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AXIN1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1DK8, 1EMU, 1O9U, 3ZDI, 4B7T, 4NM0, 4NM3, 4NM5, 4NM7, 4NU1
Identifiers
Aliases	AXIN1, AXIN, PPP1R49, axin 1
External IDs	OMIM: 603816; MGI: 1096327; HomoloGene: 2614; GeneCards: AXIN1; OMA:AXIN1 - orthologs
Gene location (Human) Chr. Chromosome 16 (human) Band 16p13.3 Start 287,440 bp End 352,723 bp
Gene location (Mouse) Chr. Chromosome 17 (mouse) Band 17 A3.3|17 13.07 cM Start 26,357,662 bp End 26,414,785 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in granulocyte mucosa of transverse colon right hemisphere of cerebellum gastrocnemius muscle skin of leg mononuclear cell monocyte skin of abdomen blood popliteal artery Top expressed in Ileal epithelium tail of embryo ventricular zone genital tubercle epiblast zygote Paneth cell corneal stroma thymus granulocyte More reference expression data BioGPS More reference expression data
Gene ontology Molecular function beta-catenin binding protein homodimerization activity I-SMAD binding GTPase activator activity protein binding enzyme binding signaling receptor complex adaptor activity SMAD binding ubiquitin protein ligase binding molecular adaptor activity protein kinase binding armadillo repeat domain binding identical protein binding signaling adaptor activity Cellular component cytoplasm cytosol lateral plasma membrane membrane plasma membrane perinuclear region of cytoplasm cytoplasmic vesicle nucleus beta-catenin destruction complex cell periphery Biological process forebrain anterior/posterior pattern specification negative regulation of fat cell differentiation positive regulation of protein phosphorylation olfactory placode formation positive regulation of protein catabolic process positive regulation of canonical Wnt signaling pathway embryonic eye morphogenesis negative regulation of Wnt signaling pathway positive regulation of JNK cascade negative regulation of transcription elongation from RNA polymerase II promoter positive regulation of peptidyl-serine phosphorylation positive regulation of transcription, DNA-templated multicellular organism development lens placode formation determination of left/right symmetry canonical Wnt signaling pathway involved in neural plate anterior/posterior pattern formation positive regulation of ubiquitin-protein transferase activity positive regulation of peptidyl-threonine phosphorylation positive regulation of ubiquitin-dependent protein catabolic process cytoplasmic microtubule organization canonical Wnt signaling pathway embryonic skeletal joint morphogenesis axial mesoderm formation positive regulation of protein ubiquitination activation of protein kinase activity muscle cell development Wnt-activated signaling pathway involved in forebrain neuron fate commitment negative regulation of canonical Wnt signaling pathway signal transduction apoptotic process beta-catenin destruction complex disassembly positive regulation of GTPase activity Wnt signaling pathway beta-catenin destruction complex assembly regulation of Wnt signaling pathway regulation of intracellular estrogen receptor signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 8312 12005 Ensembl ENSG00000103126 ENSMUSG00000024182 UniProt O15169 O35625 RefSeq (mRNA) NM_003502 NM_181050 NM_001159598 NM_009733 NM_001394381 NM_001394382 NM_001394389 RefSeq (protein) NP_003493 NP_851393 NP_001153070 NP_033863 NP_001381310 NP_001381311 NP_001381318 Location (UCSC) Chr 16: 0.29 – 0.35 Mb Chr 17: 26.36 – 26.41 Mb PubMed search
Wikidata
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Axin-1 is a protein that in humans is encoded by the AXIN1 gene.

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.

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. 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. 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. 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.

Interactions

AXIN1 has been shown to interact with:

• APC,
• CTNNB1,
• CSNK1E,
• CSNK1A1,
• DVL1,
• GSK3B,
• LRP5,
• MAP3K1,
• PPP2R5A,
• RNF43, and
• TSC2.

