title: Mutations in the human naked cuticle homolog NKD1 found in colorectal cancer alter Wnt/Dvl/beta-catenin signaling.
abstract: BACKGROUND
  Mutation of Wnt signal antagonists Apc or Axin activates beta-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 beta-catenin accumulation and TCF-dependent transcription, but human NKD genes have yet to be directly implicated in cancer.
  
  
  RESULTS
  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 beta-catenin and promote cell proliferation, in part due to a reduced ability of each mutant Nkd1 protein to bind and destabilize Dvl proteins.
  
  
  CONCLUSIONS
  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.
authors: Department of Genetics, Louisiana State University Health Sciences Center/Stanley S Scott Cancer Center, New Orleans, Louisiana, United States of America.
authors: Jianhui
authors: J
authors: Guo
authors: Tolga
authors: T
authors: Cagatay
authors: Guangjin
authors: G
authors: Zhou
authors: Chih-Chiang
authors: CC
authors: Chan
authors: Shelby
authors: S
authors: Blythe
authors: Kaye
authors: K
authors: Suyama
authors: Li
authors: L
authors: Zheng
authors: Kaifeng
authors: K
authors: Pan
authors: Chiping
authors: C
authors: Qian
authors: Richard
authors: R
authors: Hamelin
authors: Stephen N
authors: SN
authors: Thibodeau
authors: Peter S
authors: PS
authors: Klein
authors: Keith A
authors: KA
authors: Wharton
authors: Wanguo
authors: W
authors: Liu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins / Q000235:genetics*; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D000072261:Dishevelled Proteins; D004330:Drosophila; D029721:Drosophila Proteins; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D010750:Phosphoproteins / Q000378:metabolism*; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism*; D014981:Xenopus; D029867:Xenopus Proteins; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; C000606586:DVL1 protein, Xenopus; D000072261:Dishevelled Proteins; D029721:Drosophila Proteins; C449091:NKD1 protein, human; D010750:Phosphoproteins; D051153:Wnt Proteins; D029867:Xenopus Proteins; D051176:beta Catenin; C000606588:dsh protein, Drosophila