AXIN2 (axin 2)

2007-01-01   Thomas A Hughes 

Pathology and Tumour Biology Section, Leeds Institute of Molecular Medicine, Wellcome Trust Brenner Building, St Jamess University Hospital, University of Leeds, Leeds LS9 7TF, UK




Atlas Image
The 5 end of the human AXIN2 gene. An alignment of human genomic DNA (top line) with the 5 end of different Axin2 mRNA variants. Exons are shown as boxes (non-coding: filled; coding: open) and the translational start codon is marked (ATG).


The AXIN2 gene spans about 35 kbp including 10 coding exons and 3 non-coding 5 exons (E0a, 0b and 0c; see above). Nearby genes: about 70 kbp upstream is CCDC46 (coiled-coil domain containing 46), about 300 kbp downstream is RGS9 (regulator of G-protein signalling 9). In addition, there is a putative gene that overlaps the AXIN2 non-coding 5 exons and coding exon 1 (E1) and is transcribed from the same strand (Gnomon model hmm119498); there is no published data on whether this is actually expressed.


Transcription occurs from three separate promoters leading to initiation at each of the three non-coding 5 exons. mRNAs are spliced so that that each non-coding exon is expressed separately, rather than in combinations. It is unclear whether transcription can initiate at the first coding exon (E1). Promoters can be activated by TCF transcription factors binding at multiple sites and by E2F1 binding at up to 4 sites, although E2F1 can also induce transcription in the absence of consensus sites. It has been reported that exon 6 can be omitted in an alternatively-spliced form.


None identified


Atlas Image


Human Axin2 is an 843 amino acids protein (777 amino acids from delta exon 6 mRNAs) containing an RGS domain (regulator of G protein signalling; amino acids 81-200), a GSK-3 beta binding domain (amino acids 327-413), a beta-catenin binding domain (amino acids 413-476), and a DIX domain (domain in dishevelled and axin; amino acids 761-843).


Expression appears to be ubiquitous in adult tissues (although at differing levels), but is limited to specific regions during embryonic development. Expression is regulated at multiple levels including transcription, mRNA stability, translation and protein stability.


Axin2 protein has been localised to the cytoplasm, the nucleus and the mitotic spindle.


Molecular functions :
1) Axin2 acts as a negative regulator of canonical Wnt/TCF signalling by enhancing formation of the beta-catenin destruction complex. Since expression of Axin2 is itself activated by canonical Wnt/TCF signalling, this results in a negative feedback-loop that restricts TCF activity.
2) Axin2 may influence TCF activity by re-localising beta-catenin to the cytoplasm.
3) Activity of the GSK-3 beta target snail1 can be regulated by Axin2s ability to influence the nucleo-cytoplasmic localisation of GSK-3 beta.
4) Axin2 binds polo-like kinase 1 (PLK1) during mitosis and influences the accuracy of chromosome segregation.
Cellular/physiological functions :
1) Axin2 expression oscillates during early embryogenesis in response to Wnt3a - this is required to achieve correct the temporal TCF activity to allow somatogenesis.
2) A requirement for Axin2 for correct calvarial morphogenesis and craniosynostosis has been revealed in Axin2 -/- mice.
3) Axin2 appears to act as a tumour suppressor, and somatic mutations have been seen in many different tumour types (see below).


Axin2 is 44% identical to axin in mice and knock-in experiments suggest that the proteins can be functionally equivalent.



A large number of different mutations in the AXIN2 gene have been identified. In many cases (but not all) these lead to premature translational termination and protein truncation. Truncated Axin2 protein is more stable than the wild type, while there has been speculation that the mRNA may be less stable.


Heterozygous germ line mutations in exon 7 that lead to premature termination are associated with familial tooth agenesis and a predisposition to colorectal cancer. Further germ line polymorphisms associated with familial tooth agenesis have been identified in exons 2 and 7. A polymorphism within exon 1 has been identified that is associated with risk of lung cancer. Many other polymorphisms that have yet to be associated with any function have been detected.


