New insights into the regulation of Axin function in canonical Wnt signaling pathway

Abstract

The Wnt signaling pathway plays crucial roles during embryonic development, whose aberration is implicated in a variety of human cancers. Axin, a key component of canonical Wnt pathway, plays dual roles in modulating Wnt signaling: on one hand, Axin scaffolds the “β-catenin destruction complex” to promote β-catenin degradation and therefore inhibits the Wnt signal transduction; on the other hand, Axin interacts with LRP5/6 and facilitates the recruitment of GSK3 to the plasma membrane to promote LRP5/6 phosphorylation and Wnt signaling. The differential assemblies of Axin with these two distinct complexes have to be tightly controlled for appropriate transduction of the “on” or “off” Wnt signal. So far, there are multiple mechanisms revealed in the regulation of Axin activity, such as post-transcriptional modulation, homo/hetero-polymerization and auto-inhibition. These mechanisms may work cooperatively to modulate the function of Axin, thereby playing an important role in controlling the canonical Wnt signaling. In this review, we will focus on the recent progresses regarding the regulation of Axin function in canonical Wnt signaling.

Keywords

Wnt signaling / Axin / post-transcriptional modification / polymerization / auto-inhibition

References

[1] Bao R, Christova T, Song S, Angers S, Yan X, Attisano L (2012) Inhibition of tankyrases induces Axin stabilization and blocks Wnt signalling in breast cancer cells. PLoS ONE7: e48670

[2] Bilic J, Huang YL, Davidson G, Zimmermann T, Cruciat CM, Bienz M, Niehrs C (2007) Wnt induces LRP6 signalosomes and promotes dishevelled-dependent LRP6 phosphorylation. Science316: 1619-1622

[3] Callow MG, Tran H, Phu L, Lau T, Lee J, Sandoval WN, Liu PS, Bheddah S, Tao J, Lill JR (2011) Ubiquitin ligase RNF 146 regulates tankyrase and Axin to promote Wnt signaling. PloS ONE6: e22595

[4] Cha B, Kim W, Kim YK, Hwang BN, Park SY, Yoon JW, Park WS, Cho JW, Bedford MT, Jho EH (2011) Methylation by protein arginine methyltransferase 1 increases stability of Axin, a negative regulator of Wnt signaling. Oncogene30: 2379-2389

[5] Chan DW, Chan CY, Yam JW, Ching YP, Ng IO (2006) Prickle-1 negatively regulates Wnt/beta-catenin pathway by promoting Dishevelled ubiquitination/degradation in liver cancer. Gastroenterology131: 1218-1227

[6] Chen G, AJ, Wang M, Farley S, Lee LY, Lee LC, Sawicki MP (2008) Menin promotes the Wnt signaling pathway in pancreatic endocrine cells. Mol Cancer Res6: 1894-1907

[7] Chen T, Li M, Ding Y, Zhang LS, Xi Y, Pan WJ, Tao DL, Wang JY, Li L (2009) Identification of zinc-finger BED domain-containing 3 (Zbed3) as a novel Axin-interacting protein that activates Wnt/beta-catenin signaling. J Biol Chem284: 6683-6689

[8] Chia IV, Costantini F (2005) Mouse axin and axin2/conductin proteins are functionally equivalent in vivo. Mol Cell Biol25: 4371-4376

[9] Choi J, Park SY, Costantini F, Jho EH, Joo CK (2004) Adenomatous polyposis coli is down-regulated by the ubiquitin-proteasome pathway in a process facilitated by Axin. J Biol Chem279: 49188-49198

[10] Choi SH, Choi KM, Ahn HJ (2010) Coexpression and protein-protein complexing of DIX domains of human Dvl1 and Axin1 protein. BMB Rep43: 609-613

[11] Ding Y, Xi Y, Chen T, Wang JY, Tao DL, Wu ZL, Li YP, Li C, Zeng R, Li L (2008) Caprin-2 enhances canonical Wnt signaling through regulating LRP5/6 phosphorylation. J Cell Biol182: 865-872

