Vol. 13, No. 3, 2004
Issue release date: May–June 2004
Neurosignals 2004;13:99–113
(DOI:10.1159/000076563)
Review
Add to my selection

Axin: A Master Scaffold for Multiple Signaling Pathways

Luo W. · Lin S.-C.
Department of Biochemistry, Hong Kong University of Science and Technology, Hong Kong, and Department of Biology, Xiamen University, Xiamen, China
email Corresponding Author


 goto top of outline Key Words

  • Axin, biological function
  • Axin, identification
  • Axin/JNK signaling pathway
  • Wnt pathway

 goto top of outline Abstract

Axin was originally identified from the characterization of the Fused locus, the disruption of which leads to duplication of axis and embryonic lethality. It is a multidomain protein that interacts with multiple proteins and functions as a negative regulator of Wnt signaling by downregulating the β-catenin levels. Recently, it was demonstrated that Axin also plays an important role in a JNK signaling pathway. Axin utilizes discriminatory domains for its distinct roles in the Wnt pathway and in the Axin/JNK pathway. Here we review the data that show how Axin regulates multiple signaling pathways by serving as a scaffold protein, controlling diverse cellular functions in proliferation, fate determination, and suppression of tumorigenesis.

Copyright © 2004 S. Karger AG, Basel


 goto top of outline References
  1. Wodarz A, Nusse R: Mechanisms of Wnt signaling in development. Annu Rev Cell Dev Biol 1998;14:59–88.
  2. Pandur P, Maurus D, Kuhl M: Increasingly complex: New players enter the Wnt signaling network. Bioessays 2002;24:881–884.
  3. Mao J, Wang J, Liu B, Pan W, Farr GH 3rd, Flynn C, Yuan H, Takada S, Kimelman D, Li L, Wu D: Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway. Mol Cell 2001;7:801–809.
  4. Wehrli M, Dougan ST, Caldwell K, O’Keefe L, Schwartz S, Vaizel D: arrow encodes an LDL-receptor-related protein essential for Wingless signaling. Nature 2000;407:527–530.
  5. Tolwinski NS, Wehrli M, Rives A, Erdeniz N, DiNardo S, Wieschaus E: Wg/Wnt signal can be transmitted through arrow/LRP5,6 and Axin independently of Zw3/GSK-3β activity. Dev Cell 2003;4:407–418.
  6. Kishida S, Yamamoto H, Hino S, Ikeda M, Kishida M, Kikuchi A: DIX domains of Dvl and Axin are necessary for protein interactions and their ability to regulate β-catenin stability. Mol Cell Biol 1999;19:4414–4422.
  7. Li L, Yuan H, Weaver CD, Mao J, Farr GH, Sussman DJ, Jonkers J, Kimelman D, Wu D: Axin and Frat1 interact with Dvl and GSK, bridging Dvl to GSK in Wnt-mediated regulation of LEF-1. EMBO J 1999;18:4233–4240.
  8. Kishida S, Yamamoto H, Ikeda S, Kishida M, Sakamoto I, Koyama S, Kikuchi A: Axin, a negative regulator of the wnt signaling pathway, directly interacts with adenomatous polyposis coli and regulates the stabilization of β-catenin. J Biol Chem 1998;273:10823–10826.
  9. Hart MJ, de los Santos R, Albert IN, Rubinfeld B, Polakis P: Downregulation of β-catenin by human Axin and its association with the APC tumor suppressor, β-catenin and GSK-3β. Curr Biol 1998;8:573–581.
  10. Nakamura T, Hamada F, Ishidate T, Anai K, Kawahara K, Toyoshima K, Akiyama T: Axin, an inhibitor of the Wnt signaling pathway, interacts with β-catenin, GSK-3β and APC and reduces the β-catenin level. Genes Cells 1998;3:395–403.
  11. Rubinfeld B, Tice DA, Polakis P: Axin-dependent phosphorylation of the adenomatous polyposis coli protein mediated by casein kinase Iε. J Biol Chem 2001;276:39037–39045.
  12. Hsu W, Zeng L, Costantini F: Identification of a domain of Axin that binds to the serine/threonine protein phosphatase 2A and a self-binding domain. J Biol Chem 1999;274:3439–3445.
