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β-Catenin destruction complex: insights and questions from a structural perspective

Abstract

At the heart of the canonical Wnt signaling pathway is the β-catenin destruction complex, which functions in the absence of Wnt signaling to keep the cytosolic and nuclear levels of β-catenin very low by promoting the phosphorylation and ubiquitination of β-catenin. Structural studies, combined with other experimental approaches, have begun to provide important insights into the mechanism of the destruction complex. We suggest a working model for the destruction complex based on the existing structural and experimental data, and focus on the questions that this model and other studies have raised about the function of the complex in both the normal and Wnt-inhibited states.

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References

  • Amit S, Hatzubai A, Birman Y, Andersen JS, Ben-Shushan E, Mann M et al. (2002). Axin-mediated CKI phosphorylation of β-catenin at Ser 45: a molecular switch for the Wnt pathway. Genes Dev 16: 1066–1076.

    Article  CAS  Google Scholar 

  • Axelrod JD, Miller JR, Shulman JM, Moon RT, Perrimon N . (1998). Differential recruitment of Dishevelled provides signaling specificity in the planar cell polarity and Wingless signaling pathways. Genes Dev 12: 2610–2622.

    Article  CAS  Google Scholar 

  • Bajpai R, Makhijani K, Rao PR, Shashidhara LS . (2004). Drosophila Twins regulates Armadillo levels in response to Wg/Wnt signal. Development 131: 1007–1016.

    Article  CAS  Google Scholar 

  • Carthew RW, Rubin GM . (1990). Seven in absentia, a gene required for specification of R7 cell fate in the Drosophila eye. Cell 63: 561–577.

    Article  CAS  Google Scholar 

  • Cliffe A, Hamada F, Bienz M . (2003). A role of Dishevelled in relocating Axin to the plasma membrane during Wingless signaling. Curr Biol 13: 960–966.

    Article  CAS  Google Scholar 

  • Cohen P, Frame S . (2001). The renaissance of GSK3. Nat Rev Mol Cell Biol 2: 769–776.

    Article  CAS  Google Scholar 

  • Cong F, Schweizer L, Varmus H . (2004a). Casein kinase Iɛ modulates the signaling specificities of dishevelled. Mol Cell Biol 24: 2000–2011.

    Article  CAS  Google Scholar 

  • Cong F, Schweizer L, Varmus H . (2004b). Wnt signals across the plasma membrane to activate the β-catenin pathway by forming oligomers containing its receptors, Frizzled and LRP. Development 131: 5103–5115.

    Article  CAS  Google Scholar 

  • Cook D, Fry MJ, Hughes K, Sumathipala R, Woodgett JR, Dale TC . (1996). Wingless inactivates glycogen synthase kinase-3 via an intracellular signalling pathway which involves a protein kinase C. EMBO J 15: 4526–4536.

    Article  CAS  Google Scholar 

  • Creyghton MP, Roel G, Eichhorn PJ, Hijmans EM, Maurer I, Destree O et al. (2005). PR72, a novel regulator of Wnt signaling required for Naked cuticle function. Genes Dev 19: 376–386.

    Article  CAS  Google Scholar 

  • Creyghton MP, Roel G, Eichhorn PJ, Vredeveld LC, Destree O, Bernards R . (2006). PR130 is a modulator of the Wnt-signaling cascade that counters repression of the antagonist Naked cuticle. Proc Natl Acad Sci USA 103: 5397–5402.

    Article  CAS  Google Scholar 

  • Dajani R, Fraser E, Roe SM, Yeo M, Good VM, Thompson V et al. (2003). Structural basis for recruitment of glycogen synthase kinase 3β to the axin-APC scaffold complex. EMBO J 22: 494–501.

    Article  CAS  Google Scholar 

  • Dale T . (2006). Kinase cogs go forward and reverse in the Wnt signaling machine. Nat Struct Mol Biol 13: 9–11.

    Article  CAS  Google Scholar 

  • Ding Q, Xia W, Liu JC, Yang JY, Lee DF, Xia J et al. (2005). Erk associates with and primes GSK-3β for its inactivation resulting in upregulation of β-catenin. Mol Cell 19: 159–170.

    Article  CAS  Google Scholar 

  • Ding VW, Chen RH, McCormick F . (2000). Differential regulation of glycogen synthase kinase 3β by insulin and Wnt signaling. J Biol Chem 275: 32475–32481.

    Article  CAS  Google Scholar 

  • Farr III GH, Ferkey DM, Yost C, Pierce SB, Weaver C, Kimelman D . (2000). Interaction among GSK-3, GBP, Axin, and APC in Xenopus axis specification. J Cell Biol 148: 691–702.

    Article  CAS  Google Scholar 

  • Ferkey DM, Kimelman D . (2002). Glycogen synthase kinase-3β mutagenesis identifies a common binding domain for GBP and Axin. J Biol Chem 277: 16147–16152.

