Premium
Disease‐associated casein kinase I δ mutation may promote adenomatous polyps formation via a Wnt/β‐catenin independent mechanism
Author(s) -
Tsai IChun,
Woolf Margaret,
Neklason Deborah W.,
Branford William W.,
Yost H. Joseph,
Burt Randall W.,
Virshup David M.
Publication year - 2006
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.22368
Subject(s) - wnt signaling pathway , adenomatous polyposis coli , biology , missense mutation , cancer research , beta catenin , mutation , casein kinase 1 , signal transduction , catenin , colorectal cancer , kinase , cancer , genetics , protein kinase a , gene
The Wnt signaling pathway is critical for embryonic development and is dysregulated in multiple cancers. Two closely related isoforms of casein kinase I (CKIδ and ϵ) are positive regulators of this pathway. We speculated that mutations in the autoinhibitory domain of CKIδ/ϵ might upregulate CKIδ/ϵ activity and hence Wnt signaling and increase the risk of adenomatous polyps and colon cancer. Exons encoding the CKIϵ and CKIδ 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 CKIδ 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 CKIδ(R324H) in Xenopus embryos results in secondary axis formation with an additional distinctive phenotype (altered morphological movements) similar to that seen with unregulated CKIϵ. Second, CKIδ(R324H) is more potent than wildtype CKIδ in transformation of RKO colon cancer cells. Although the R324H mutation does not significantly change CKIδ kinase activity in an in vitro kinase assay or Wnt/β‐catenin signal transduction as assessed by a β‐catenin reporter assay, it alters morphogenetic movements via a β‐catenin‐independent mechanism in early Xenopus development. This novel human CKIδ mutation may alter the physiological role and enhance the transforming ability of CKIδ through a Wnt/β‐catenin independent mechanism and thereby influence colonic adenoma development. © 2006 Wiley‐Liss, Inc.