Skip to main content
PMC home page
Genetics logoLink to Genetics
. 2001 Sep;159(1):159–172. doi: 10.1093/genetics/159.1.159

The divergent Caenorhabditis elegans beta-catenin proteins BAR-1, WRM-1 and HMP-2 make distinct protein interactions but retain functional redundancy in vivo.

L Natarajan 1, N E Witwer 1, D M Eisenmann 1
PMCID: PMC1461775  PMID: 11560894

Abstract

beta-Catenins function both in cell adhesion as part of the cadherin/catenin complex and in Wnt signal transduction as transcription factors. Vertebrates express two related proteins, beta-catenin and plakoglobin, while Drosophila has a single family member, Armadillo. Caenorhabditis elegans expresses three beta-catenin-related proteins, BAR-1, HMP-2, and WRM-1, which are quite diverged in sequence from each other and other beta-catenins. While BAR-1 and WRM-1 are known to act in Wnt-mediated processes, and HMP-2 acts in a complex with cadherin/alpha-catenin homologs, it is unclear whether all three proteins retain the other functions of beta-catenin. Here we show that BAR-1, like vertebrate beta-catenin, has redundant transcription activation domains in its amino- and carboxyl-terminal regions but that HMP-2 and WRM-1 also possess the ability to activate transcription. We show via yeast two-hybrid analysis that these three proteins display distinct patterns of protein interactions. Surprisingly, we find that both WRM-1 and HMP-2 can substitute for BAR-1 in C. elegans when expressed from the bar-1 promoter. Therefore, although their mutant phenotypes and protein interaction patterns strongly suggest that the functions of beta-catenin in other species have been segregated among three diverged proteins in C. elegans, these proteins still retain sufficient similarity to display functional redundancy in vivo.

Full Text

The Full Text of this article is available as a PDF (251.1 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Altschul S. F., Gish W., Miller W., Myers E. W., Lipman D. J. Basic local alignment search tool. J Mol Biol. 1990 Oct 5;215(3):403–410. doi: 10.1016/S0022-2836(05)80360-2. [DOI] [PubMed] [Google Scholar]
  2. Anastasiadis P. Z., Reynolds A. B. The p120 catenin family: complex roles in adhesion, signaling and cancer. J Cell Sci. 2000 Apr;113(Pt 8):1319–1334. doi: 10.1242/jcs.113.8.1319. [DOI] [PubMed] [Google Scholar]
  3. Arm R. N., Kennon S., Wig P. P., Tasch E. G. Relationship of accumulated plaque to development of caries among various age groups. Clin Prev Dent. 1979 Nov-Dec;1(6):23–27. [PubMed] [Google Scholar]
  4. Behrens J., von Kries J. P., Kühl M., Bruhn L., Wedlich D., Grosschedl R., Birchmeier W. Functional interaction of beta-catenin with the transcription factor LEF-1. Nature. 1996 Aug 15;382(6592):638–642. doi: 10.1038/382638a0. [DOI] [PubMed] [Google Scholar]
  5. Ben-Ze'ev A., Geiger B. Differential molecular interactions of beta-catenin and plakoglobin in adhesion, signaling and cancer. Curr Opin Cell Biol. 1998 Oct;10(5):629–639. doi: 10.1016/s0955-0674(98)80039-2. [DOI] [PubMed] [Google Scholar]
  6. Bierkamp C., Mclaughlin K. J., Schwarz H., Huber O., Kemler R. Embryonic heart and skin defects in mice lacking plakoglobin. Dev Biol. 1996 Dec 15;180(2):780–785. doi: 10.1006/dbio.1996.0346. [DOI] [PubMed] [Google Scholar]
  7. Brenner S. The genetics of Caenorhabditis elegans. Genetics. 1974 May;77(1):71–94. doi: 10.1093/genetics/77.1.71. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Butz S., Stappert J., Weissig H., Kemler R. Plakoglobin and beta-catenin: distinct but closely related. Science. 1992 Aug 21;257(5073):1142–1144. doi: 10.1126/science.257.5073.1142-a. [DOI] [PubMed] [Google Scholar]
  9. C. elegans Sequencing Consortium Genome sequence of the nematode C. elegans: a platform for investigating biology. Science. 1998 Dec 11;282(5396):2012–2018. doi: 10.1126/science.282.5396.2012. [DOI] [PubMed] [Google Scholar]
