signal strength. Genes Dev. 28:305–316. DOI: 10.1101/gad.235473.113. PMID: 24532711. PMCID: PMC3937510.

45. Peng WC, de Lau W, Madoori PK, Forneris F, Granneman JC, Clevers H, Gros P. 2013; Structures of Wnt-antagonist ZNRF3 and its complex with R-spondin 1 and implications for signaling. PLoS One. 8:e83110. DOI: 10.1371/journal.pone.0083110. PMID: 24349440. PMCID: PMC3861454. PMID: ffe8805d8728401daf6954e4ef9835cb.

46. Zebisch M, Xu Y, Krastev C, MacDonald BT, Chen M, Gilbert RJ, He X, Jones EY. 2013; Structural and molecular basis of ZNRF3/RNF43 transmembrane ubiquitin ligase inhibition by the Wnt agonist R-spondin. Nat Commun. 4:2787. DOI: 10.1038/ncomms3787. PMID: 24225776. PMCID: PMC3905715.

47. Jiang X, Charlat O, Zamponi R, Yang Y, Cong F. 2015; Dishe-velled promotes Wnt receptor degradation through recruitment of ZNRF3/RNF43 E3 ubiquitin ligases. Mol Cell. 58:522–533. DOI: 10.1016/j.molcel.2015.03.015. PMID: 25891077.

48. Lebensohn AM, Rohatgi R. 2018; R-spondins can potentiate WNT signaling without LGRs. Elife. 7:e33126. DOI: 10.7554/eLife.33126. PMID: 29405118. PMCID: PMC5800842. PMID: 223eee0f4ab844d9b6592e4320906d61.

49. Szenker-Ravi E, Altunoglu U, Leushacke M, Bosso-Lefèvre C, Khatoo M, Thi Tran H, Naert T, Noelanders R, Hajamo-hideen 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, Reve-rsade B. 2018; RSPO2 inhibition of RNF43 and ZNRF3 governs limb development independently of LGR4/5/6. Nature. 557:564–569. DOI: 10.1038/s41586-018-0118-y. PMID: 29769720.

50. Schulte G, Bryja V. 2007; The frizzled family of unconventional G-protein-coupled receptors. Trends Pharmacol Sci. 28:518–525. DOI: 10.1016/j.tips.2007.09.001. PMID: 17884187.

51. Bhanot P, Brink M, Samos CH, Hsieh JC, Wang Y, Macke JP, Andrew D, Nathans J, Nusse R. 1996; A new member of the frizzled family from Drosophila functions as a Wingless receptor. Nature. 382:225–230. DOI: 10.1038/382225a0. PMID: 8717036.

52. Tauriello DV, Jordens I, Kirchner K, Slootstra JW, Kruit-wagen T, Bouwman BA, Noutsou M, Rüdiger SG, Schwa-mborn K, Schambony A, Maurice MM. 2012; Wnt/β-catenin signaling requires interaction of the Dishevelled DEP domain and C terminus with a discontinuous motif in Frizzled. Proc Natl Acad Sci U S A. 109:E812–E820. DOI: 10.1073/pnas.1114802109. PMID: 22411803. PMCID: PMC3325702.

53. Umbhauer M, Djiane A, Goisset C, Penzo-Méndez A, Riou JF, Boucaut JC, Shi DL. 2000; The C-terminal cytoplasmic Lys-thr-X-X-X-Trp motif in frizzled receptors mediates Wnt/beta-catenin signalling. EMBO J. 19:4944–4954. DOI: 10.1093/emboj/19.18.4944. PMID: 10990458. PMCID: PMC314225.

54. Ko SB, Mihara E, Park Y, Roh K, Kang C, Takagi J, Bang I, Choi HJ. 2022; Functional role of the frizzled linker domain in the Wnt signaling pathway. Commun Biol. 5:421. DOI: 10.1038/s42003-022-03370-4. PMID: 35513706. PMCID: PMC9072438. PMID: 080ac9acde79442fb05c5f4dde94f497.

55. Spit M, Fenderico N, Jordens I, Radaszkiewicz T, Linde-boom 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 BK, Vermeulen M, Maurice MM. 2020; RNF43 truncations trap CK1 to drive niche-independent self-renewal in cancer. EMBO J. 39:e103932. DOI: 10.15252/embj.2019103932. PMID: 32965059. PMCID: PMC7503102.

56. 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. 2020; A phospho-switch controls RNF43-me-diated degradation of Wnt receptors to suppress tumorigenesis. Nat Commun. 11:4586. DOI: 10.1038/s41467-020-18257-3. PMID: 32934222. PMCID: PMC7492264. PMID: 8bbcf86e1ff943ee8f363d3d01a94e7d.

57. Ci Y, Li X, Chen M, Zhong J, North BJ, Inuzuka H, He X, Li Y, Guo J, Dai X. 2018; SCFβ-TRCP E3 ubiquitin ligase targets the tumor suppressor ZNRF3 for ubiquitination and degradation. Protein Cell. 9:879–889. DOI: 10.1007/s13238-018-0510-2. PMID: 29497989. PMCID: PMC6160385. PMID: 93722ce5a2c342c2829a17d45616a3ea.