    Article  CAS  Google Scholar 

  • Graham TA, Clements WK, Kimelman D, Xu W . (2002). The crystal structure of the β-catenin/ICAT complex reveals the inhibitory mechanism of ICAT. Mol Cell 10: 563–571.

    Article  CAS  Google Scholar 

  • Graham TA, Weaver C, Mao F, Kimelman D, Xu W . (2000). Crystal structure of a β-catenin/Tcf complex. Cell 103: 885–896.

    Article  CAS  Google Scholar 

  • Ha NC, Tonozuka T, Stamos JL, Choi HJ, Weis WI . (2004). Mechanism of phosphorylation-dependent binding of APC to β-catenin and its role in β-catenin degradation. Mol Cell 15: 511–521.

    Article  CAS  Google Scholar 

  • Hedgepeth CM, Deardorff MA, Rankin K, Klein PS . (1999). Regulation of glycogen synthase kinase 3β and downstream Wnt signaling by Axin. Mol Cell Biol 19: 7147–7157.

    Article  CAS  Google Scholar 

  • Hsu W, Zeng L, Costantini F . (1999). Identification of a domain of Axin that binds to the serine/threonine protein phosphatase 2A and a self-binding domain. J Biol Chem 274: 3439–3445.

    Article  CAS  Google Scholar 

  • Huber AH, Nelson WJ, Weis WI . (1997). Three-dimensional structure of the armadillo repeat region of β-catenin. Cell 90: 871–882.

    Article  CAS  Google Scholar 

  • Huber AH, Weis WI . (2001). The structure of the β-catenin/E-cadherin complex and the molecular basis of diverse ligand recognition by β-catenin. Cell 105: 391–402.

    Article  CAS  Google Scholar 

  • Ikeda S, Kishida S, Yamamoto H, Murai H, Koyama S, Kikuchi A . (1998). 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 17: 1371–1384.

    Article  CAS  Google Scholar 

  • Itoh K, Antipova A, Ratcliffe MJ, Sokol S . (2000). Interaction of dishevelled and Xenopus axin-related protein is required for wnt signal transduction. Mol Cell Biol 20: 2228–2238.

    Article  CAS  Google Scholar 

  • Katanaev VL, Ponzielli R, Semeriva M, Tomlinson A . (2005). Trimeric G protein-dependent frizzled signaling in Drosophila. Cell 120: 111–122.

    Article  CAS  Google Scholar 

  • Kikuchi A, Kishida S, Yamamoto H . (2006). Regulation of Wnt signaling by protein-protein interaction and post-translational modifications. Exp Mol Med 38: 1–10.

    Article  CAS  Google Scholar 

  • Kishida S, Yamamoto H, Hino S, Ikeda S, Kishida M, Kikuchi A . (1999). DIX domains of Dvl and axin are necessary for protein interactions and their ability to regulate β-catenin stability. Mol Cell Biol 19: 4414–4422.

    Article  CAS  Google Scholar 

  • Lee E, Salic A, Kruger R, Heinrich R, Kirschner MW . (2003). The roles of APC and Axin derived from experimental and theoretical analysis of the Wnt pathway. PLoS Biol 1: e10.

    Article  Google Scholar 

  • Li L, Mao J, Sun L, Liu W, Wu D . (2002). Second cysteine-rich domain of Dickkopf-2 activates canonical Wnt signaling pathway via LRP-6 independently of dishevelled. J Biol Chem 277: 5977–5981.

    Article  CAS  Google Scholar 

  • Li L, Yuan H, Weaver C, Mao J, Farr III GH, Sussman DJ et al. (1999). Axin and Frat-1 interact with Dvl and GSK, bridging Dvl to GSK in Wnt-mediated regulation of LEF-1. EMBO J 18: 4233–4240.

    Article  CAS  Google Scholar 

  • Li X, Yost HJ, Virshup DM, Seeling JM . (2001). Protein phosphatase 2A and its B56 regulatory subunit inhibit Wnt signaling in Xenopus. EMBO J 20: 4122–4131.

    Article  CAS  Google Scholar 

  • Liu C, Li Y, Semenov M, Han C, Baeg GH, Tan Y et al. (2002). Control of β-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell 108: 837–847.

    Article  CAS  Google Scholar 

  • Liu J, Stevens J, Rote CA, Yost HJ, Hu Y, Neufeld KL et al. (2001a). Siah-1 mediates a novel β-catenin degradation pathway linking p53 to the adenomatous polyposis coli protein. Mol Cell 7: 927–936.

    Article  CAS  Google Scholar 

  • Liu J, Xing Y, Hinds TR, Zheng J, Xu W . (2006). The third 20 amino acid repeat is the tightest binding site of APC for β-catenin. J Mol Biol 360: 133–144.

