pubmed.ncbi.nlm.nih.gov

Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling - PubMed

  • ️Thu Jan 01 2009

Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling

Shih-Min A Huang et al. Nature. 2009.

Abstract

The stability of the Wnt pathway transcription factor beta-catenin is tightly regulated by the multi-subunit destruction complex. Deregulated Wnt pathway activity has been implicated in many cancers, making this pathway an attractive target for anticancer therapies. However, the development of targeted Wnt pathway inhibitors has been hampered by the limited number of pathway components that are amenable to small molecule inhibition. Here, we used a chemical genetic screen to identify a small molecule, XAV939, which selectively inhibits beta-catenin-mediated transcription. XAV939 stimulates beta-catenin degradation by stabilizing axin, the concentration-limiting component of the destruction complex. Using a quantitative chemical proteomic approach, we discovered that XAV939 stabilizes axin by inhibiting the poly-ADP-ribosylating enzymes tankyrase 1 and tankyrase 2. Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway. Thus, our study provides new mechanistic insights into the regulation of axin protein homeostasis and presents new avenues for targeted Wnt pathway therapies.

PubMed Disclaimer

Comment in

Similar articles

Cited by

References

    1. Nat Cell Biol. 2005 Nov;7(11):1133-9 - PubMed
    1. Cell. 2006 Nov 3;127(3):469-80 - PubMed
    1. Science. 1998 Apr 24;280(5363):596-9 - PubMed
    1. Curr Biol. 1998 May 7;8(10):573-81 - PubMed
    1. Development. 2007 Feb;134(3):479-89 - PubMed

MeSH terms

Substances