AXIN1 explained

Axin-1 is a protein that in humans is encoded by the AXIN1 gene.^[1]

Function

This gene encodes a cytoplasmic protein which contains a regulation of G-protein signaling (RGS) domain and a dishevelled and axin (DIX) domain. The encoded protein interacts with adenomatosis polyposis coli, catenin (cadherin-associated protein) beta 1, glycogen synthase kinase 3 beta, protein phosphatase 2, and itself. This protein functions as a negative regulator of the wingless-type MMTV integration site family, member 1 (WNT) signaling pathway and can induce apoptosis. The crystal structure of a portion of this protein, alone and in a complex with other proteins, has been resolved. Mutations in this gene have been associated with hepatocellular carcinoma, hepatoblastomas, ovarian endometrioid adenocarcinomas, and medulloblastomas. Two transcript variants encoding distinct isoforms have been identified for this gene.^[2]

The AXIN proteins attract substantial interest in cancer research as AXIN1 and AXIN2 work synergistically to control pro-oncogenic β-catenin signaling. Importantly, activity in the β-catenin destruction complex can be increased by tankyrase inhibitors and are a potential therapeutic option to reduce the growth of β-catenin-dependent cancers.^[3] Mutation in AXIN1 can provoke cancerous disease. AXIN1-truncating mutations at least partially affect β-catenin regulation, whereas this is only the case for a subset of missense mutations. Consistently, most colorectal and liver cancers carrying missense variants acquire mutations in other β-catenin regulatory genes such as APC and CTNNB1.^[4] Thus AXIN1 has emerged as an important oncogen in various gastrointestinal and liver cancers.

Structure

The full-length human protein comprises 862 amino acids with a (predicted) molecular mass of 96 kDa. The N-terminal RGS domain, a GSK3 kinase interacting peptide of Axin1 and homologs of the C-terminal DIX domains have been solved at atomic resolution. Large WNT-downregulating central regions have been characterized as intrinsically disordered by biophysical experiments and bioinformatic analysis.^[5] Biophysical destabilization of the folded RGS domain induces formation of nanoaggregates that expose and locally concentrate intrinsically disordered regions, which in turn misregulate Wnt signalling. Many other large IDPs (Intrinsically Disordered Proteins) are affected by missense mutations, such as BRCA1, Adenomatous polyposis coli, CREB-binding protein/(CBP) and might be affected in similar ways by missense mutations of their folded domains.^[6]

Interactions

AXIN1 has been shown to interact with:

• APC,
• CTNNB1,^{[7] [8]}
• CSNK1E,
• CSNK1A1,
• DVL1,^[9]
• GSK3B,^{[7] [10]}
• LRP5,^{[11] [12]}
• MAP3K1,^{[13] [14]}
• PPP2R5A,^[15]
• RNF43,^[16] and
• TSC2.^[10]