[12] Ding Y, Zhang Y, Xu C, Tao QH, Chen YG (2013) HECT domaincontaining E3 ubiquitin ligase NEDD4L negatively regulates Wnt signaling by targeting dishevelled for proteasomal degradation. J Biol Chem288: 8289-8298

[13] Egea V, Zahler S, Rieth N, Neth P, Popp T, Kehe K, Jochum M, Ries C (2012) Tissue inhibitor of metalloproteinase-1 (TIMP-1) regulates mesenchymal stem cells through let-7f microRNA and Wnt/betacatenin signaling. Proc Natl Acad Sci USA109: E309-E316

[14] Fang WQ, Ip JP, Li R, Ng YP, Lin SC, Chen Y, Fu AK, Ip NY (2011) Cdk5-mediated phosphorylation of Axin directs axon formation during cerebral cortex development. J Neurosci31: 13613-13624

[15] Fei C, Li Z, Li C, Chen Y, Chen Z, He X, Mao L, Wang X, Zeng R, Li L (2013) Smurf1-mediated Lys29-linked non-proteolytic poly-ubiquitination of Axin negatively regulates Wnt/beta-catenin signaling. Mol Cell Biol33: 4095-4105

[16] Fiedler M, Mendoza-Topaz C, Rutherford TJ, Mieszczanek J, Bienz M (2011) Dishevelled interacts with the DIX domain polymerization interface of Axin to interfere with its function in downregulating beta-catenin. Proc Natl Acad Sci USA108: 1937-1942

[17] Gao ZH, Seeling JM, Hill V, Yochum A, Virshup DM (2002) Casein kinase I phosphorylates and destabilizes the beta-catenin degradation complex. Proc Natl Acad Sci USA99: 1182-1187

[18] Han Y, Zhang Y, Yang LH, Mi XY, Dai SD, Li QC, Xu HT, Yu JH, Li G, Zhao J (2012) X-radiation inhibits histone deacetylase 1 and 2, upregulates Axin expression and induces apoptosis in nonsmall cell lung cancer. Radiat Oncol7: 183

[19] Hu T, Li C, Cao Z, Van Raay TJ, Smith JG, Willert K, Solnica-Krezel L, Coffey RJ (2010) Myristoylated Naked2 antagonizes Wnt-betacatenin activity by degrading Dishevelled-1 at the plasma membrane. J Biol Chem285: 13561-13568

[20] Huang SM, Mishina YM, Liu S, Cheung A, Stegmeier F, Michaud GA, Charlat O, Wiellette E, Zhang Y, Wiessner S (2009) Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature461: 614-620

[21] James RG, Davidson KC, Bosch KA, Biechele TL, Robin NC, Taylor RJ, Major MB, Camp ND, Fowler K, Martins TJ (2012) WIKI4, a novel inhibitor of tankyrase and Wnt/ss-catenin signaling. PLoS ONE7: e50457

[22] Jho E, Lomvardas S, Costantini F (1999) A GSK3beta phosphorylation site in axin modulates interaction with beta-catenin and Tcf-mediated gene expression. Biochem Biophys Res Commun266: 28-35

[23] Jho EH, Zhang T, Domon C, Joo CK, Freund JN, Costantini F (2002) Wnt/beta-catenin/Tcf signaling induces the transcription of Axin2, a negative regulator of the signaling pathway. Mol Cell Biol22: 1172-1183

[24] Jiang Y, Luo W, Howe PH (2009) Dab2 stabilizes Axin and attenuates Wnt/beta-catenin signaling by preventing protein phosphatase 1 (PP1)-Axin interactions. Oncogene28: 2999-3007

[25] Johnson SM, Grosshans H, Shingara J, Byrom M, Jarvis R, Cheng A, Labourier E, Reinert KL, Brown D, Slack FJ (2005) RAS is regulated by the let-7 microRNA family. Cell120: 635-647

[26] Kim S, Jho EH (2010) The protein stability of Axin, a negative regulator of Wnt signaling, is regulated by Smad ubiquitination regulatory factor 2 (Smurf2). J Biol Chem285: 36420-36426

[27] Kim SI, Park CS, Lee MS, Kwon MS, Jho EH, Song WK (2004) Cyclin-dependent kinase 2 regulates the interaction of Axin with beta-catenin. Biochem Biophys Res Commun317: 478-483