  13. Schwarz-Romond T, Asbrand C, Bakkers J, Kuhl M, Schaeffer HJ, Huelsken J, Behrens J, Hammerschmidt M, Birchmeier W: The ankyrin repeat protein diversin recruits casein kinase Iε to the β-catenin degradation complex and acts in both canonical Wnt and Wnt/JNK signaling. Genes Dev 2002;16:2073–2084.
  14. Shiomi K, Uchida H, Keino-Masu K, Masu M: Ccd1, a novel protein with a DIX domain, is a positive regulator in the Wnt signaling during zebrafish neural patterning. Curr Biol 2003;13:73–77.
  15. Kadoya T, Kishida S, Fukui A, Hinoi T, Michiue T, Asashima M, Kikuchi A: Inhibition of Wnt signaling pathway by a novel Axin-binding protein. J Biol Chem 2000;275:37030–37037.
  16. Cliffe A, Hamada F, Bienz M: A role of Dishevelled in relocating axin to the plasma membrane during wingless signaling. Curr Biol 2003;13:960–966.
  17. Yamamoto H, Kishida S, Kishida M, Ikeda S, Takada S, Kikuchi A: Phosphorylation of axin, a Wnt signal negative regulator, by glycogen synthase kinase-3β regulates its stability. J Biol Chem 1999;274:10681–10684.
  18. Zhang Y, Neo SY, Wang X, Han J, Lin SC: Axin forms a complex with MEKK1 and activates c-Jun NH(2)-terminal kinase/stress-activated protein kinase through domains distinct from Wnt signaling. J Biol Chem 1999;274:35247–35254.
  19. Luo W, Ng WW, Jin LH, Ye Z, Han J, Lin SC: Axin utilizes distinct regions for competitive MEKK1 and MEKK4 binding and JNK activation. J Biol Chem 2003;278:37451–37458.
  20. Kusano S, Raab-Traub N: I-mfa domain proteins interact with Axin and affect its regulation of the Wnt and c-Jun N-terminal kinase signaling pathways. Mol Cell Biol 2002;22:6393–6405.
  21. Yamazaki H, Nusse R: Identification of DCAP, a Drosophila homolog of a glucose transport regulatory complex. Mech Dev 2002;119:115–119.
  22. Cowan CA, Henkemeyer M: The SH2/SH3 adaptor Grb4 transduces B-ephrin reverse signals. Nature 2001;413:174–179.
  23. Furuhashi M, Yagi K, Yamamoto H, Furukawa Y, Shimada S, Nakamura Y, Kikuchi A, Miyazono K, Kato M: Axin facilitates Smad3 activation in the transforming growth factor beta signaling pathway. Mol Cell Biol 2001;21:5132–5141.
  24. Zhang Y, Qiu WJ, Liu DX, Neo SY, He X, Lin SC: Differential molecular assemblies underlie the dual function of Axin in modulating the Wnt and JNK pathways. J Biol Chem 2001;276:32152–32159.
  25. Zhang Y, Neo SY, Han J, Lin SC: Dimerization choices control the ability of Axin and dishevelled to activate c-Jun N-terminal kinase/stress-activated protein kinase. J Biol Chem 2000;275:25008–25014.
  26. Zhang Y, Qiu WJ, Chan SC, Han J, He X, Lin SC: Casein kinase I and casein kinase II differentially regulate Axin function in Wnt and JNK pathways. J Biol Chem 2002;277:17706–17712.
  27. Rui HL, Fan E, Zhou HM, Xu Z, Zhang Y, Lin SC: SUMO-1 modification of the C-terminal KVEKVD of Axin is required for JNK activation but has no effect on Wnt signaling. J Biol Chem 2002;277:42981–42986.
  28. Zeng L, Fagotto F, Zhang T, Hsu W, Vasicek TJ, Perry WL, Lee JJ, Tilghman SM, Gumbiner BM, Costantini F: The mouse Fused locus encodes Axin, an inhibitor of the Wnt signaling pathway that regulates embryonic axis formation. Cell 1997;90:181–192.
  29. Lyon MF, Rastan S, Brown SD: Genetic Variants and Strains of the Laboratory Mouse. Oxford, Oxford University Press, 1996.
  30. Ruvinsky A, Flood WD, Zhang T, Costantini F: Unusual inheritance of the Axin Fu mutation in mice is associated with widespread rearrangements in the proximal region of chromosome 17. Genet Res 2000;76:135–147.
  31. Vasicek TJ, Zeng L, Guan XJ, Zhang T, Costantini F, Tilghman SM: Two dominant mutations in the mouse fused gene are the result of transposon insertions. Genetics 1997;147:777–786.
  32. Rakyan VK, Chong S, Champ ME, Cuthbert PC, Morgan HD, Luu KV, Whitelaw E: Transgenerational inheritance of epigenetic states at the murine AxinFu allele occurs after maternal and paternal transmission. Proc Natl Acad Sci USA 2003;100:2538–2543.