Further reading

• Segditsas S, Tomlinson I . Colorectal cancer and genetic alterations in the Wnt pathway. . Oncogene . 25 . 57 . 7531–7 . 2007 . 17143297 . 10.1038/sj.onc.1210059 . 19546579 .
• Flint J, Thomas K, Micklem G, Raynham H, Clark K, Doggett NA, King A, Higgs DR . The relationship between chromosome structure and function at a human telomeric region . Nat. Genet. . 15 . 3 . 252–7 . 1997 . 9054936 . 10.1038/ng0397-252 . 20630444 .
• 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-3beta and beta-catenin and promotes GSK-3beta-dependent phosphorylation of beta-catenin . EMBO J. . 17 . 5 . 1371–84 . 1998 . 9482734 . 1170485 . 10.1093/emboj/17.5.1371 .
• Hart MJ, de los Santos R, Albert IN, Rubinfeld B, Polakis P . Downregulation of beta-catenin by human Axin and its association with the APC tumor suppressor, beta-catenin and GSK3 beta . Curr. Biol. . 8 . 10 . 573–81 . 1998 . 9601641 . 10.1016/S0960-9822(98)70226-X . 2863360 . free . 1998CBio....8..573H .
• Nakamura T, Hamada F, Ishidate T, Anai K, Kawahara K, Toyoshima K, Akiyama T . Axin, an inhibitor of the Wnt signalling pathway, interacts with beta-catenin, GSK-3beta and APC and reduces the beta-catenin level . Genes Cells . 3 . 6 . 395–403 . 1998 . 9734785 . 10.1046/j.1365-2443.1998.00198.x . 10875463 . free .
• 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. . 274 . 6 . 3439–45 . 1999 . 9920888 . 10.1074/jbc.274.6.3439 . free .
• Kitagawa M, Hatakeyama S, Shirane M, Matsumoto M, Ishida N, Hattori K, Nakamichi I, Kikuchi A, Nakayama K, Nakayama K . An F-box protein, FWD1, mediates ubiquitin-dependent proteolysis of beta-catenin . EMBO J. . 18 . 9 . 2401–10 . 1999 . 10228155 . 1171323 . 10.1093/emboj/18.9.2401 .
• Fagotto F, ((Jho Eh)), 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. . 145 . 4 . 741–56 . 1999 . 10330403 . 2133179 . 10.1083/jcb.145.4.741 .
• Kodama S, Ikeda S, Asahara T, Kishida M, Kikuchi A . Axin directly interacts with plakoglobin and regulates its stability . J. Biol. Chem. . 274 . 39 . 27682–8 . 1999 . 10488109 . 10.1074/jbc.274.39.27682 . free .
• ((Jho Eh)), Lomvardas S, Costantini F . A GSK3beta phosphorylation site in axin modulates interaction with beta-catenin and Tcf-mediated gene expression . Biochem. Biophys. Res. Commun. . 266 . 1 . 28–35 . 2000 . 10581160 . 10.1006/bbrc.1999.1760 . free .
• Ikeda S, Kishida M, Matsuura Y, Usui H, Kikuchi A . GSK-3beta-dependent phosphorylation of adenomatous polyposis coli gene product can be modulated by beta-catenin and protein phosphatase 2A complexed with Axin . Oncogene . 19 . 4 . 537–45 . 2000 . 10698523 . 10.1038/sj.onc.1203359 . free .
• Satoh S, Daigo Y, Furukawa Y, Kato T, Miwa N, Nishiwaki T, Kawasoe T, Ishiguro H, Fujita M, Tokino T, Sasaki Y, Imaoka S, Murata M, Shimano T, Yamaoka Y, Nakamura Y . AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1 . Nat. Genet. . 24 . 3 . 245–50 . 2000 . 10700176 . 10.1038/73448 . 27531668 .
• Spink KE, Polakis P, Weis WI . Structural basis of the Axin-adenomatous polyposis coli interaction . EMBO J. . 19 . 10 . 2270–9 . 2000 . 10811618 . 384355 . 10.1093/emboj/19.10.2270 .
• 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. . 275 . 32 . 25008–14 . 2000 . 10829020 . 10.1074/jbc.M002491200 . free .
• Daniels RJ, Peden JF, Lloyd C, Horsley SW, Clark K, Tufarelli C, Kearney L, Buckle VJ, Doggett NA, Flint J, Higgs DR . Sequence, structure and pathology of the fully annotated terminal 2 Mb of the short arm of human chromosome 16 . Hum. Mol. Genet. . 10 . 4 . 339–52 . 2001 . 11157797 . 10.1093/hmg/10.4.339 . free .
• 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. . 276 . 29 . 26875–82 . 2001 . 11297546 . 10.1074/jbc.M100443200 . free .
• Mao J, Wang J, Liu B, Pan W, Farr GH, 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 . 7 . 4 . 801–9 . 2001 . 11336703 . 10.1016/S1097-2765(01)00224-6 . free .
• 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. . 21 . 15 . 5132–41 . 2001 . 11438668 . 87238 . 10.1128/MCB.21.15.5132-5141.2001 .
• Rubinfeld B, Tice DA, Polakis P . Axin-dependent phosphorylation of the adenomatous polyposis coli protein mediated by casein kinase 1epsilon . J. Biol. Chem. . 276 . 42 . 39037–45 . 2001 . 11487578 . 10.1074/jbc.M105148200 . free .

