Abstract
Background: Mutation of Wnt signal antagonists Apc or Axin activates β-catenin signaling in many cancers including the majority of human colorectal adenocarcinomas. The phenotype of apc or axin mutation in the fruit fly Drosophila melanogaster is strikingly similar to that caused by mutation in the segment-polarity gene, naked cuticle (nkd). Nkd inhibits Wnt signaling by binding to the Dishevelled (Dsh/Dvl) family of scaffold proteins that link Wnt receptor activation to β-catenin accumulation and TCF-dependent transcription, but human NKD genes have yet to be directly implicated in cancer. Methodology/Principal Findings: We identify for the first time mutations in NKD1 - one of two human nkd homologs - in a subset of DNA mismatch repair-deficient colorectal tumors that are not known to harbor mutations in other Wnt-pathway genes. The mutant Nkd1 proteins are defective at inhibiting Wnt signaling; in addition, the mutant Nkd1 proteins stabilize β-catenin and promote cell proliferation, in part due to a reduced ability of each mutant Nkd1 protein to bind and destabilize Dvl proteins. Conclusions/Significance: Our data raise the hypothesis that specific NKD1 mutations promote Wnt-dependent tumorigenesis in a subset of DNA mismatch-repair-deficient colorectal adenocarcinomas and possibly other Wnt-signal driven human cancers.
Original language | English (US) |
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Article number | e7982 |
Journal | PloS one |
Volume | 4 |
Issue number | 11 |
DOIs | |
State | Published - Nov 24 2009 |
Funding
Thanks to Mikhail Semenov for human Dvl1-3 cDNAs; Trevor Dale for mouse Dvl2 cDNA; Leon Avery for help with statistics; Xiaowu Zhang and Cell Signaling Technology for α-Nkd1; Roel Nusse for α-Dsh; Adi Gazdar and Ubaradka Sathyanaryana for reagents; Yashi Ahmed for the apc cuticle image; and Scott Cameron, John Minna, and Duojia Pan for critical reading of the manuscript. KW acknowledges Matthew P. Scott and HHMI for support of KS. This paper is dedicated to the memory of John C. Sisson, a pioneer in the analysis of segment-polarity gene function.
ASJC Scopus subject areas
- General