  33. Gluecksohn-Schoenheimer S: The effects of a lethal mutation responsible for duplications and twinning in mouse embryos. J Exp Zool 1949;110:47–76.
  34. Jacobs-Cohen RJ, Spiegelman M, Cookingham JC, Bennett D: Knobbly, a new dominant mutation in the mouse that affects embryonic ectoderm organization. Genet Res 1984;43:43–50.
  35. Perry WL, Vasicek TJ, Lee JJ, Rossi JM, Zeng L, Zhang T, Tilghman SM, Costantini F: Phenotypic and molecular analysis of a transgenic insertional allele of the mouse Fused locus. Genetics 1995;141:321–332.
  36. Druey KM, Blumer KJ, Kang VH, Kehrl JH: Inhibition of G-protein-mediated MAP kinase activation by a new mammalian gene family. Nature 1996;379:742–746.
  37. Burchett SA: Regulators of G protein signaling: A bestiary of modular protein binding domains. J Neurochem 2000;75:1335–1351.
  38. Ikeda S, Kishida S, Yamamoto H, Murai H, Koyama S, Kikuchi A: Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3β and β-catenin and promotes GSK-3β-dependent phosphorylation of β-catenin. EMBO J 1998;17:1371–1384.
  39. Yamamoto H, Kishida S, Uochi T, Ikeda S, Koyama S, Asashima M, Kikuchi A: Axil, a member of the Axin family, interacts with both glycogen synthase kinase 3beta and beta-catenin and inhibits axis formation of Xenopus embryos. Mol Cell Biol 1998;18:2867–2875.
  40. Behrens J, Jerchow BA, Wurele M, Grimm J, Asbrand C, Wirtz R, Kuhl M, Wedlich D, Birchmeier W: Functional interaction of an axin homolog, conductin, with β-catenin, APC, and GSK3β. Science 1998;280:596–599.
  41. Hedgepeth CM, Deardorff MA, Klein PS: Xenopus axin interacts with glycogen synthase kinase-3β and is expressed in the anterior midbrain. Mech Dev 1999;80:147–151.
  42. Hamada F, Tomoyasu Y, Takatsu Y, Nakamura M, Nagai S, Suzuki A, Fujita F, Shibuya H, Toyoshima K, Ueno N, Akiyama T: Negative regulation of Wingless signaling by D-axin, a Drosophila homolog of axin. Science 1999;283:1739–1742.
  43. Korswagen HC, Coudreuse DY, Betist MC, van de Water S, Zivkovic D, Clevers HC: The Axin-like protein PRY-1 is a negative regulator of a canonical Wnt pathway in C. elegans. Genes Dev 2002;16:1291–1302.
  44. Peifer M, Polakis P: Wnt signaling in oncogenesis and embryogenesis – a look outside the nucleus. Science 2000;287:1606–1609.
  45. Sakanaka C, Weiss JB, Williams LT: Bridging of β-catenin and glycogen synthase kinase-3β by axin and inhibition of β-catenin-mediated transcription. Proc Natl Acad Sci USA 1998;95:3020–3023.
  46. Fagotto F, Jho E, Zeng L, Kurth T, Joos T, Kaufmann C, Costantini F: Domains of axin involved in protein-protein interactions, Wnt pathway inhibition, and intracellular localization. J Cell Biol 1999;145:741–756.
  47. Willert K, Logan CY, Arora A, Fish M, Nusse R: A Drosophila Axin homolog, Daxin, inhibits Wnt signaling. Development 1999;126:4165–4173.
  48. Farr GH 3rd, Ferkey DM, Yost C, Pierce SB, Weaver C, Kimelman D: Interaction among GSK-3, GBP, axin, and APC in Xenopus axis specification. J Cell Biol 2000;148:691–702.
  49. Satoh S, Daigo Y, Furukawa Y, Kato T, Miwa N, Nishiwaki T, Kawasoe T, Ishiguro H, Fujita M, Tokino T: AXIN1 mutations in hepatocellular carcinomas and growth suppression in cancer cells by virus-mediated transfer of AXIN1. Nat Genet 2000;24:245–250.
  50. Miao J, Kusafuka T, Udatsu Y, Okada A: Sequence variants of the Axin gene in hepatoblastoma. Hepatol Res 2003;25:174–179.
  51. Taniguchi K, Roberts LR, Aderca IN, Dong X, Qian C, Murphy LM, Nagorney DM, Burgart LJ, Roche PC, Smith DI, Ross JA, Liu W: Mutational spectrum of β-catenin, AXIN1, and AXIN2 in hepatocellular carcinomas and hepatoblastomas. Oncogene 2002;31:4863–4871.