[28] Kim MJ, Chia IV, Costantini F (2008) SUMOylation target sites at the C terminus protect Axin from ubiquitination and confer protein stability. FASEB J22: 3785-3794

[29] Kim JT, Li J, Jang ER, Gulhati P, Rychahou PG, Napier DL, Wang C, Weiss HL, Lee EY, Anthony L (2013a) Deregulation of Wnt/beta-catenin signaling through genetic or epigenetic alterations in human neuroendocrine tumors. Carcinogenesis34: 953-961

[30] Kim SE, Huang H, Zhao M, Zhang X, Zhang A, Semonov MV, MacDonald BT, Zhang X, Garcia Abreu J, Peng L (2013b) Wnt stabilization of beta-catenin reveals principles for morphogen receptor-scaffold assemblies. Science340: 867-870

[31] Koinuma K, Yamashita Y, Liu W, Hatanaka H, Kurashina K, Wada T, Takada S, Kaneda R, Choi YL, Fujiwara SI (2006) Epigenetic silencing of AXIN2 in colorectal carcinoma with microsatellite instability. Oncogene25: 139-146

[32] Kulathu Y, Komander D (2012) Atypical ubiquitylation- the unexplored world of polyubiquitin beyond Lys48 and Lys63 linkages. Nat Rev Mol Cell Biol13: 508-523

[33] Lee I, Ajay SS, Yook JI, Kim HS, Hong SH, Kim NH, Dhanasekaran SM, Chinnaiyan AM, Athey BD (2009) New class of microRNA targets containing simultaneous 5′-UTR and 3′-UTR interaction sites. Genome Res19: 1175-1183

[34] Lee MA, Kim WK, Park HJ, Kang SS, Lee SK (2013) Antiproliferative activity of hydnocarpin, a natural lignan, is associated with the suppression of Wnt/beta-catenin signaling pathway in colon cancer cells. Bioorg Med Chem Lett23: 5511-5514

[35] Leung JY, Kolligs FT, Wu R, Zhai Y, Kuick R, Hanash S, Cho KR, Fearon ER (2002) Activation of AXIN2 expression by betacatenin-T cell factor. A feedback repressor pathway regulating Wnt signaling. J Biol Chem277: 21657-21665

[36] Li VS, Ng SS, Boersema PJ, Low TY, Karthaus WR, Gerlach JP, Mohammed S, Heck AJ, Maurice MM, Mahmoudi T (2012) Wnt signaling through inhibition of beta-catenin degradation in an intact Axin1 complex. Cell149: 1245-1256

[37] Liu C, Kato Y, Zhang Z, Do VM, Yankner BA, He X (1999) beta-Trcp couples beta-catenin phosphorylation-degradation and regulates Xenopus axis formation. Proc Natl Acad Sci USA96: 6273-6278

[38] Liu J, Stevens J, Rote CA, Yost HJ, Hu Y, Neufeld KL, White RL, Matsunami N (2001) Siah-1 mediates a novel beta-catenin degradation pathway linking p53 to the adenomatous polyposis coli protein. Mol Cell7: 927-936

[39] Liu YT, Dan QJ, Wang J, Feng Y, Chen L, Liang J, Li Q, Lin SC, Wang ZX, Wu JW (2011) Molecular basis of Wnt activation via the DIX domain protein Ccd1. J Biol Chem286: 8597-8608

[40] Lu J, Ma Z, Hsieh JC, Fan CW, Chen B, Longgood JC, Williams NS, Amatruda JF, Lum L, Chen C (2009) Structure-activity relationship studies of small-molecule inhibitors of Wnt response. Bioorg Med Chem Lett19: 3825-3827

[41] Lui TT, Lacroix C, Ahmed SM, Goldenberg SJ, Leach CA, Daulat AM, Angers S (2011) The ubiquitin-specific protease USP34 regulates axin stability and Wnt/beta-catenin signaling. Mol Cell Biol31: 2053-2065