References

1. ^ GRCh38: Ensembl release 89: ENSG00000103126 – Ensembl, May 2017
2. ^ GRCm38: Ensembl release 89: ENSMUSG00000024182 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Zeng L, Fagotto F, Zhang T, Hsu W, Vasicek TJ, Perry WL, et al. (August 1997). "The mouse Fused locus encodes Axin, an inhibitor of the Wnt signaling pathway that regulates embryonic axis formation". Cell. 90 (1): 181–92. doi:10.1016/S0092-8674(00)80324-4. PMID 9230313. S2CID 10565695.
6. "Entrez Gene: AXIN1 axin 1".
7. Wang W, Liu P, Lavrijsen M, Li S, Zhang R, Li S, et al. (April 2021). "Evaluation of AXIN1 and AXIN2 as targets of tankyrase inhibition in hepatocellular carcinoma cell lines". Scientific Reports. 11 (1): 7470. Bibcode:2021NatSR..11.7470W. doi:10.1038/s41598-021-87091-4. PMC 8018973. PMID 33811251.
8. Zhang R, Li S, Schippers K, Li Y, Eimers B, Lavrijsen M, et al. (May 2024). "Analysis of Tumor-Associated AXIN1 Missense Mutations Identifies Variants That Activate β-Catenin Signaling". Cancer Research. 84 (9): 1443–1459. doi:10.1158/0008-5472.CAN-23-2268. PMC 11063763. PMID 38359148.
9. Noutsou M, Duarte AM, Anvarian Z, Didenko T, Minde DP, Kuper I, et al. (2011). "Critical scaffolding regions of the tumor suppressor Axin1 are natively unfolded". J Mol Biol. 405 (3): 773–86. doi:10.1016/j.jmb.2010.11.013. PMID 21087614.
10. Anvarian Z, Nojima H, van Kappel EC, Madl T, Spit M, Viertler M, et al. (2016). "Axin cancer mutants form nanoaggregates to rewire the Wnt signaling network". Nat Struct Mol Biol. 23 (4): 324–32. doi:10.1038/nsmb.3191. hdl:1874/344404. PMID 26974125. S2CID 30761541.
11. ^ Nakamura T, Hamada F, Ishidate T, Anai K, Kawahara K, Toyoshima K, et al. (June 1998). "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. doi:10.1046/j.1365-2443.1998.00198.x. PMID 9734785. S2CID 10875463.
12. Hocevar BA, Mou F, Rennolds JL, Morris SM, Cooper JA, Howe PH (June 2003). "Regulation of the Wnt signaling pathway by disabled-2 (Dab2)". EMBO J. 22 (12): 3084–94. doi:10.1093/emboj/cdg286. PMC 162138. PMID 12805222.
13. ^ Zhang Y, Qiu WJ, Chan SC, Han J, He X, Lin SC (May 2002). "Casein kinase I and casein kinase II differentially regulate axin function in Wnt and JNK pathways". J. Biol. Chem. 277 (20): 17706–12. doi:10.1074/jbc.M111982200. PMID 11884395.
14. ^ Kim MJ, Chia IV, Costantini F (November 2008). "SUMOylation target sites at the C terminus protect Axin from ubiquitination and confer protein stability". FASEB J. 22 (11): 3785–94. doi:10.1096/fj.08-113910. PMC 2574027. PMID 18632848.
15. Li L, Yuan H, Weaver CD, Mao J, Farr GH, Sussman DJ, et al. (August 1999). "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. doi:10.1093/emboj/18.15.4233. PMC 1171499. PMID 10428961.
16. ^ Mak BC, Takemaru K, Kenerson HL, Moon RT, Yeung RS (February 2003). "The tuberin-hamartin complex negatively regulates beta-catenin signaling activity". J. Biol. Chem. 278 (8): 5947–51. doi:10.1074/jbc.C200473200. PMID 12511557.
17. Mao J, Wang J, Liu B, Pan W, Farr GH, Flynn C, et al. (April 2001). "Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway". Mol. Cell. 7 (4): 801–9. doi:10.1016/S1097-2765(01)00224-6. PMID 11336703.
18. Zhang Y, Neo SY, Han J, Lin SC (August 2000). "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. doi:10.1074/jbc.M002491200. PMID 10829020.
19. Yamamoto H, Hinoi T, Michiue T, Fukui A, Usui H, Janssens V, et al. (July 2001). "Inhibition of the Wnt signaling pathway by the PR61 subunit of protein phosphatase 2A". J. Biol. Chem. 276 (29): 26875–82. doi:10.1074/jbc.M100443200. PMID 11297546.
20. Spit M, Fenderico N, Jordens I, Radaszkiewicz T, Lindeboom RG, Bugter JM, et al. (September 2020). "RNF43 truncations trap CK1 to drive niche-independent self-renewal in cancer". The EMBO Journal. 39 (18): e103932. doi:10.15252/embj.2019103932. PMC 7503102. PMID 32965059.

