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

Abstract

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.

Effects of altered expression and activity levels of CK1δ and ɛ on tumor growth and survival of colorectal cancer patients

“…Increased oncogenic potential has been reported for a CK1δ mutant identified in a patient with large and multiple colonic polyps and CK1δ expression and activity is elevated in crypts in a murine colonic hyperplasia model . Hence, detailed analysis of CK1δ became more relevant since several amino acids within exon 3 seem to influence binding of ATP into the ATP pocket and mediate the interaction and selectivity of CK1δ‐specific inhibitors .…”

“…Furthermore, CK1δ expression and activity is elevated in crypts in a murine colonic hyperplasia model . In this context a CK1δ point mutation (R324H) identified in a patient with large and multiple polyps has been correlated with a significantly increased oncogenic potential . However, so far the role of CK1 isoforms in CRC development and progression as well as their potential as valid drug targets in the treatment of CRC has not been addressed in detail.…”

The CK1 Family: Contribution to Cellular Stress Response and Its Role in Carcinogenesis

“…Foldynová-Trantírková and co-workers provided evidence that mutations in CK1ε, which are frequently found in breast cancer, lead to loss of function in the Wnt/β-catenin pathway but result in activation of the Wnt/Rac1/JNK and Wnt/Ca 2+ pathway, consequently leading to increased migratory capacity and decreased cell-adhesion (334). A mutation within the C-terminal region of CK1δ detected in an adenomatous colorectal polyp leads to a higher oncogenic potential and promotes the development of adenomas in the intestinal mucosa (335). Furthermore, conditional knock-out of CK1α in the intestinal epithelium leads to activation of p53 and Wnt-signaling, while in p53 deficient gut, loss of heterozygosity of the CK1α gene causes a highly invasive carcinoma, indicating that CK1α acts as a tumor suppressor when p53 is inactivated (336).…”

Circadian gene variants in cancer

“…It also regulates gluconeogenic genes in response to PGC-1α activation and modulates lipoprotein metabolism by phosphorylating PGC-1β (118, 119). Mutations and/or deregulation of Ck1δ and ε are associated with colorectal, pancreatic, prostate, breast, and ovarian cancers (102, 120–126), neurodegeneration and sleep disorders (127–131), chronic inflammation and aging (132, 133), as well as metabolic syndromes (134, 135). Disruption or deregulation of Ck1δ or ε in mice deregulates circadian homeostasis (136) and increases the risk of mammary carcinogenesis (137) and autoimmune diseases (138).…”