[42] Luo W, Peterson A, Garcia BA, Coombs G, Kofahl B, Heinrich R, Shabanowitz J, Hunt DF, Yost HJ, Virshup DM (2007) Protein phosphatase 1 regulates assembly and function of the betacatenin degradation complex. EMBO J26: 1511-1521

[43] Mao J, Wang J, Liu B, Pan W, Farr GH3rd, Flynn C, Yuan H, Takada S, Kimelman D, Li L (2001) Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway. Mol Cell7: 801-809

[44] Mayr C, Hemann MT, Bartel DP (2007) Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation. Science315: 1576-1579

[45] Mendoza-Topaz C, Mieszczanek J, Bienz M (2011) The Adenomatous polyposis coli tumour suppressor is essential for Axin complex assembly and function and opposes Axin's interaction with Dishevelled. Open Biol1: 110013

[46] Metcalfe C, Mendoza-Topaz C, Mieszczanek J, Bienz M (2010) Stability elements in the LRP6cytoplasmic tail confer efficient signalling upon DIX-dependent polymerization. J Cell Sci123: 1588-1599

[47] Miyaki M, Konishi M, Kikuchi-Yanoshita R, Enomoto M, Igari T, Tanaka K, Muraoka M, Takahashi H, Amada Y, Fukayama M (1994) Characteristics of somatic mutation of the adenomatous polyposis coli gene in colorectal tumors. Cancer Res54: 3011-3020

[48] Najdi R, Holcombe RF, Waterman ML (2011) Wnt signaling and colon carcinogenesis: beyond APC. J Carcinog10: 5

[49] Nikuseva Martic T, Pecina-Slaus N, Kusec V, Kokotovic T, Musinovic H, Tomas D, Zeljko M (2010) Changes of AXIN-1 and beta-catenin in neuroepithelial brain tumors. Pathol Oncol Res16: 75-79

[50] Pecina-Slaus N, Martic TN, Kokotovic T, Kusec V, Tomas D, Hrascan R (2011) AXIN-1 protein expression and localization in glioblastoma. Collegium Antropologicum35(Suppl 1): 101-106

[51] Reinhart BJ, Slack FJ, Basson M, Pasquinelli AE, Bettinger JC, Rougvie AE, Horvitz HR, Ruvkun G (2000) The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature403: 901-906

[52] Rui HL, Fan E, Zhou HM, Xu Z, Zhang Y, Lin SC (2002) SUMO-1 modification of the C-terminal KVEKVD of Axin is required for JNK activation but has no effect on Wnt signaling. J Biol Chem277: 42981-42986

[53] Sakanaka C, Williams LT (1999) Functional domains of axin. Importance of the C terminus as an oligomerization domain. J Biol Chem274: 14090-14093

[54] Schmitz Y, Rateitschak K, Wolkenhauer O (2013) Analysing the impact of nucleo-cytoplasmic shuttling of beta-catenin and its antagonists APC, Axin and GSK3 on Wnt/beta-catenin signalling. Cell Signal25: 2210-2221

[55] Schwarz-Romond T, Fiedler M, Shibata N, Butler PJ, Kikuchi A, Higuchi Y, Bienz M (2007a) The DIX domain of Dishevelled confers Wnt signaling by dynamic polymerization. Nat Struct Mol Biol14: 484-492

[56] Schwarz-Romond T, Metcalfe C, Bienz M (2007b) Dynamic recruitment of axin by Dishevelled protein assemblies. J Cell Sci120: 2402-2412

[57] Shibata N, Tomimoto Y, Hanamura T, Yamamoto R, Ueda M, Ueda Y, Mizuno N, Ogata H, Komori H, Shomura Y (2007) Crystallization and preliminary X-ray crystallographic studies of the axin DIX domain. Acta Crystallogr Sect F Struct Biol Cryst Commun63: 529-531

[58] Shiomi K, Uchida H, Keino-Masu K, Masu M (2003) Ccd1, a novel protein with a DIX domain, is a positive regulator in the Wnt signaling during zebrafish neural patterning. Curr Biol13: 73-77

[59] Shultz MD, Kirby CA, Stams T, Chin DN, Blank J, Charlat O, Cheng H, Cheung A, Cong F, Feng Y (2012) [1,2,4]triazol-3-ylsulfanylmethyl)-3-phenyl-[1,2,4]oxadiazoles: antagonists of the Wnt pathway that inhibit tankyrases 1 and 2 via novel adenosine pocket binding. J Med Chem55: 1127-1136