    External Resources

  52. Neo SY, Zhang Y, Yaw LP, Li P, Lin SC: Axin-induced apoptosis depends on the extent of its JNK activation and its ability to down-regulate β-catenin levels. Biochem Biophys Res Commun 2000;272:144–150.
  53. Hsu W, Shakya R, Costantini F: Impaired mammary gland and lymphoid development caused by inducible expression of Axin in transgenic mice. J Cell Biol 2001;155:1055–1064.
  54. Webster MT, Rozycka M, Sara E, Davis E, Smalley M, Young N, Dale TC, Wooster R: Sequence variants of the axin gene in breast, colon, and other cancers: An analysis of mutations that interfere with GSK3 binding. Genes Chromosomes Cancer 2000;28:443–453.
  55. Yokota N, Nishizawa S, Ohta S, Date H, Sugimura H, Namba H, Maekawa M: Role of Wnt pathway in medulloblastoma oncogenesis. Int J Cancer 2002;101:198–201.
  56. Dahmen RP, Koch A, Denkhaus D, Tonn JC, Sorensen N, Berthold F, Behrens J, Birchmeier W, Wiestler OD, Pietsch T: Deletions of AXIN1, a component of the WNT/wingless pathway, in sporadic medulloblastomas. Cancer Res 2001;61:7039–7043.
  57. Baeza N, Masuoka J, Kleihues P, Ohgaki H: AXIN1 mutants but not deletions in cerebellar medulloblastomas. Oncogene 2003;22:632–636.
  58. Jin LH, Shao QJ, Luo W, Ye ZY, Li Q, Lin SC: Detection of point mutations of the Axin1 gene in colorectal cancers. Int J Cancer 2003;107:696–699.
  59. Habas R, Kato Y, He X: Wnt/Frizzled activation of Rho regulates vertebrate gastrulation and requires a novel Formin homology protein, Daam1. Cell 2001;107:843–854.
  60. Tada M, Smith JC: Xwnt11 is a target of Xenopus Brachyury: Regulation of gastrulation movements via Dishevelled, but not through the canonical Wnt pathway. Development 2000;127:2227–2238.
  61. Wallingford JB, Rowning BA, Vögeli KM, Rothbacher U, Fraser SE, Harland RM: Dishevelled controls cell polarity during Xenopus gastrulation. Nature 2000;405:81–85.
  62. Gho M, Schweisguth F: Frizzled signalling controls orientation of asymmetric sense organ precursor cell divisions in Drosophila. Nature 1998;393:178–181.
  63. Cadigan KM, Nusse R: Wnt signaling: A common theme in animal development. Genes Dev 1997;11:3286–3305.
  64. Capelluto DG, Kutateladze TG, Habas R, Finkielstein CV, He X, Overduin M: The DIX domain targets dishevelled to actin stress fibres and vesicular membranes. Nature 2002;419:726–729.
  65. Christian JL, Moon RT: Interactions between Xwnt-8 and Spemann organizer signaling pathways generate dorsoventral pattern in the embryonic mesoderm of Xenopus. Genes Dev 1993;7:13–28.
  66. Greenspan RJ, O’Brien MC: Genetic analysis of mutations at the fused locus in the mouse. Proc Natl Acad Sci USA 1986;83:4413–4417.
  67. Spink KE, Polakis P, Weis WI: Structural basis of the axin-adenomatous polyposis coli interaction. EMBO J 2000;19:2270–2279.
  68. Rosin-Arbesfeld R, Cliffe A, Brabletz T, Bienz M: Nuclear export of the APC tumor suppressor controls beta-catenin function in transcription. EMBO J 2003;22:1101–1113.
