Mutations in the human naked cuticle homolog NKD1 found in colorectal cancer alter Wnt/Dvl/β-catenin signaling

Jianhui Guo, Tolga Cagatay, Guangjin Zhou, Chih Chiang Chan, Shelby Blythe, Kaye Suyama, Li Zheng, Kaifeng Pan, Chiping Qian, Richard Hamelin, Stephen N Thibodeau, Peter S. Klein, Keith A. Wharton, Wanguo Liu

Research output: Contribution to journalArticle

29 Citations (Scopus)

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 languageEnglish (US)
Article numbere7982
JournalPLoS One
Volume4
Issue number11
DOIs
StatePublished - Nov 24 2009

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Catenins
colorectal neoplasms
Colorectal Neoplasms
Genes
mutation
Mutation
Repair
Mutant Proteins
Wnt Receptors
Proteins
DNA Mismatch Repair
DNA
Cell proliferation
Transcription
Ports and harbors
Fruits
adenocarcinoma
Scaffolds
mutants
neoplasms

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Guo, J., Cagatay, T., Zhou, G., Chan, C. C., Blythe, S., Suyama, K., ... Liu, W. (2009). Mutations in the human naked cuticle homolog NKD1 found in colorectal cancer alter Wnt/Dvl/β-catenin signaling. PLoS One, 4(11), [e7982]. https://doi.org/10.1371/journal.pone.0007982

Mutations in the human naked cuticle homolog NKD1 found in colorectal cancer alter Wnt/Dvl/β-catenin signaling. / Guo, Jianhui; Cagatay, Tolga; Zhou, Guangjin; Chan, Chih Chiang; Blythe, Shelby; Suyama, Kaye; Zheng, Li; Pan, Kaifeng; Qian, Chiping; Hamelin, Richard; Thibodeau, Stephen N; Klein, Peter S.; Wharton, Keith A.; Liu, Wanguo.

In: PLoS One, Vol. 4, No. 11, e7982, 24.11.2009.

Research output: Contribution to journalArticle

Guo, J, Cagatay, T, Zhou, G, Chan, CC, Blythe, S, Suyama, K, Zheng, L, Pan, K, Qian, C, Hamelin, R, Thibodeau, SN, Klein, PS, Wharton, KA & Liu, W 2009, 'Mutations in the human naked cuticle homolog NKD1 found in colorectal cancer alter Wnt/Dvl/β-catenin signaling', PLoS One, vol. 4, no. 11, e7982. https://doi.org/10.1371/journal.pone.0007982
Guo, Jianhui ; Cagatay, Tolga ; Zhou, Guangjin ; Chan, Chih Chiang ; Blythe, Shelby ; Suyama, Kaye ; Zheng, Li ; Pan, Kaifeng ; Qian, Chiping ; Hamelin, Richard ; Thibodeau, Stephen N ; Klein, Peter S. ; Wharton, Keith A. ; Liu, Wanguo. / Mutations in the human naked cuticle homolog NKD1 found in colorectal cancer alter Wnt/Dvl/β-catenin signaling. In: PLoS One. 2009 ; Vol. 4, No. 11.
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