[60] Silver SJ, Hagen JW, Okamura K, Perrimon N, Lai EC (2007) Functional screening identifies miR-315 as a potent activator of Wingless signaling. Proc Natl Acad Sci USA104: 18151-18156

[61] Strovel ET, Wu D, Sussman DJ (2000) Protein phosphatase 2Calpha dephosphorylates axin and activates LEF-1-dependent transcription. J Biol Chem275: 2399-2403

[62] Tran H, Polakis P (2012) Reversible modification of adenomatous polyposis coli (APC) with K63-linked polyubiquitin regulates the assembly and activity of the beta-catenin destruction complex. J Biol Chem287: 28552-28563

[63] Tran H, Bustos D, Yeh R, Rubinfeld B, Lam C, Shriver S, Zilberleyb I, Lee MW, Phu L, Sarkar AA (2013) HectD1 E3 ligase modifies adenomatous polyposis coli (APC) with polyubiquitin to promote the APC-axin interaction. J Biol Chem288: 3753-3767

[64] Wang S, Yin J, Chen D, Nie F, Song X, Fei C, Miao H, Jing C, Ma W, Wang L (2013) Small-moleculemodulation ofWnt signaling via modulating the Axin-LRP5/6 interaction. Nat Chem Biol9: 579-585

[65] Wei W, Li M, Wang J, Nie F, Li L (2012) The E3 ubiquitin ligase ITCH negatively regulates canonical Wnt signaling by targeting dishevelled protein. Mol Cell Biol32: 3903-3912

[66] Willert K, Jones KA (2006) Wnt signaling: is the party in the nucleus? Genes Dev20: 1394-1404

[67] Willert K, Shibamoto S, Nusse R (1999) Wnt-induced dephosphorylation of axin releases beta-catenin from the axin complex. Genes Dev13: 1768-1773

[68] Winston JT, Strack P, Beer-Romero P, Chu CY, Elledge SJ, Harper JW (1999) The SCFbeta-TRCP-ubiquitin ligase complex associates specifically with phosphorylated destruction motifs in IkappaBalpha and beta-catenin and stimulates IkappaBalpha ubiquitination in vitro. Genes Dev13: 270-283

[69] Wong CK, Luo W, Deng Y, Zou H, Ye Z, Lin SC (2004) The DIX domain protein coiled-coil-DIX1 inhibits c-Jun N-terminal kinase activation by Axin and dishevelled through distinct mechanisms. J Biol Chem279: 39366-39373

[70] Yamamoto H, Kishida S, Kishida M, Ikeda S, Takada S, Kikuchi A (1999) Phosphorylation of axin, a Wnt signal negative regulator, by glycogen synthase kinase-3beta regulates its stability. J Biol Chem274: 10681-10684

[71] Yan D, Wiesmann M, Rohan M, Chan V, Jefferson AB, Guo L, Sakamoto D, Caothien RH, Fuller JH, Reinhard C (2001) Elevated expression of axin2 and hnkd mRNA provides evidence that Wnt/beta-catenin signaling is activated in human colon tumors. Proc Natl Acad Sci USA98: 14973-14978

[72] Yang LH, Xu HT, Li QC, Jiang GY, Zhang XP, Zhao HY, Xu K, Wang EH (2013) Abnormal hypermethylation and clinicopathological significance of Axin gene in lung cancer. Tumour Biol34: 749-757

[73] Yokoyama N, Markova NG, Wang HY, Malbon CC (2012) Assembly of Dishevelled 3-based supermolecular complexes via phosphorylation and Axin. J Mol Signal7: 8

[74] Zhang Y, Liu S, Mickanin C, Feng Y, Charlat O, Michaud GA, Schirle M, Shi X, Hild M, Bauer A (2011) RNF146 is a poly(ADPribose)-directed E3 ligase that regulates axin degradation and Wnt signalling. Nat Cell Biol13: 623-629

RIGHTS & PERMISSIONS

2014 This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.