  69. Henderson BR, Fagotto F: The ins and outs of APC and beta-catenin nuclear transport. EMBO Rep 2002;3:834–839.
  70. Ahmed Y, Hayashi S, Levine A, Wieschaus E: Regulation of armadillo by a Drosophila APC inhibits neuronal apoptosis during retinal development. Cell 1998;93:1171–1182.
  71. Hinoi T, Yamamoto H, Kishida M, Takada S, Kishida S, Kikuchi A: Complex formation of adenomatous polyposis coli gene product and axin facilitates glycogen synthase kinase-3β-dependent phosphorylation of beta-catenin and down-regulates beta-catenin. J Biol Chem 2000;275:34399–34406.
  72. Kawahara K, Morishita T, Nakamura T, Hamada F, Toyoshima K, Akiyama T: Down-regulation of beta-catenin by the colorectal tumor suppressor APC requires association with Axin and β-catenin. J Biol Chem 2000;275:8369–8374.
  73. Rubinfeld B, Albert I, Porfiri E, Munemitsu S, Polakis P: Loss of beta-catenin regulation by the APC tumor suppressor protein correlates with loss of structure due to common somatic mutations of the gene. Cancer Res 1997;57:4624–4630.
  74. Itoh K, Krupnik VE, Sokol SY: Axis determination in Xenopus involves biochemical interactions of axin, glycogen synthase kinase 3 and β-catenin. Curr Biol 1998;8:591–594.
  75. Ding Y, Dale T: Wnt signal transduction: Kinase cogs in a nano-machine? Trends Biochem Sci 2002;27:327–329.
  76. Dajani R, Fraser E, Roe SM, Yeo M, Good VM, Thompson V, Dale TC, Pearl LH: Structural basis for recruitment of glycogen synthase kinase 3β to the axin-APC scaffold complex. EMBO J 2003;22:494–501.
  77. Plyte SE, Hughes K, Nikolakaki E, Pulverer BJ, Woodgett JR: Glycogen synthase kinase-3:Functions in oncogenesis and development. Biochim Biophys Acta 1992;1114:147–162.
  78. Mandelkow EM, Drewes G, Biernat J, Gustke N, Van Lint J, Vandenheede JR, Mandelkow E: Glycogen synthase kinase-3 and the Alzheimer-like state of microtubule-associated protein tau. FEBS Lett 1992;314:315–321.
  79. Rubinfeld B, Albert I, Porfiri E, Fiol C, Munemitsu S, Polakis P: Binding of GSK-3β to the APC-β-catenin complex and regulation of complex assembly. Science 1996;272:1023–1026.
  80. Fujimuro M, Wu FY, ApRhys C, Kajumbula H, Young DB, Hayward GS, Hayward SD: A novel viral mechanism for dysregulation of β-catenin in Kaposi’s sarcoma-associated herpesvirus latency. Nat Med 2003;9:300–306.
  81. Liu C, Li Y, Semenov M, Han C, Baeg GH, Tan Y, Zhang Z, Lin X, He X: Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell 2002;108:837–847.
  82. Gumbiner BM, McCrea PD: Catenins as mediators of the cytoplasmic functions of cadherins. J Cell Sci Suppl 1993;17:155–158.
  83. Schneider S, Herrenknecht K, Butz S, Kemler R, Hausen P: Catenins in Xenopus embryogenesis and their relation to the cadherin-mediated cell-cell adhesion system. Development 1993;118:629–640.
  84. Gottardi CJ, Gumbiner BM: Adhesion signaling: How β-catenin interacts with its partners. Curr Biol 2001;11:R792–R794.