    Article  CAS  Google Scholar 

  • Liu T, DeCostanzo AJ, Liu X, Wang H, Hallagan S, Moon RT et al. (2001b). G protein signaling from activated rat frizzled-1 to the β-catenin-Lef-Tcf pathway. Science 292: 1718–1722.

    Article  CAS  Google Scholar 

  • Liu X, Rubin JS, Kimmel AR . (2005). Rapid, Wnt-induced changes in GSK3β associations that regulate β-catenin stabilization are mediated by Gα proteins. Curr Biol 15: 1989–1997.

    Article  CAS  Google Scholar 

  • Logan CY, Nusse R . (2004). The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol 20: 781–810.

    Article  CAS  Google Scholar 

  • Mao J, Wang J, Liu B, Pan W, Farr III GH, Flynn C et al. (2001). Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway. Mol Cell 7: 801–809.

    Article  CAS  Google Scholar 

  • Matsubayashi H, Sese S, Lee JS, Shirakawa T, Iwatsubo T, Tomita T et al. (2004). Biochemical characterization of the Drosophila wingless signaling pathway based on RNA interference. Mol Cell Biol 24: 2012–2024.

    Article  CAS  Google Scholar 

  • Matsuzawa SI, Reed JC . (2001). Siah-1, SIP, and Ebi collaborate in a novel pathway for β-catenin degradation linked to p53 responses. Mol Cell 7: 915–926.

    Article  CAS  Google Scholar 

  • Moon RT, Kohn AD, De Ferrari GV, Kaykas A . (2004). WNT and β-catenin signalling: diseases and therapies. Nat Rev Genet 5: 691–701.

    Article  CAS  Google Scholar 

  • Nusse R . (2005). Cell biology: relays at the membrane. Nature 438: 747–749.

    Article  CAS  Google Scholar 

  • Park TJ, Gray RS, Sato A, Habas R, Wallingford JB . (2005). Subcellular localization and signaling properties of dishevelled in developing vertebrate embryos. Curr Biol 15: 1039–1044.

    Article  CAS  Google Scholar 

  • Ratcliffe MJ, Itoh K, Sokol SY . (2000). A positive role for the PP2A catalytic subunit in Wnt signal transduction. J Biol Chem 275: 35680–35683.

    Article  CAS  Google Scholar 

  • Reya T, Clevers H . (2005). Wnt signalling in stem cells and cancer. Nature 434: 843–850.

    Article  CAS  Google Scholar 

  • Rothbacher U, Laurent MN, Deardorff MA, Klein PS, Cho KW, Fraser SE . (2000). Dishevelled phosphorylation, subcellular localization and multimerization regulate its role in early embryogenesis. EMBO J 19: 1010–1022.

    Article  CAS  Google Scholar 

  • Rubinfeld B, Tice DA, Polakis P . (2001). Axin-dependent phosphorylation of the adenomatous polyposis coli protein mediated by casein kinase 1ɛ. J Biol Chem 276: 39037–39045.

    Article  CAS  Google Scholar 

  • Salic A, Lee E, Mayer L, Kirschner MW . (2000). Control of β-catenin stability: reconstitution of the cytoplasmic steps of the Wnt pathway in Xenopus egg extracts. Mol Cell 5: 523–532.

    Article  CAS  Google Scholar 

  • Schwarz-Romond T, Asbrand C, Bakkers J, Kuhl M, Schaeffer HJ, Huelsken J et al. (2002). The ankyrin repeat protein Diversin recruits Casein kinase Iɛ to the β-catenin degradation complex and acts in both canonical Wnt and Wnt/JNK signaling. Genes Dev 16: 2073–2084.

    Article  CAS  Google Scholar 

  • Schweizer L, Varmus H . (2003). Wnt/Wingless signaling through β-catenin requires the function of both LRP/Arrow and frizzled classes of receptors. BMC Cell Biol 4: 4.

    Article  Google Scholar 

  • Seeling JM, Miller JR, Gil R, Moon RT, White R, Virshup DM . (1999). Regulation of β-catenin signaling by the B56 subunit of protein phosphatase 2A. Science 283: 2089–2091.

    Article  CAS  Google Scholar 

  • Sobrado P, Jedlicki A, Bustos VH, Allende CC, Allende JE . (2005). Basic region of residues 228–231 of protein kinase CK1α is involved in its interaction with axin: binding to axin does not affect the kinase activity. J Cell Biochem 94: 217–224.

    Article  CAS  Google Scholar 

  • Spink K, Fridman SG, Weis WI . (2001). Molecular mechanisms of β-catenin recognition by adenomatous polyposis coli revealed by the structure of an APC-β-catenin complex. EMBO J 20: 6203–6212.