58. Chang LS, Kim M, Glinka A, Reinhard C, Niehrs C. 2020; The tumor suppressor PTPRK promotes ZNRF3 internalization and is required for Wnt inhibition in the Spemann orga-nizer. Elife. 9:e51248. DOI: 10.7554/eLife.51248. PMID: 31934854. PMCID: PMC6996932. PMID: 893298afe7204b6cb05baedb04797b55.

59. Kim M, Reinhard C, Niehrs C. 2021; A MET-PTPRK kinase-phosphatase rheostat controls ZNRF3 and Wnt signaling. Elife. 10:e70885. DOI: 10.7554/eLife.70885. PMID: 34590584. PMCID: PMC8516413. PMID: 88df3c98cdff49679723ce343f08a758.

60. Martin BL, Kimelman D. 2009; Wnt signaling and the evolution of embryonic posterior development. Curr Biol. 19:R215–R219. DOI: 10.1016/j.cub.2009.01.052. PMID: 19278640. PMCID: PMC5560127.

61. Loh KM, van Amerongen R, Nusse R. 2016; Generating cellular diversity and spatial form: Wnt signaling and the evolution of multicellular animals. Dev Cell. 38:643–655. DOI: 10.1016/j.devcel.2016.08.011. PMID: 27676437.

62. Eichinger L, Pachebat JA, Glöckner G, Rajandream MA, Sucgang R, Berriman M, Song J, Olsen R, Szafranski K, Xu Q, Tunggal B, Kummerfeld S, Madera M, Konfortov BA, Rivero F, Bankier AT, Lehmann R, Hamlin N, Davies R, Gaudet P, Fey P, Pilcher K, Chen G, Saunders D, Sodergren E, Davis P, Kerhornou A, Nie X, Hall N, Anjard C, Hem-phill L, Bason N, Farbrother P, Desany B, Just E, Morio T, Rost R, Churcher C, Cooper J, Haydock S, van Driessche N, Cronin A, Goodhead I, Muzny D, Mourier T, Pain A, Lu M, Harper D, Lindsay R, Hauser H, James K, Quiles M, Madan Babu M, Saito T, Buchrieser C, Wardroper A, Felder M, Thangavelu M, Johnson D, Knights A, Loulseged H, Mungall K, Oliver K, Price C, Quail MA, Urushihara H, Hernandez J, Rabbinowitsch E, Steffen D, Sanders M, Ma J, Kohara Y, Sharp S, Simmonds M, Spiegler S, Tivey A, Sugano S, White B, Walker D, Woodward J, Winckler T, Tanaka Y, Shaulsky G, Schleicher M, Weinstock G, Rosenthal A, Cox EC, Chisholm RL, Gibbs R, Loomis WF, Platzer M, Kay RR, Williams J, Dear PH, Noegel AA, Barrell B, Kuspa A. 2005; The genome of the social amoeba Dictyostelium discoideum. Nature. 435:43–57. DOI: 10.1038/nature03481. PMID: 15875012. PMCID: PMC1352341.

63. Prabhu Y, Eichinger L. 2006; The Dictyostelium repertoire of seven transmembrane domain receptors. Eur J Cell Biol. 85:937–946. DOI: 10.1016/j.ejcb.2006.04.003. PMID: 16735079.

64. Harwood AJ. 2008; Dictyostelium development: a prototypic Wnt pathway? Methods Mol Biol. 469:21–32. DOI: 10.1007/978-1-60327-469-2_2. PMID: 19109699.

65. Cai C, Tang YD, Zhai J, Zheng C. 2022; The RING finger protein family in health and disease. Signal Transduct Target Ther. 7:300. DOI: 10.1038/s41392-022-01152-2. PMID: 36042206. PMCID: PMC9424811. PMID: 42d9b539f30343e082cfa08f0285eb67.

66. Anandasabapathy N, Ford GS, Bloom D, Holness C, Paragas V, Seroogy C, Skrenta H, Hollenhorst M, Fathman CG, Soares L. 2003; GRAIL: an E3 ubiquitin ligase that inhibits cytokine gene transcription is expressed in anergic CD4+ T cells. Immunity. 18:535–547. DOI: 10.1016/S1074-7613(03)00084-0. PMID: 12705856.

67. Wang H, Rogers JC, Jiang L. 2011; Plant RMR proteins: unique vacuolar sorting receptors that couple ligand sorting with membrane internalization. FEBS J. 278:59–68. DOI: 10.1111/j.1742-4658.2010.07923.x. PMID: 21078125.

68. Zebisch M, Jones EY. 2015; ZNRF3/RNF43--a direct linkage of extracellular recognition and E3 ligase activity to modulate cell surface signalling. Prog Biophys Mol Biol. 118:112–118. DOI: 10.1016/j.pbiomolbio.2015.04.006. PMID: 25937466.