    External Resources

  85. Behrens J, von Kries JP, Kuhl M, Bruhn L, Wedlich D, Grosschedl R, Birchmeier W: Functional interaction of beta-catenin with the transcription factor LEF-1. Nature 1996;382:638–642.
  86. Gumbiner BM: Signal transduction of beta-catenin. Curr Opin Cell Biol 1995;7:634–640.
  87. Peifer M, Orsulic S, Pai LM, Loureiro J: A model system for cell adhesion and signal transduction in Drosophila. Dev Suppl 1993:163–176.
  88. Papkoff J, Rubinfeld B, Schryver B, Polakis P: Wnt-1 regulates free pools of catenins and stabilizes APC-catenin complexes. Mol Cell Biol 1996;16:2128–2134.
  89. Peifer M, Sweeton D, Casey M, Wieschaus E: Wingless signal and Zeste-white 3 kinase trigger opposing changes in the intracellular distribution of Armadillo. Development 1994;120:369–380.
  90. Aberle HA, Bauer A, Stappert J, Kispert A, Kemler R: β-Catenin is a target for the ubiquitin-proteasome pathway. EMBO J 1997;16:3797–3804.
  91. Brannon M, Gomperts M, Sumoy L, Moon RT, Kimelman D: A β-catenin/XTcf-3 complex binds to the siamois promoter to regulate dorsal axis specification in Xenopus. Genes Dev 1997;11:2359–2370.
  92. Laurent MN, Blitz IL, Hashimoto C, Rothbacher U, Cho KW: The Xenopus homeobox gene twin mediates Wnt induction of goosecoid in establishment of Spemann’s organizer. Development 1997;124:4905–4916.
  93. Molenaar M, van de Wetering M, Oosterwegel M, Peterson-Maduro J, Godsave S, Korinek V, Roose J, Destree O, Clevers H: XTcf-3 transcription factor mediates beta-catenin-induced axis formation in Xenopus embryos. Cell 1996;86:391–399.
  94. McKendry R, Hsu SC, Harland RM, Grosschedl R: LEF-1/TCF proteins mediate wnt-inducible transcription from the Xenopus nodal-related 3 promoter. Dev Biol 1997;192:420–431.
  95. Tetsu O, McCormick F: Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 1999;398:422–426.
  96. He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT, Morin PJ, Vogelstein B, Kinzler KW: Identification of c-MYC as a target of the APC pathway. Science 1998;281:1509–1512.
  97. Seeling JM, Miller JR, Gil R, Moon RT, White R, Virshup DM: Regulation of β-catenin signaling by the B56 subunit of protein phosphatase 2A. Science 1999;283:2089–2091.
  98. Ikeda S, Kishida M, Matsuura Y, Usui H, Kikuchi A: GSK-3β-dependent phosphorylation of adenomatous polyposis coli gene product can be modulated by β-catenin and protein phosphatase 2A complexed with Axin. Oncogene 2000;19:537–545.
  99. Ratcliffe MJ, Itoh K, Sokol SY: A positive role for the PP2A catalytic subunit in Wnt signal transduction. J Biol Chem 2000;275:35680–35683.
  100. Yamamoto H, Hinoi T, Michiue T, Fukui A, Usui H, Janssens V, Van Hoof C, Goris J, Asashima M, Kikuchi A: Inhibition of the Wnt signaling pathway by the PR61 subunit of protein phosphatase 2A. J Biol Chem 2001;276:26875–26882.
  101. Li X, Yost HJ, Virshup DM, Seeling JM: Protein phosphatase 2A and its B56 regulatory subunit inhibit Wnt signaling in Xenopus. EMBO J 2001;20:4122–4131.
  102. Rubinfeld B, Souza B, Albert I, Muller O, Chamberlain SH, Masiarz FR, Munemitsu S, Polakis P: Association of the APC gene product with beta-catenin. Science 1993;262:1731–1734.
  103. Fish KJ, Cegielska A, Getman ME, Landes GM, Virshup DM: Isolation and characterization of human casein kinase I epsilon (CKIε), a novel member of the CKI gene family. J Biol Chem 1995;270:14875–14883.
  104. Vielhaber E, Eide E, Rivers A, Gao ZH, Virshup DM: Nuclear entry of the circadian regulator mPER1 is controlled by mammalian casein kinase I epsilon. Mol Cell Biol 2000;20:4888–4899.
  105. Lowrey PL, Shimomura K, Antoch MP, Yamazaki S, Zemenides PD, Ralph MR, Menaker M, Takahashi JS: Positional syntenic cloning and functional characterization of the mammalian circadian mutation tau. Science 2000;288:483–492.
  106. Polakis P: Casein kinase 1: A Wnt’er of disconnect. Curr Biol 2002;12:R499–R501.