The genomic region containing the AXIN2 gene shows loss of heterozygosity and re-arrangements in a variety of cancers. In addition somatic point mutations and deletions have been identified in colorectal cancer, hepatocellular carcinomas, ovarian endometrioid adenocarcinomas and hepatoblastomas. Many of these mutations/deletions result in translation of truncated proteins that are likely to be functionally inactive, although one report has suggested that these truncated proteins have a dominant negative activity.

Implicated in

Entity name
Colorectal cancer (CRC)
Axin2 is often over-expressed in CRC as a result of the deregulation of canonical Wnt/beta-catenin signalling that is an early event in CRC development (usually caused by mutations/deletions in APC or beta-catenin). Somatic inactivating mutations within Axin2 have been reported in CRC and theoretically these could contribute to further deregulation of Wnt/beta-catenin - suggesting that Axin2 is a tumour suppressor. However mutations have only been seen in microsatellite unstable tumours and often within regions of mono-nucleotide repeats (exon 7), hence whether Axin2 mutations are cause or effect in these tumours remains undetermined. In support of Axin2s role as a tumour suppressor are observations that Axin2 is silenced by promoter methylation in many microsatellite unstable tumours. As discussed above, heterozygotes for some germ line mutations in AXIN2 are predisposed to CRC although this seems to be involved with only a very small proportion of familial colorectal cancer.
Entity name
Other cancers (hepatocellular carcinomas, hepatoblastomas, ovarian endometrioid adenocarcinomas)
Somatic mutations in Axin2 have been detected in a range of cancer types. It is usually assumed that these lead to partial inactivation of Axin2 function thereby deregulation of canonical Wnt/beta-catenin signalling. In most cases this has not formally been demonstrated, and the contribution of Axin2 mutations to any putative change in Wnt/beta-catenin activity and to the development of these cancers remains mostly unclear.
Entity name
Familial Tooth Agenesis (see above)


Pubmed IDLast YearTitleAuthors
120725592002Subcellular distribution of Wnt pathway proteins in normal and neoplastic colon.Anderson CB et al
126369202003Wnt3a plays a major role in the segmentation clock controlling somitogenesis.Aulehla A et al
95548521998Functional interaction of an axin homolog, conductin, with beta-catenin, APC, and GSK3beta.Behrens J et al
158998432005Mouse axin and axin2/conductin proteins are functionally equivalent in vivo.Chia IV et al
114741732001Genomic structure, chromosome mapping and expression analysis of the human AXIN2 gene.Dong X et al
168159672006Aberrant Wnt/beta-catenin signaling can induce chromosomal instability in colon cancer.Hadjihannas MV et al
158858872006Regulation of axin2 expression at the levels of transcription, translation and protein stability in lung and colon cancer.Hughes TA et al
150673282004Immunohistochemical analysis and mutational analyses of beta-catenin, Axin family and APC genes in hepatocellular carcinomas.Ishizaki Y et al
118098082002Wnt/beta-catenin/Tcf signaling induces the transcription of Axin2, a negative regulator of the signaling pathway.Jho EH et al
168209352006Single nucleotide polymorphism of the AXIN2 gene is preferentially associated with human lung cancer risk in a Japanese population.Kanzaki H et al
155387502004Mutations and elevated transcriptional activity of conductin (AXIN2) in hepatoblastomas.Koch A et al
162474842006Epigenetic silencing of AXIN2 in colorectal carcinoma with microsatellite instability.Koinuma K et al
165544432006Nucleo-cytoplasmic distribution of beta-catenin is regulated by retention.Krieghoff E et al
150425112004Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal cancer.Lammi L et al
119405742002Activation of AXIN2 expression by beta-catenin-T cell factor. A feedback repressor pathway regulating Wnt signaling.Leung JY et al
110170672000Mutations in AXIN2 cause colorectal cancer with defective mismatch repair by activating beta-catenin/TCF signalling.Liu W et al
118098092002Negative feedback loop of Wnt signaling through upregulation of conductin/axin2 in colorectal and liver tumors.Lustig B et al
164326382006Axis inhibition protein 2 (AXIN2) polymorphisms may be a risk factor for selective tooth agenesis.Mostowska A et al
158414892005Germline mutations of AXIN2 are not associated with nonsyndromic colorectal cancer.Peterlongo P et al
95004631998Consortium study on 1280 breast carcinomas: allelic loss on chromosome 17 targets subregions associated with family history and clinical parameters.Phelan CM et al
94087511997Four regions of allelic imbalance on 17q12-qter associated with high-grade breast tumors.Plummer SJ et al
157351512005The links between axin and carcinogenesis.Salahshor S et al
167083702006Mutations within Wnt pathway genes in sporadic colorectal cancers and cell lines.Suraweera N et al
121014262002Mutational spectrum of beta-catenin, AXIN1, and AXIN2 in hepatocellular carcinomas and hepatoblastomas.Taniguchi K et al
158020152005Genetic and epigenetic changes of components affecting the WNT pathway in colorectal carcinomas stratified by microsatellite instability.Thorstensen L et al
117194572001Diverse mechanisms of beta-catenin deregulation in ovarian endometrioid adenocarcinomas.Wu R et al
95669051998Axil, a member of the Axin family, interacts with both glycogen synthase kinase 3beta and beta-catenin and inhibits axis formation of Xenopus embryos.Yamamoto H et al
170723032006A Wnt-Axin2-GSK3beta cascade regulates Snail1 activity in breast cancer cells.Yook JI et al
157909732005The role of Axin2 in calvarial morphogenesis and craniosynostosis.Yu HM et al