Further reading

• Segditsas S, Tomlinson I (2007). "Colorectal cancer and genetic alterations in the Wnt pathway". Oncogene. 25 (57): 7531–7. doi:10.1038/sj.onc.1210059. PMID 17143297. S2CID 19546579.
• Flint J, Thomas K, Micklem G, Raynham H, Clark K, Doggett NA, et al. (1997). "The relationship between chromosome structure and function at a human telomeric region". Nat. Genet. 15 (3): 252–7. doi:10.1038/ng0397-252. PMID 9054936. S2CID 20630444.
• 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-3beta and beta-catenin and promotes GSK-3beta-dependent phosphorylation of beta-catenin". EMBO J. 17 (5): 1371–84. doi:10.1093/emboj/17.5.1371. PMC 1170485. PMID 9482734.
• Hart MJ, de los Santos R, Albert IN, Rubinfeld B, Polakis P (1998). "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. Bibcode:1998CBio....8..573H. doi:10.1016/S0960-9822(98)70226-X. PMID 9601641. S2CID 2863360.
• Nakamura T, Hamada F, Ishidate T, Anai K, Kawahara K, Toyoshima K, et al. (1998). "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. doi:10.1046/j.1365-2443.1998.00198.x. PMID 9734785. S2CID 10875463.
• 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 (6): 3439–45. doi:10.1074/jbc.274.6.3439. PMID 9920888.
• Kitagawa M, Hatakeyama S, Shirane M, Matsumoto M, Ishida N, Hattori K, et al. (1999). "An F-box protein, FWD1, mediates ubiquitin-dependent proteolysis of beta-catenin". EMBO J. 18 (9): 2401–10. doi:10.1093/emboj/18.9.2401. PMC 1171323. PMID 10228155.
• Fagotto F, Jho Eh, Zeng L, Kurth T, Joos T, Kaufmann C, et al. (1999). "Domains of axin involved in protein-protein interactions, Wnt pathway inhibition, and intracellular localization". J. Cell Biol. 145 (4): 741–56. doi:10.1083/jcb.145.4.741. PMC 2133179. PMID 10330403.
• Kodama S, Ikeda S, Asahara T, Kishida M, Kikuchi A (1999). "Axin directly interacts with plakoglobin and regulates its stability". J. Biol. Chem. 274 (39): 27682–8. doi:10.1074/jbc.274.39.27682. PMID 10488109.
• Jho Eh, Lomvardas S, Costantini F (2000). "A GSK3beta phosphorylation site in axin modulates interaction with beta-catenin and Tcf-mediated gene expression". Biochem. Biophys. Res. Commun. 266 (1): 28–35. doi:10.1006/bbrc.1999.1760. PMID 10581160.
• Ikeda S, Kishida M, Matsuura Y, Usui H, Kikuchi A (2000). "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. doi:10.1038/sj.onc.1203359. PMID 10698523.
• Satoh S, Daigo Y, Furukawa Y, Kato T, Miwa N, Nishiwaki T, et al. (2000). "AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1". Nat. Genet. 24 (3): 245–50. doi:10.1038/73448. PMID 10700176. S2CID 27531668.
• Spink KE, Polakis P, Weis WI (2000). "Structural basis of the Axin-adenomatous polyposis coli interaction". EMBO J. 19 (10): 2270–9. doi:10.1093/emboj/19.10.2270. PMC 384355. PMID 10811618.
• Zhang Y, Neo SY, Han J, Lin SC (2000). "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. doi:10.1074/jbc.M002491200. PMID 10829020.
• Daniels RJ, Peden JF, Lloyd C, Horsley SW, Clark K, Tufarelli C, et al. (2001). "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. doi:10.1093/hmg/10.4.339. PMID 11157797.
• Yamamoto H, Hinoi T, Michiue T, Fukui A, Usui H, Janssens V, et al. (2001). "Inhibition of the Wnt signaling pathway by the PR61 subunit of protein phosphatase 2A". J. Biol. Chem. 276 (29): 26875–82. doi:10.1074/jbc.M100443200. PMID 11297546.
• Mao J, Wang J, Liu B, Pan W, Farr 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 (4): 801–9. doi:10.1016/S1097-2765(01)00224-6. PMID 11336703.
• Furuhashi M, Yagi K, Yamamoto H, Furukawa Y, Shimada S, Nakamura Y, et al. (2001). "Axin facilitates Smad3 activation in the transforming growth factor beta signaling pathway". Mol. Cell. Biol. 21 (15): 5132–41. doi:10.1128/MCB.21.15.5132-5141.2001. PMC 87238. PMID 11438668.
• Rubinfeld B, Tice DA, Polakis P (2001). "Axin-dependent phosphorylation of the adenomatous polyposis coli protein mediated by casein kinase 1epsilon". J. Biol. Chem. 276 (42): 39037–45. doi:10.1074/jbc.M105148200. PMID 11487578.

External links

• Human AXIN1 genome location and AXIN1 gene details page in the UCSC Genome Browser.
• Overview of all the structural information available in the PDB for UniProt: O15169 (Axin-1) at the PDBe-KB.

• Genes on human chromosome 16