AXIN2 (axin 2)

Identity

Other names	axil (mostly in rat)
	conductin
	DKFZp781B0869 (single database entry only)
	MGC126582 (single database entry only)
HGNC	AXIN2
Location	17q24.1

DNA/RNA

	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).
Description	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	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.
Pseudogene	None identified

Protein

Description	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	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.
Localisation	Axin2 protein has been localised to the cytoplasm, the nucleus and the mitotic spindle.
Function	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 Axin2's 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 ð 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).
Homology	Axin2 is 44% identical to axin in mice and knock-in experiments suggest that the proteins can be functionally equivalent.

Mutations

Note	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.
Germinal	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.
Somatic	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	Colorectal cancer (CRC)
Oncogenesis	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 ð 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 Axin2's 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	Other cancers (hepatocellular carcinomas, hepatoblastomas, ovarian endometrioid adenocarcinomas)
Oncogenesis	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	Familial Tooth Agenesis (see above)

External links

	Nomenclature
HGNC	AXIN2   904
Entrez_Gene	AXIN2  8313  axin 2
	Cards
Atlas	AXIN2ID456ch17q24
GeneCards	AXIN2
Ensembl	AXIN2 [Search_View]   ENSG00000168646 [Gene_View]
Genatlas	AXIN2
GeneLynx	AXIN2
eGenome	AXIN2
euGene	8313
	Genomic and cartography
GoldenPath	AXIN2  -  17q24.1   chr17:60955145-60988227 -  17q23-q24   [Description]    (hg18-Mar_2006)
Ensembl	AXIN2 - 17q23-q24 [CytoView]
NCBI	Mapview
OMIM	Disease map [OMIM]
HomoloGene	AXIN2
	Gene and transcription
Genbank	AB052751 [ ENTREZ ]
Genbank	AF078165 [ ENTREZ ]
Genbank	AF205888 [ ENTREZ ]
Genbank	AK025718 [ ENTREZ ]
Genbank	AK308888 [ ENTREZ ]
RefSeq	NM_004655 [ SRS ]    NM_004655 [ ENTREZ ]
RefSeq	AC_000060 [ SRS ]    AC_000060 [ ENTREZ ]
RefSeq	AC_000149 [ SRS ]    AC_000149 [ ENTREZ ]
RefSeq	NC_000017 [ SRS ]    NC_000017 [ ENTREZ ]
RefSeq	NT_010783 [ SRS ]    NT_010783 [ ENTREZ ]
RefSeq	NW_001838454 [ SRS ]    NW_001838454 [ ENTREZ ]
RefSeq	NW_926918 [ SRS ]    NW_926918 [ ENTREZ ]
AceView	AXIN2 AceView - NCBI
Unigene	Hs.156527 [ SRS ]    Hs.156527 [ NCBI ]     HS156527 [ spliceNest ]
Fast-db	14129 (alternative variants)
	Protein : pattern, domain, 3D structure
SwissProt	Q5H9R8 [ SRS]    Q5H9R8 [ EXPASY ]     Q5H9R8 [ INTERPRO ]     Q5H9R8 [ UNIPROT ]
Prosite	PS50841 DIX [ SRS ]    PS50841 DIX [ Expasy ]
Prosite	PS50132 RGS [ SRS ]    PS50132 RGS [ Expasy ]
Interpro	IPR014936 Axin_b-cat_bd [ SRS ]    IPR014936 Axin_b-cat_bd [ EBI ]
Interpro	IPR001158 DIX [ SRS ]    IPR001158 DIX [ EBI ]
Interpro	IPR000342 Regulat_G_prot_signal [ SRS ]    IPR000342 Regulat_G_prot_signal [ EBI ]
CluSTr	Q5H9R8
Pfam	PF08833 Axin_b-cat_bind [ SRS ]    PF08833 Axin_b-cat_bind [ Sanger ]    pfam08833 [ NCBI-CDD ]
Pfam	PF00778 DIX [ SRS ]    PF00778 DIX [ Sanger ]    pfam00778 [ NCBI-CDD ]
Pfam	PF00615 RGS [ SRS ]    PF00615 RGS [ Sanger ]    pfam00615 [ NCBI-CDD ]
Smart	SM00021 DAX [EMBL]
Smart	SM00315 RGS [EMBL]
Prodom	PD003639 DIX[INRA-Toulouse]
Prodom	Q5H9R8 Q5H9R8_HUMAN [ Domain structure ]   Q5H9R8 Q5H9R8_HUMAN  [ sequences sharing at least 1 domain ]
Prodom	PD003639[INRA-Toulouse]
Prodom	Q5H9R8 Q5H9R8_HUMAN [ Domain structure ]   Q5H9R8 Q5H9R8_HUMAN  [ sequences sharing at least 1 domain ]
Blocks	Q5H9R8
HPRD	04935
	Protein Interaction databases
DIP	Q5H9R8
IntAct	Q5H9R8
	Polymorphism : SNP, mutations, diseases
OMIM	114500;604025;608615    [ map ]
GENECLINICS	114500;604025;608615
SNP	AXIN2 [dbSNP-NCBI]
SNP	NM_004655 [SNP-NCI]
SNP	AXIN2 [GeneSNPs - Utah]  AXIN2] [HGBASE - SRS]
HAPMAP	AXIN2 [HAPMAP]
COSMIC	AXIN2 [Somatic mutation (COSMIC-CGP-Sanger)]
HGMD	AXIN2
	General knowledge
Family Browser	AXIN2 [UCSC Family Browser]
SOURCE	NM_004655
SMD	Hs.156527
SAGE	Hs.156527
GO	signal transducer activity [Amigo]  signal transducer activity
GO	intracellular [Amigo]  intracellular
GO	nucleus [Amigo]  nucleus
GO	cytoplasm [Amigo]  cytoplasm
GO	signal transduction [Amigo]  signal transduction
GO	multicellular organismal development [Amigo]  multicellular organismal development
GO	Wnt receptor signaling pathway [Amigo]  Wnt receptor signaling pathway
KEGG	Wnt signaling pathway
KEGG	Colorectal cancer
PubGene	AXIN2
TreeFam	AXIN2
CTD	8313 [Comparative ToxicoGenomics Database]
	Other databases
	Probes
Probe	AXIN2 Related clones (RZPD - Berlin)
	PubMed
PubMed	26 Pubmed reference(s) in LocusLink

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PMID 15042511

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PMID 15899843

Cross-talk between pRb/E2F and Wnt/beta-catenin pathways: E2F1 induces axin2 leading to repression of Wnt signalling and to increased cell death.

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Contributor(s)

Written	01-2007	Thomas A Hughes

Citation

This paper should be referenced as such :

Hughes TA . AXIN2 (axin 2). Atlas Genet Cytogenet Oncol Haematol. January 2007 . URL : http://AtlasGeneticsOncology.org/Genes/AXIN2ID456ch17q24.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

indexed on : Mon Aug 11 21:12:18 2008