  10. Cadigan K. M., Nusse R. Wnt signaling: a common theme in animal development. Genes Dev. 1997 Dec 15;11(24):3286–3305. doi: 10.1101/gad.11.24.3286. [DOI] [PubMed] [Google Scholar]
  11. Costa M., Raich W., Agbunag C., Leung B., Hardin J., Priess J. R. A putative catenin-cadherin system mediates morphogenesis of the Caenorhabditis elegans embryo. J Cell Biol. 1998 Apr 6;141(1):297–308. doi: 10.1083/jcb.141.1.297. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Cowin P., Burke B. Cytoskeleton-membrane interactions. Curr Opin Cell Biol. 1996 Feb;8(1):56–65. doi: 10.1016/s0955-0674(96)80049-4. [DOI] [PubMed] [Google Scholar]
  13. Eastman Q., Grosschedl R. Regulation of LEF-1/TCF transcription factors by Wnt and other signals. Curr Opin Cell Biol. 1999 Apr;11(2):233–240. doi: 10.1016/s0955-0674(99)80031-3. [DOI] [PubMed] [Google Scholar]
  14. Eisenmann D. M., Kim S. K. Protruding vulva mutants identify novel loci and Wnt signaling factors that function during Caenorhabditis elegans vulva development. Genetics. 2000 Nov;156(3):1097–1116. doi: 10.1093/genetics/156.3.1097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Fields S., Song O. A novel genetic system to detect protein-protein interactions. Nature. 1989 Jul 20;340(6230):245–246. doi: 10.1038/340245a0. [DOI] [PubMed] [Google Scholar]
  16. Gumbiner B. M. Cell adhesion: the molecular basis of tissue architecture and morphogenesis. Cell. 1996 Feb 9;84(3):345–357. doi: 10.1016/s0092-8674(00)81279-9. [DOI] [PubMed] [Google Scholar]
  17. Guo B., Styles C. A., Feng Q., Fink G. R. A Saccharomyces gene family involved in invasive growth, cell-cell adhesion, and mating. Proc Natl Acad Sci U S A. 2000 Oct 24;97(22):12158–12163. doi: 10.1073/pnas.220420397. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Haegel H., Larue L., Ohsugi M., Fedorov L., Herrenknecht K., Kemler R. Lack of beta-catenin affects mouse development at gastrulation. Development. 1995 Nov;121(11):3529–3537. doi: 10.1242/dev.121.11.3529. [DOI] [PubMed] [Google Scholar]
  19. Hatzfeld M., Kristjansson G. I., Plessmann U., Weber K. Band 6 protein, a major constituent of desmosomes from stratified epithelia, is a novel member of the armadillo multigene family. J Cell Sci. 1994 Aug;107(Pt 8):2259–2270. doi: 10.1242/jcs.107.8.2259. [DOI] [PubMed] [Google Scholar]
  20. Hatzfeld M., Nachtsheim C. Cloning and characterization of a new armadillo family member, p0071, associated with the junctional plaque: evidence for a subfamily of closely related proteins. J Cell Sci. 1996 Nov;109(Pt 11):2767–2778. doi: 10.1242/jcs.109.11.2767. [DOI] [PubMed] [Google Scholar]
  21. Hecht A., Litterst C. M., Huber O., Kemler R. Functional characterization of multiple transactivating elements in beta-catenin, some of which interact with the TATA-binding protein in vitro. J Biol Chem. 1999 Jun 18;274(25):18017–18025. doi: 10.1074/jbc.274.25.18017. [DOI] [PubMed] [Google Scholar]
  22. Herman M. A., Ch'ng Q., Hettenbach S. M., Ratliff T. M., Kenyon C., Herman R. K. EGL-27 is similar to a metastasis-associated factor and controls cell polarity and cell migration in C. elegans. Development. 1999 Feb;126(5):1055–1064. doi: 10.1242/dev.126.5.1055. [DOI] [PubMed] [Google Scholar]
  23. Herman M. C. elegans POP-1/TCF functions in a canonical Wnt pathway that controls cell migration and in a noncanonical Wnt pathway that controls cell polarity. Development. 2001 Feb;128(4):581–590. doi: 10.1242/dev.128.4.581. [DOI] [PubMed] [Google Scholar]
  24. Higgins D. G., Thompson J. D., Gibson T. J. Using CLUSTAL for multiple sequence alignments. Methods Enzymol. 1996;266:383–402. doi: 10.1016/s0076-6879(96)66024-8. [DOI] [PubMed] [Google Scholar]