    External Resources

  107. Peters JM, McKay RM, McKay JP, Graff JM: Casein kinase I transduces Wnt signals. Nature 1999;401:345–350.
  108. Sakanaka C, Leong P, Xu L, Harrison SD, Williams LT: Casein kinase Iepsilon in the Wnt pathway: Regulation of β-catenin function. Proc Natl Acad Sci USA 1999;96:12548–12552.
  109. Gao ZH, Seeling JM, Hill V, Yochum A, Virshup DM: Casein kinase I phosphorylates and destabilizes the β-catenin degradation complex. Proc Natl Acad Sci USA 2002;99:1182–1187.
  110. Hino S, Michiue T, Asashima M, Kikuchi A: Casein kinase I epsilon enhances the binding of Dvl-1 to Frat-1 and is essential for Wnt-3a-induced accumulation of beta-catenin. J Biol Chem 2003;278:14066–14073.
  111. Polakis P: Wnt signaling and cancer. Genes Dev 2000;14:1837–1851.
  112. Amit S, Hatzubai A, Birman Y, Andersen JS, Ben-Shushan E, Mann M, Ben-Neriah Y, Alkalay I: Axin-mediated CKI phosphorylation of β-catenin at Ser 45: A molecular switch for the Wnt pathway. Genes Dev 2002;16:1066–1076.
  113. Sussman DJ, Klingensmith J, Salinas P, Adams PS, Nusse R, Perrimon N: Isolation and characterization of a mouse homolog of the Drosophila segment polarity gene dishevelled. Dev Biol 1994;166:73–86.
  114. Willert K, Brink M, Wodarz A, Varmus H, Nusse R: Casein kinase 2 associates with and phosphorylates dishevelled. EMBO J 1997;16:3089–3096.
  115. Jonkers J, Korswagen HC, Acton D, Breuer M, Berns A: Activation of a novel proto-oncogene, Frat1, contributes to progression of mouse T-cell lymphomas. EMBO J 1997;16:441–450.
  116. Kadoya T, Yamamoto H, Suzuki T, Yukita A, Fukui A, Michiue T, Asahara T, Tanaka K, Asashima M, Kikuchi A: Desumoylation activity of Axam, a novel Axin-binding protein, is involved in downregulation of β-catenin. Mol Cell Biol 2002;22:3803–3819.
  117. Yamamoto H, Ihara M, Matsuura Y, Kikuchi A: Sumoylation is involved in β-catenin-dependent activation of Tcf-4. EMBO J 2003;22:2047–2059.
  118. Herz J, Strickland DK: LRP: A multifunctional scavenger and signaling receptor. J Clin Invest 2001;108:779–784.
  119. Pinson KI, Brennan J, Monkley S, Avery BJ, Skarnes WC: An LDL-receptor-related protein mediates Wnt signaling in mice. Nature 2000;407:535–538.
  120. Tamai K, Semenov M, Kato Y, Spokony R, Liu C, Katsuyama Y, Hess F, Saint-Jeannet JP, He X: LDL-receptor-related proteins in Wnt signal transduction. Nature 2000;407:530–535.
  121. Semenov MV, Tamai K, Brott BK, Kuhl M, Sokol S, He X: Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6. Curr Biol 2001;11:951–961.
  122. Johnson GL, Lapadat R: Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 2002;298:1911–1912.
  123. Hagemann C, Blank JL: The ups and downs of MEK kinase interactions. Cell Signal 2001;13:863–875.
  124. Schmidt D, Müller S: Members of the PIAS family act as SUMO ligases for c-Jun and p53 and repress p53 activity. Proc Natl Acad Sci USA 2002;99:2872–2877.
  125. Müller S, Hoege C, Pyrowolakis G, Jentsch S: SUMO, ubiquitin’s mysterious cousin. Nat Rev Mol Cell Biol 2001;2:202–210.
  126. Kwek SS, Derry J, Tyner AL, Shen Z, Gudkov AV: Functional analysis and intracellular localization of p53 modified by SUMO-1. Oncogene 2001;20:2587–2599.
  127. Melchior F, Hengst L: SUMO-1 and p53. Cell Cycle 2002;1:245–249.
  128. Verger A, Perdomo J, Crossley M: Modification with SUMO: A role in transcriptional regulation. EMBO Rep 2003;4:137–142.
  129. Pepper MS: Transforming growth factor-beta: Vasculogenesis, angiogenesis, and vessel wall integrity. Cytokine Growth Factor Rev 1997;8:21–43.

