Disease-associated casein kinase I δ mutation may promote adenomatous polyps formation via a Wnt/β-catenin independent mechanism

The Writ signaling pathway is critical for embryonic development and is dysregulated in multiple cancers. Two closely related isoforms of casein kinase I (CKI delta and CKI epsilon) are positive regulators of this pathway. We speculated that mutations in the autoinhibitory domain of CKI delta/epsilon might upregulate CKI delta/epsilon activity and hence Writ signaling and increase the risk of adenomatous Polyps and colon cancer. Exons encoding the CKI epsilon. and CKI delta 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 non-polyposis colorectal cancer (HNPCC). A CKI delta 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 CK1 delta(R324H) in Xenopus embryos results in secondary axis formation with an additional distinctive phenotype (altered morphological movements) similar to that seen with unregulated CKI epsilon.. Second, CKI delta(R324H) is more potent than wildtype CKI delta in transformation of RKO colon cancer cells. Although the R324H mutation does not significantly change CKI delta 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 CKI delta mutation may alter the physiological role and enhance the transforming abilitv of CKI delta through a Writ/beta-catenin independent mechanism and thereby influence colonic adenoma development. (c) 2006 Wilev-Liss, Inc.