  25. Hobmayer E., Hatta M., Fischer R., Fujisawa T., Holstein T. W., Sugiyama T. Identification of a Hydra homologue of the beta-catenin/plakoglobin/armadillo gene family. Gene. 1996 Jun 12;172(1):155–159. doi: 10.1016/0378-1119(96)00162-x. [DOI] [PubMed] [Google Scholar]
  26. Hoier E. F., Mohler W. A., Kim S. K., Hajnal A. The Caenorhabditis elegans APC-related gene apr-1 is required for epithelial cell migration and Hox gene expression. Genes Dev. 2000 Apr 1;14(7):874–886. [PMC free article] [PubMed] [Google Scholar]
  27. Holland P. W. The future of evolutionary developmental biology. Nature. 1999 Dec 2;402(6761 Suppl):C41–C44. doi: 10.1038/35011536. [DOI] [PubMed] [Google Scholar]
  28. Hsu S. C., Galceran J., Grosschedl R. Modulation of transcriptional regulation by LEF-1 in response to Wnt-1 signaling and association with beta-catenin. Mol Cell Biol. 1998 Aug;18(8):4807–4818. doi: 10.1128/mcb.18.8.4807. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. James P., Halladay J., Craig E. A. Genomic libraries and a host strain designed for highly efficient two-hybrid selection in yeast. Genetics. 1996 Dec;144(4):1425–1436. doi: 10.1093/genetics/144.4.1425. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Jiang L. I., Sternberg P. W. An HMG1-like protein facilitates Wnt signaling in Caenorhabditis elegans. Genes Dev. 1999 Apr 1;13(7):877–889. doi: 10.1101/gad.13.7.877. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Jiang L. I., Sternberg P. W. Interactions of EGF, Wnt and HOM-C genes specify the P12 neuroectoblast fate in C. elegans. Development. 1998 Jun;125(12):2337–2347. doi: 10.1242/dev.125.12.2337. [DOI] [PubMed] [Google Scholar]
  32. Jin Y., Hoskins R., Horvitz H. R. Control of type-D GABAergic neuron differentiation by C. elegans UNC-30 homeodomain protein. Nature. 1994 Dec 22;372(6508):780–783. doi: 10.1038/372780a0. [DOI] [PubMed] [Google Scholar]
  33. Kemler R. From cadherins to catenins: cytoplasmic protein interactions and regulation of cell adhesion. Trends Genet. 1993 Sep;9(9):317–321. doi: 10.1016/0168-9525(93)90250-l. [DOI] [PubMed] [Google Scholar]
  34. Knoll A. H., Carroll S. B. Early animal evolution: emerging views from comparative biology and geology. Science. 1999 Jun 25;284(5423):2129–2137. doi: 10.1126/science.284.5423.2129. [DOI] [PubMed] [Google Scholar]
  35. Kodama S., Ikeda S., Asahara T., Kishida M., Kikuchi A. Axin directly interacts with plakoglobin and regulates its stability. J Biol Chem. 1999 Sep 24;274(39):27682–27688. doi: 10.1074/jbc.274.39.27682. [DOI] [PubMed] [Google Scholar]
  36. Kolligs F. T., Kolligs B., Hajra K. M., Hu G., Tani M., Cho K. R., Fearon E. R. gamma-catenin is regulated by the APC tumor suppressor and its oncogenic activity is distinct from that of beta-catenin. Genes Dev. 2000 Jun 1;14(11):1319–1331. [PMC free article] [PubMed] [Google Scholar]
  37. Korswagen H. C., Herman M. A., Clevers H. C. Distinct beta-catenins mediate adhesion and signalling functions in C. elegans. Nature. 2000 Aug 3;406(6795):527–532. doi: 10.1038/35020099. [DOI] [PubMed] [Google Scholar]
  38. Lin R., Thompson S., Priess J. R. pop-1 encodes an HMG box protein required for the specification of a mesoderm precursor in early C. elegans embryos. Cell. 1995 Nov 17;83(4):599–609. doi: 10.1016/0092-8674(95)90100-0. [DOI] [PubMed] [Google Scholar]
  39. Maloof J. N., Whangbo J., Harris J. M., Jongeward G. D., Kenyon C. A Wnt signaling pathway controls hox gene expression and neuroblast migration in C. elegans. Development. 1999 Jan;126(1):37–49. doi: 10.1242/dev.126.1.37. [DOI] [PubMed] [Google Scholar]
  40. Meneghini M. D., Ishitani T., Carter J. C., Hisamoto N., Ninomiya-Tsuji J., Thorpe C. J., Hamill D. R., Matsumoto K., Bowerman B. MAP kinase and Wnt pathways converge to downregulate an HMG-domain repressor in Caenorhabditis elegans. Nature. 1999 Jun 24;399(6738):793–797. doi: 10.1038/21666. [DOI] [PubMed] [Google Scholar]
