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General Information
Name
cancer, multiple, AXIN-related
FlyBase ID
FBhh0001045
Disease Ontology Term
Parent Disease
OMIM
Overview

Mutations (primarily somatic) of human AXIN1 and AXIN2 have been found in a number of cancers. AXIN1 encodes a scaffolding protein for the multiprotein beta-catenin destruction complex, which drives the phosphorylation and subsequent proteolysis of the transcriptional regulator β-catenin. There is a single Axin in Drosophila, encoded by Dmel\Axn, for which classical loss-of-function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.

Neither human gene, AXIN1 nor AXIN2, has been introduced into flies.

Animals homozygous for loss-of-function mutations of Dmel\Axn typically die during the embryonic stage. In wing discs, somatic clones of Axn loss-of-function mutations exhibit an overgrowth phenotype at the expense of surrounding wild-type tissue.

Work in flies has focused on characterization of variants analogous to disease-associated variants found in AXIN1. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): V72R in the fly Axn gene (corresponds to L106R in the human AXIN1 gene); L67P in the fly Axn gene (corresponds to L101P in the human AXIN1 gene). The Axn L67P mutation has only mild effects. The V72R mutation results in phenotypes observed for Axn loss-of-function mutations: animals homozygous for the V72R mutation die at early developmental stages; in wing discs, somatic clones of Axn carrying the V72R variant exhibit an overgrowth phenotype at the expense of surrounding wild-type tissue. In human, the L106R variant has been observed as somatic mutation in hepatocellular carcinoma (Taniguchi, et al., 2002; pubmed:12101426).

The fly genes Apc and Apc2, which encode components of the beta-catenin destruction complex (see FBgg0000896), are orthologous to human APC. As is observed for Axn, somatic clones mutant for Apc/Apc2 result in overgrowth due to the elimination of surrounding wild-type cells. APC is implicated in familial adenomatous polyposis 1; this disease has also been modeled in flies (see FBhh0000135).

Work done in human cells has pointed to destabilization of the AXIN1 protein and subsequent self-aggregation as a pathological mechanism for specific missense mutations; work in Drosophila supports this hypothesis. A Dmel\Axn transgene carrying both the V72R variant and mutation of the 'aggregon' site was tested. Animals carrying the double mutant survive up to the adult stage at 18 degrees C; somatic clones exhibit a reduced overgrowth phenotype.

[updated May 2019 by FlyBase; FBrf0222196]

Disease Summary Information
Disease Summary: cancer, multiple, AXIN-related
OMIM report
Human gene(s) implicated
Symptoms and phenotype
Mutations in the AXIN1 have been associated with hepatocellular carcinoma, hepatoblastomas, ovarian endometriod adenocarcinomas, and medullablastomas. [Gene Cards, AXIN1; 2019.06.03]
Diseases associated with AXIN2 include Oligodontia-Colorectal Cancer Syndrome. [Gene Cards, AXIN2; 2019.06.03]
Genetics
AXIN1 has been implicated in hepatocellular carcinoma due to somatic mutation. [from OMIM:114550; 2019.06.03]
Cellular phenotype and pathology
Molecular information
The primary role of Axin is to scaffold a multiprotein beta-catenin destruction complex, which drives the phosphorylation and subsequent proteolysis of the transcriptional regulator beta-catenin.
Contains a regulation of G-protein signaling (RGS) domain and a dishevelled and axin (DIX) domain. [Gene Cards, AXIN1; 2019.06.03]
AXIN1 has both positive and negative regulatory roles in Wnt-beta-catenin signaling. AXIN1 is a core component of a 'destruction complex' that promotes phosphorylation and polyubiquitination of cytoplasmic beta-catenin, resulting in beta-catenin proteasomal degradation in the absence of Wnt signaling. [from OMIM:603816; 2019.06.03]
External links
Disease synonyms
cancer, intestinal, AXIN-related
Search term: beta-catenin destruction complex
Ortholog Information
Human gene(s) in FlyBase
    Human gene (HGNC)
    Symbol / Name
    D. melanogaster ortholog (based on DIOPT)
    Comments on ortholog(s)
    Many to one: 2 human to 1 Drosophila.
    Human gene (HGNC)
    Symbol / Name
    D. melanogaster ortholog (based on DIOPT)
    Comments on ortholog(s)
    Many to one: 2 human to 1 Drosophila.
    Other mammalian ortholog(s) used
      D. melanogaster Gene Information (1)
      Gene Snapshot
      Axin (Axn) encodes the key scaffolding protein for the canonical Wnt signalling pathway. In the absence of signal, it targets the product of arm for proteolysis inhibiting Wnt signalling. In the presence of signal, it forms a part of the membrane activation complex, disrupting the product of arm degradation. This pathway play roles in cell proliferation (imaginal disc), differentiation (embryonic patterning), death and stemness. [Date last reviewed: 2019-03-07]
      Gene Groups / Pathways
      Comments on ortholog(s)
      High-scoring ortholog of human AXIN1; moderate-scoring ortholog of AXIN2 (1 Drosophila to 2 human). Dmel\Axn shares 22-23% identity and 35-36% similarity with human genes.
      Orthologs and Alignments from DRSC
      DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
      Synthetic Gene(s) Used (0)
      Summary of Physical Interactions (12 groups)
      protein-protein
      Interacting group
      Assay
      References
      bimolecular fluorescence complementation, fluorescence microscopy, anti tag coimmunoprecipitation, anti tag western blot, western blot, two hybrid
      pull down, western blot, anti tag coimmunoprecipitation, two hybrid
      pull down, autoradiography, western blot
      pull down, molecular weight estimation by staining
      anti bait coimmunoprecipitation, western blot
      anti tag coimmunoprecipitation, western blot
      pull down, western blot, anti tag coimmunoprecipitation
      anti tag coimmunoprecipitation, peptide massfingerprinting, two hybrid, bimolecular fluorescence complementation, fluorescence microscopy
      anti tag coimmunoprecipitation, anti tag western blot
      RNA-RNA
      Interacting group
      Assay
      References
      luminiscence technology, necessary binding region, fluorescence technology
      Alleles Reported to Model Human Disease (Disease Ontology) (1 alleles)
      Models Based on Experimental Evidence ( 0 )
      Allele
      Disease
      Evidence
      References
      Modifiers Based on Experimental Evidence ( 1 )
      Allele
      Disease
      Interaction
      References
      Genetic Tools, Stocks and Reagents
      Sources of Stocks
      Contact lab of origin for a reagent not available from a public stock center.
      Bloomington Stock Center Disease Page
      Selected mammalian transgenes
      Allele
      Transgene
      Publicly Available Stocks
      Selected Drosophila transgenes
      Allele
      Transgene
      Publicly Available Stocks
      RNAi constructs available
      Allele
      Transgene
      Publicly Available Stocks
      Selected Drosophila classical alleles
      Allele
      Allele class
      Mutagen
      Publicly Available Stocks
      amorphic allele - molecular evidence
      I-SceI
      amorphic allele - molecular evidence
      FLPase
      References (6)