An AXIN2 Mutant Allele Associated With Predisposition to Colorectal Neoplasia Has Context-Dependent Effects on AXIN2 Protein Function

Neoplasia. 2015 May;17(5):463-72. doi: 10.1016/j.neo.2015.04.006.


Heterozygous, germline nonsense mutations in AXIN2 have been reported in two families with oligodontia and colorectal cancer (CRC) predisposition, including an AXIN2 1989G>A mutation. Somatic AXIN2 mutations predicted to generate truncated AXIN2 (trAXIN2) proteins have been reported in some CRCs. Our studies of cells from an AXIN2 1989G>A mutation carrier showed that the mutant transcripts are not significantly susceptible to nonsense-mediated decay and, thus, could encode a trAXIN2 protein. In transient transfection assays, trAXIN2 was more abundant than wild-type AXIN2 protein, and in contrast to AXIN2, glycogen synthase kinase 3β inhibition did not increase trAXIN2 levels. Like AXIN2, the trAXIN2 protein interacts with β-catenin destruction complex proteins. When ectopically overexpressed, trAXIN2 inhibits β-catenin/T-cell factor-dependent reporter gene activity and SW480 CRC cell colony formation. These findings suggest the trAXIN2 protein may retain some wild-type functions when highly expressed. However, when stably expressed in rat intestinal IEC-6 cells, the trAXIN2 protein did not match AXIN2's activity in inhibiting Wnt-mediated induction of Wnt-regulated target genes, and SW480 cells with stable expression of trAXIN2 but not AXIN2 could be generated. Our data suggest the AXIN2 1989G>A mutation may not have solely a loss-of-function role in CRC. Rather, its contribution may depend on context, with potential loss-of-function when AXIN2 levels are low, such as in the absence of Wnt pathway activation. However, given its apparent increased stability in some settings, the trAXIN2 protein might have gain-of-function in cells with substantially elevated AXIN2 expression, such as Wnt pathway-defective CRC cells.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alleles
  • Animals
  • Axin Protein / genetics*
  • Axin Protein / metabolism*
  • Codon, Nonsense
  • Colorectal Neoplasms / genetics*
  • Genetic Predisposition to Disease / genetics*
  • Germ-Line Mutation
  • Humans
  • Immunoblotting
  • Immunoprecipitation
  • Mutagenesis, Site-Directed
  • Polymerase Chain Reaction
  • Rats
  • Transfection


  • AXIN2 protein, human
  • Axin Protein
  • Codon, Nonsense