  41. Mertens C., Kuhn C., Franke W. W. Plakophilins 2a and 2b: constitutive proteins of dual location in the karyoplasm and the desmosomal plaque. J Cell Biol. 1996 Nov;135(4):1009–1025. doi: 10.1083/jcb.135.4.1009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Morin P. J., Sparks A. B., Korinek V., Barker N., Clevers H., Vogelstein B., Kinzler K. W. Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science. 1997 Mar 21;275(5307):1787–1790. doi: 10.1126/science.275.5307.1787. [DOI] [PubMed] [Google Scholar]
  43. Nevels M., Wolf H., Dobner T. Quantitation of beta-galactosidase from yeast cells using a chemiluminescent substrate. Biotechniques. 1999 Jan;26(1):57–58. doi: 10.2144/99261bm08. [DOI] [PubMed] [Google Scholar]
  44. Näthke I. S., Adams C. L., Polakis P., Sellin J. H., Nelson W. J. The adenomatous polyposis coli tumor suppressor protein localizes to plasma membrane sites involved in active cell migration. J Cell Biol. 1996 Jul;134(1):165–179. doi: 10.1083/jcb.134.1.165. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Orsulic S., Peifer M. An in vivo structure-function study of armadillo, the beta-catenin homologue, reveals both separate and overlapping regions of the protein required for cell adhesion and for wingless signaling. J Cell Biol. 1996 Sep;134(5):1283–1300. doi: 10.1083/jcb.134.5.1283. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Pai L. M., Orsulic S., Bejsovec A., Peifer M. Negative regulation of Armadillo, a Wingless effector in Drosophila. Development. 1997 Jun;124(11):2255–2266. doi: 10.1242/dev.124.11.2255. [DOI] [PubMed] [Google Scholar]
  47. Peifer M., McCrea P. D., Green K. J., Wieschaus E., Gumbiner B. M. The vertebrate adhesive junction proteins beta-catenin and plakoglobin and the Drosophila segment polarity gene armadillo form a multigene family with similar properties. J Cell Biol. 1992 Aug;118(3):681–691. doi: 10.1083/jcb.118.3.681. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Peifer M., Wieschaus E. The segment polarity gene armadillo encodes a functionally modular protein that is the Drosophila homolog of human plakoglobin. Cell. 1990 Dec 21;63(6):1167–1176. doi: 10.1016/0092-8674(90)90413-9. [DOI] [PubMed] [Google Scholar]
  49. Reynolds A. B., Herbert L., Cleveland J. L., Berg S. T., Gaut J. R. p120, a novel substrate of protein tyrosine kinase receptors and of p60v-src, is related to cadherin-binding factors beta-catenin, plakoglobin and armadillo. Oncogene. 1992 Dec;7(12):2439–2445. [PubMed] [Google Scholar]
  50. Rocheleau C. E., Downs W. D., Lin R., Wittmann C., Bei Y., Cha Y. H., Ali M., Priess J. R., Mello C. C. Wnt signaling and an APC-related gene specify endoderm in early C. elegans embryos. Cell. 1997 Aug 22;90(4):707–716. doi: 10.1016/s0092-8674(00)80531-0. [DOI] [PubMed] [Google Scholar]
  51. Rocheleau C. E., Yasuda J., Shin T. H., Lin R., Sawa H., Okano H., Priess J. R., Davis R. J., Mello C. C. WRM-1 activates the LIT-1 protein kinase to transduce anterior/posterior polarity signals in C. elegans. Cell. 1999 Jun 11;97(6):717–726. doi: 10.1016/s0092-8674(00)80784-9. [DOI] [PubMed] [Google Scholar]
  52. Rubinfeld B., Souza B., Albert I., Müller O., Chamberlain S. H., Masiarz F. R., Munemitsu S., Polakis P. Association of the APC gene product with beta-catenin. Science. 1993 Dec 10;262(5140):1731–1734. doi: 10.1126/science.8259518. [DOI] [PubMed] [Google Scholar]
