Disease-associated casein kinase I delta mutation may promote adenomatous polyps formation via a Wnt/beta-catenin independent mechanism.
The Wnt signaling pathway is critical for embryonic development and is dysregulated in multiple cancers. Two closely related isoforms of casein kinase I (CKIdelta and epsilon) are positive regulators of this pathway. We speculated that mutations in the autoinhibitory domain of CKIdelta/epsilon might upregulate CKIdelta/epsilon activity and hence Wnt signaling and increase the risk of adenomatous polyps and colon cancer. Exons encoding the CKIepsilon and CKIdelta regulatory domains were sequenced from DNA obtained from individuals with adenomatous polyps and a family history of colon cancer unaffected by familial adenomatous polyposis or hereditary nonpolyposis colorectal cancer (HNPCC). A CKIdelta missense mutation, changing a highly conserved residue, Arg324, to His (R324H), was found in an individual with large and multiple polyps diagnosed at a relatively young age. Two findings indicate that this mutation is biologically active. First, ectopic ventral expression of CKIdelta(R324H) in Xenopus embryos results in secondary axis formation with an additional distinctive phenotype (altered morphological movements) similar to that seen with unregulated CKIepsilon. Second, CKIdelta(R324H) is more potent than wildtype CKIdelta in transformation of RKO colon cancer cells. Although the R324H mutation does not significantly change CKIdelta kinase activity in an in vitro kinase assay or Wnt/beta-catenin signal transduction as assessed by a beta-catenin reporter assay, it alters morphogenetic movements via a beta-catenin-independent mechanism in early Xenopus development. This novel human CKIdelta mutation may alter the physiological role and enhance the transforming ability of CKIdelta through a Wnt/beta-catenin independent mechanism and thereby influence colonic adenoma development.
Tsai, I-C; Woolf, M; Neklason, DW; Branford, WW; Yost, HJ; Burt, RW; Virshup, DM
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