Notes and References

1. 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 . 90 . 1 . 181–92 . August 1997 . 9230313 . 10.1016/S0092-8674(00)80324-4 . 10565695 . free .
2. Web site: Entrez Gene: AXIN1 axin 1.
3. Wang W, Liu P, Lavrijsen M, Li S, Zhang R, Li S, van de Geer WS, van de Werken HJ, Peppelenbosch MP, Smits R. Evaluation of AXIN1 and AXIN2 as targets of tankyrase inhibition in hepatocellular carcinoma cell lines . Scientific Reports . 11 . 7470 . April 2021 . 1 . 33811251 . 8018973 . 10.1038/s41598-021-87091-4 . 2021NatSR..11.7470W .
4. Zhang R, Li S, Schippers K, Li Y, Eimers B, Lavrijsen M, Wang L, Cui G, Chen X, Peppelenbosch MP, Lebbink JH, Smits R . Analysis of Tumor-Associated AXIN1 Missense Mutations Identifies Variants That Activate β-Catenin Signaling. . Cancer Research . 84 . 9 . 1443-1459 . May 2024 . 38359148 . 10.1158/0008-5472.CAN-23-2268 . free. 11063763 .
5. Noutsou M, Duarte AM, Anvarian Z, Didenko T, Minde DP, Kuper I, de Ridder I, Oikonomou C, Friedler A, Boelens R, Rüdiger SG, Maurice MM . Critical scaffolding regions of the tumor suppressor Axin1 are natively unfolded . J Mol Biol . 405 . 3 . 773–86 . 2011 . 21087614 . 10.1016/j.jmb.2010.11.013 . free .
6. Anvarian Z, Nojima H, van Kappel EC, Madl T, Spit M, Viertler M, Jordens I, Low TY, van Scherpenzeel RC, Kuper I, Richter K, Heck AJ, Boelens R, Vincent JP, Rüdiger SG, Maurice MM . Axin cancer mutants form nanoaggregates to rewire the Wnt signaling network . Nat Struct Mol Biol . 2016 . 26974125 . 10.1038/nsmb.3191 . 23 . 4 . 324–32 . 1874/344404 . 30761541 . free .
7. Nakamura T, Hamada F, Ishidate T, Anai K, Kawahara K, Toyoshima K, Akiyama T . Axin, an inhibitor of the Wnt signalling pathway, interacts with beta-catenin, GSK-3beta and APC and reduces the beta-catenin level . Genes Cells . 3 . 6 . 395–403 . June 1998 . 9734785 . 10.1046/j.1365-2443.1998.00198.x . 10875463 . free .
8. Hocevar BA, Mou F, Rennolds JL, Morris SM, Cooper JA, Howe PH . Regulation of the Wnt signaling pathway by disabled-2 (Dab2) . EMBO J. . 22 . 12 . 3084–94 . June 2003 . 12805222 . 162138 . 10.1093/emboj/cdg286 .
9. 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. . 18 . 15 . 4233–40 . August 1999 . 10428961 . 1171499 . 10.1093/emboj/18.15.4233 .
10. Mak BC, Takemaru K, Kenerson HL, Moon RT, Yeung RS . The tuberin-hamartin complex negatively regulates beta-catenin signaling activity . J. Biol. Chem. . 278 . 8 . 5947–51 . February 2003 . 12511557 . 10.1074/jbc.C200473200 . free .
11. Kim MJ, Chia IV, Costantini F . SUMOylation target sites at the C terminus protect Axin from ubiquitination and confer protein stability . FASEB J. . 22 . 11 . 3785–94 . November 2008 . 18632848 . 2574027 . 10.1096/fj.08-113910 . free .
12. Mao J, Wang J, Liu B, Pan W, Farr GH, 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 . 7 . 4 . 801–9 . April 2001 . 11336703 . 10.1016/S1097-2765(01)00224-6 . free .
13. 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. . 277 . 20 . 17706–12 . May 2002 . 11884395 . 10.1074/jbc.M111982200 . free .
14. 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. . 275 . 32 . 25008–14 . August 2000 . 10829020 . 10.1074/jbc.M002491200 . free .
15. 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. . 276 . 29 . 26875–82 . July 2001 . 11297546 . 10.1074/jbc.M100443200 . free .
16. Spit . Maureen . Fenderico . Nicola . Jordens . Ingrid . Radaszkiewicz . Tomasz . Lindeboom . Rik GH . Bugter . Jeroen M . Cristobal . Alba . Ootes . Lars . van Osch . Max . Janssen . Eline . Boonekamp . Kim E . Hanakova . Katerina . Potesil . David . Zdrahal . Zbynek . Boj . Sylvia F . Medema . Jan Paul . Bryja . Vitezslav . Koo . Bon-Kyoung . Vermeulen . Michiel . Maurice . Madelon M . RNF 43 truncations trap CK 1 to drive niche-independent self-renewal in cancer . The EMBO Journal . 15 September 2020 . 39 . 18 . e103932 . 10.15252/embj.2019103932 . 32965059. 7503102 . free .