Mutations in the human naked cuticle homolog NKD1 found in colorectal cancer alter Wnt/Dvl/beta-catenin signaling.
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.
Guo
Jianhui
J
Department of Genetics, Louisiana State University Health Sciences Center/Stanley S Scott Cancer Center, New Orleans, Louisiana, United States of America.
Cagatay
Tolga
T
Zhou
Guangjin
G
Chan
Chih-Chiang
CC
Blythe
Shelby
S
Suyama
Kaye
K
Zheng
Li
L
Pan
Kaifeng
K
Qian
Chiping
C
Hamelin
Richard
R
Thibodeau
Stephen N
SN
Klein
Peter S
PS
Wharton
Keith A
KA
Liu
Wanguo
W
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*
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