    External Resources

  130. Henkemeyer M, Orioli D, Henderson JT, Saxton TM, Roder J, Pawson T, Klein R: Nuk controls pathfinding of commissural axons in the mammalian central nervous system. Cell 1996;86:35–46.
  131. Birgbauer E, Cowan CA, Sretavan DW, Henkemeyer M: Kinase independent function of EphB receptors in retinal axon pathfinding to the optic disc from dorsal but not ventral retina. Development 2000;127:1231–1241.
  132. Baumann CA, Ribon V, Kanzaki M, Thurmond DC, Mora S, Shigematsu S, Bickel PE, Pessin JE, Saltiel AR: CAP defines a second signaling pathway required for insulin-stimulated glucose transport. Nature 2000;407:202–207.
  133. Yamazaki H, Yanagawa S: Axin and Axin/Arrow-binding protein DCAP mediate glucose-glycogen metabolism. Biochem Biophys Res Commun 2003;304:229–235.

 goto top of outline Author Contacts

Sheng-Cai Lin
Department of Biochemistry, Hong Kong University of Science and Technology
Clear Water Bay, Kowloon
Hong Kong (China)
Tel. +852 2358 7294, E-Mail linsc@ust.hk


 goto top of outline Article Information

Received: August 12, 2003
Accepted after revision: September 5, 2003
Number of Print Pages : 15
Number of Figures : 2, Number of Tables : 1, Number of References : 133


 goto top of outline Publication Details

Neurosignals
Founded 1992 as ‘Biological Signals’ by S.F. Pang (1992–2001) continued as ‘Biological Signals and Receptors’ (1999–2001)

Vol. 13, No. 3, Year 2004 (Cover Date: May-June 2004)

Journal Editor: Nancy Y. Ip, Hong Kong
ISSN: 1424–862X (print), 1424–8638 (Online)

For additional information: http://www.karger.com/journals/nsg


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.