    Article  CAS  Google Scholar 

  • Spink KE, Polakis P, Weis WI . (2000). Structural basis of the Axin-adenomatous polyposis coli interaction. EMBO J 19: 2270–2279.

    Article  CAS  Google Scholar 

  • Tamai K, Zeng X, Liu C, Zhang X, Harada Y, Chang Z et al. (2004). A mechanism for Wnt coreceptor activation. Mol Cell 13: 149–156.

    Article  CAS  Google Scholar 

  • Tickenbrock L, Kossmeier K, Rehmann H, Herrmann C, Muller O . (2003). Differences between the interaction of β-catenin with non-phosphorylated and single-mimicked phosphorylated 20-amino acid residue repeats of the APC protein. J Mol Biol 327: 359–367.

    Article  CAS  Google Scholar 

  • van Amerongen R, Berns A . (2005). Re-evaluating the role of Frat in Wnt-signal transduction. Cell Cycle 4: 1065–1072.

    CAS  PubMed  Google Scholar 

  • van Amerongen R, Nawijn M, Franca-Koh J, Zevenhoven J, van der Gulden H, Jonkers J et al. (2005). Frat is dispensable for canonical Wnt signaling in mammals. Genes Dev 19: 425–430.

    Article  CAS  Google Scholar 

  • Wallingford JB, Habas R . (2005). The developmental biology of Dishevelled: an enigmatic protein governing cell fate and cell polarity. Development 132: 4421–4436.

    Article  CAS  Google Scholar 

  • Wharton Jr KA . (2003). Runnin' with the Dvl: proteins that associate with Dsh/Dvl and their significance to Wnt signal transduction. Dev Biol 253: 1–17.

    Article  CAS  Google Scholar 

  • Willert K, Shibamoto S, Nusse R . (1999). Wnt-induced dephosphorylation of Axin releases β-catenin from the Axin complex. Genes Dev 13: 1768–1773.

    Article  CAS  Google Scholar 

  • Wong HC, Bourdelas A, Krauss A, Lee HJ, Shao Y, Wu D et al. (2003). Direct binding of the PDZ domain of Dishevelled to a conserved internal sequence in the C-terminal region of Frizzled. Mol Cell 12: 1251–1260.

    Article  CAS  Google Scholar 

  • Wu G, Xu G, Schulman BA, Jeffrey PD, Harper JW, Pavletich NP . (2003). Structure of a β-TrCP1-Skp1-β-catenin complex: destruction motif binding and lysine specificity of the SCF(β-TrCP1) ubiquitin ligase. Mol Cell 11: 1445–1456.

    Article  CAS  Google Scholar 

  • Xing Y, Clements WK, Kimelman D, Xu W . (2003). Crystal structure of a β-catenin/Axin complex suggests a mechanism for the β-catenin Destruction complex. Genes Dev 17: 2753–2764.

    Article  CAS  Google Scholar 

  • Xing Y, Clements WK, Le Trong I, Hinds TR, Stenkamp R, Kimelman D et al. (2004). Crystal structure of a β-catenin/APC complex reveals a critical role for APC phosphorylation in APC function. Mol Cell 15: 523–533.

    Article  CAS  Google Scholar 

  • Yanagawa S, Matsuda Y, Lee JS, Matsubayashi H, Sese S, Kadowaki T et al. (2002). Casein kinase I phosphorylates the Armadillo protein and induces its degradation in Drosophila. EMBO J 21: 1733–1742.

    Article  CAS  Google Scholar 

  • Yang J, Wu J, Tan C, Klein PS . (2003). PP2A:B56ɛ is required for Wnt/β-catenin signaling during embryonic development. Development 130: 5569–5578.

    Article  CAS  Google Scholar 

  • Yang J, Zhang W, Evans PM, Chen X, He X, Liu C . (2006). Adenomatous Polyposis Coli (APC) differentially regulates β-catenin phosphorylation and ubiquitination in colon cancer cells. J Biol Chem 281: 17751–17757.

    Article  CAS  Google Scholar 

  • Yost C, Farr III GH, Pierce SB, Ferkey DM, Chen MM, Kimelman D . (1998). GBP, an inhibitor of GSK-3, is implicated in Xenopus development and oncogenesis. Cell 93: 1031–1041.

    Article  CAS  Google Scholar 

  • Yuan H, Mao J, Li L, Wu D . (1999). Suppression of glycogen synthase kinase activity is not sufficient for leukemia enhancer factor-1 activation. J Biol Chem 274: 30419–30423.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Lina Dahlberg, Hank Farr and Jing Liu for comments on the manuscript. This work was supported by NIH Grants CA90351 to WX and HD27262 to DK.

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Correspondence to D Kimelman.

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Kimelman, D., Xu, W. β-Catenin destruction complex: insights and questions from a structural perspective. Oncogene 25, 7482–7491 (2006). https://doi.org/10.1038/sj.onc.1210055

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