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- Title
Mutations in the Human naked cuticle Homolog NKD1 Found in Colorectal Cancer Alter Wnt/Dvl/β-Catenin Signaling.
- Authors
Jianhui Guo; Cagatay, Tolga; Guangjin Zhou; Chih-Chiang Chan; Blythe, Shelby; Suyama, Kaye; Li Zheng; Kaifeng Pan; Chiping Qian; Hamelin, Richard; Thibodeau, Stephen N.; Klein, Peter S.; Wharton, Jr., Keith A.; Wanguo Liu
- 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 bcatenin 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 bcatenin 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.
- Publication
PLoS ONE, 2009, Vol 4, Issue 11, pe7982
- ISSN
1932-6203
- Publication type
Article
- DOI
10.1371/journal.pone.0007982