Other Information

Locus ID:

NCBI: 8313
MIM: 604025
HGNC: 904
Ensembl: ENSG00000168646


dbSNP: 8313
ClinVar: 8313
TCGA: ENSG00000168646


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Wnt signaling pathwayKEGGko04310
Colorectal cancerKEGGko05210
Endometrial cancerKEGGko05213
Basal cell carcinomaKEGGko05217
Wnt signaling pathwayKEGGhsa04310
Pathways in cancerKEGGhsa05200
Colorectal cancerKEGGhsa05210
Endometrial cancerKEGGhsa05213
Basal cell carcinomaKEGGhsa05217
Hippo signaling pathwayKEGGhsa04390
Hippo signaling pathwayKEGGko04390
Signaling pathways regulating pluripotency of stem cellsKEGGhsa04550
Signaling pathways regulating pluripotency of stem cellsKEGGko04550
Metabolism of proteinsREACTOMER-HSA-392499
Post-translational protein modificationREACTOMER-HSA-597592
Signal TransductionREACTOMER-HSA-162582
Signaling by WntREACTOMER-HSA-195721
TCF dependent signaling in response to WNTREACTOMER-HSA-201681
Formation of the beta-catenin:TCF transactivating complexREACTOMER-HSA-201722
Binding of TCF/LEF:CTNNB1 to target gene promotersREACTOMER-HSA-4411364
Degradation of AXINREACTOMER-HSA-4641257
Ub-specific processing proteasesREACTOMER-HSA-5689880
Breast cancerKEGGko05224
Breast cancerKEGGhsa05224

Protein levels (Protein atlas)

Not detected


Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA164713176Platinum compoundsChemicalClinicalAnnotationassociatedPD24980784
PA443622Carcinoma, Non-Small-Cell LungDiseaseClinicalAnnotationassociatedPD24980784


Pubmed IDYearTitleCitations
170723032006A Wnt-Axin2-GSK3beta cascade regulates Snail1 activity in breast cancer cells.254
171432972006Colorectal cancer and genetic alterations in the Wnt pathway.198
150425112004Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal cancer.157
119405742002Activation of AXIN2 expression by beta-catenin-T cell factor. A feedback repressor pathway regulating Wnt signaling.146
217060182011Axin2 as regulatory and therapeutic target in newborn brain injury and remyelination.128
217999112011Ubiquitin ligase RNF146 regulates tankyrase and Axin to promote Wnt signaling.82
227451732012Canonical Wnt suppressor, Axin2, promotes colon carcinoma oncogenic activity.48
213830612011The ubiquitin-specific protease USP34 regulates axin stability and Wnt/β-catenin signaling.45
162474842006Epigenetic silencing of AXIN2 in colorectal carcinoma with microsatellite instability.37
195840752009Novel susceptibility loci for second primary tumors/recurrence in head and neck cancer patients: large-scale evaluation of genetic variants.36


Thomas A Hughes

AXIN2 (axin 2)

Atlas Genet Cytogenet Oncol Haematol. 2007-01-01

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