  53. Ruiz P., Brinkmann V., Ledermann B., Behrend M., Grund C., Thalhammer C., Vogel F., Birchmeier C., Günthert U., Franke W. W. Targeted mutation of plakoglobin in mice reveals essential functions of desmosomes in the embryonic heart. J Cell Biol. 1996 Oct;135(1):215–225. doi: 10.1083/jcb.135.1.215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Schmidt A., Langbein L., Prätzel S., Rode M., Rackwitz H. R., Franke W. W. Plakophilin 3--a novel cell-type-specific desmosomal plaque protein. Differentiation. 1999 Jun;64(5):291–306. doi: 10.1046/j.1432-0436.1999.6450291.x. [DOI] [PubMed] [Google Scholar]
  55. Shin T. H., Yasuda J., Rocheleau C. E., Lin R., Soto M., Bei Y., Davis R. J., Mello C. C. MOM-4, a MAP kinase kinase kinase-related protein, activates WRM-1/LIT-1 kinase to transduce anterior/posterior polarity signals in C. elegans. Mol Cell. 1999 Aug;4(2):275–280. doi: 10.1016/s1097-2765(00)80375-5. [DOI] [PubMed] [Google Scholar]
  56. Simcha I., Shtutman M., Salomon D., Zhurinsky J., Sadot E., Geiger B., Ben-Ze'ev A. Differential nuclear translocation and transactivation potential of beta-catenin and plakoglobin. J Cell Biol. 1998 Jun 15;141(6):1433–1448. doi: 10.1083/jcb.141.6.1433. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Sirotkin H., O'Donnell H., DasGupta R., Halford S., St Jore B., Puech A., Parimoo S., Morrow B., Skoultchi A., Weissman S. M. Identification of a new human catenin gene family member (ARVCF) from the region deleted in velo-cardio-facial syndrome. Genomics. 1997 Apr 1;41(1):75–83. doi: 10.1006/geno.1997.4627. [DOI] [PubMed] [Google Scholar]
  58. Solari F., Bateman A., Ahringer J. The Caenorhabditis elegans genes egl-27 and egr-1 are similar to MTA1, a member of a chromatin regulatory complex, and are redundantly required for embryonic patterning. Development. 1999 Jun;126(11):2483–2494. doi: 10.1242/dev.126.11.2483. [DOI] [PubMed] [Google Scholar]
  59. Su L. K., Vogelstein B., Kinzler K. W. Association of the APC tumor suppressor protein with catenins. Science. 1993 Dec 10;262(5140):1734–1737. doi: 10.1126/science.8259519. [DOI] [PubMed] [Google Scholar]
  60. Tanahashi H., Tabira T. Isolation of human delta-catenin and its binding specificity with presenilin 1. Neuroreport. 1999 Feb 25;10(3):563–568. doi: 10.1097/00001756-199902250-00022. [DOI] [PubMed] [Google Scholar]
  61. White P., Aberle H., Vincent J. P. Signaling and adhesion activities of mammalian beta-catenin and plakoglobin in Drosophila. J Cell Biol. 1998 Jan 12;140(1):183–195. doi: 10.1083/jcb.140.1.183. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Willert K., Nusse R. Beta-catenin: a key mediator of Wnt signaling. Curr Opin Genet Dev. 1998 Feb;8(1):95–102. doi: 10.1016/s0959-437x(98)80068-3. [DOI] [PubMed] [Google Scholar]
  63. Yap A. S., Brieher W. M., Gumbiner B. M. Molecular and functional analysis of cadherin-based adherens junctions. Annu Rev Cell Dev Biol. 1997;13:119–146. doi: 10.1146/annurev.cellbio.13.1.119. [DOI] [PubMed] [Google Scholar]
  64. Yost C., Torres M., Miller J. R., Huang E., Kimelman D., Moon R. T. The axis-inducing activity, stability, and subcellular distribution of beta-catenin is regulated in Xenopus embryos by glycogen synthase kinase 3. Genes Dev. 1996 Jun 15;10(12):1443–1454. doi: 10.1101/gad.10.12.1443. [DOI] [PubMed] [Google Scholar]
  65. van de Wetering M., Cavallo R., Dooijes D., van Beest M., van Es J., Loureiro J., Ypma A., Hursh D., Jones T., Bejsovec A. Armadillo coactivates transcription driven by the product of the Drosophila segment polarity gene dTCF. Cell. 1997 Mar 21;88(6):789–799. doi: 10.1016/s0092-8674(00)81925-x. [DOI] [PubMed] [Google Scholar]
  66. von Kries J. P., Winbeck G., Asbrand C., Schwarz-Romond T., Sochnikova N., Dell'Oro A., Behrens J., Birchmeier W. Hot spots in beta-catenin for interactions with LEF-1, conductin and APC. Nat Struct Biol. 2000 Sep;7(9):800–807. doi: 10.1038/79039. [DOI] [PubMed] [Google Scholar]

Articles from Genetics are provided here courtesy of Oxford University Press

RESOURCES