Role of casein kinase I epsilon in regulating Wnt signaling

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Publication Type dissertation
School or College College of Pharmacy
Department Pharmacology & Toxicology
Author Klimowski, Laura Kimberly
Title Role of casein kinase I epsilon in regulating Wnt signaling
Date 2005-12
Description Numerous regulatory mechanisms are involved in the controlling Wnt signal transduction in development and tumorigenesis. Members of the casein kinase I (CKI) family play a significant role in determining the molecular events in response to Wnt hormone. This dissertation primarily describes the crucial role of CKI-specific isoforms in regulating Wnt signal transduction. Investigation of the mechanisms for CKI isoform activation and identification of CKI-specific phosphorylation sites required for Wnt signal transduction are presented. First, canonical Wnt hormones transduce Wnt signal that activates intracellular CKI[epsilon] activity. CKI?; is inactive in vivo until it is specifically activated by dephosphorylation of its autoinhibitory domain. After the concentration Wnt ligand diminishes, CKI[epsilon]; autophosphorylates its carboxy-tail domain, inhibiting its activity, and CKI[epsilon]; activity returns to baseline levels. Second, CKI[epsilon];-specific phosphorylation of dishevelled on serine 139 and serine 142 modulates activation of Wnt signal transduction. Mutation of serine 139 and 142 to alanines results in diminished CKI[epsilon];-dependent activation of Wnt signaling in cell culture and Xenopus embryo model systems. These results provide molecular insights into the mechanism by which CKI?-regulates the intensity of beta-catenin signaling. Third, CKI-specific isoform activities differentially control negative regulatory components of the canonical Wnt pathway. A potential CKI[epsilon] -specific phosphorylation site was identified on beta-catenin which contributes to the negative regulation of Wnt signaling and may contribute to a molecular conformation pool of ?catenin necessary to maintain cellular homeostasis. Potential CKI[epsilon];-specific phosphorylation sites were identified on axin that may regulate cellular distribution and degradation of axin in the cell. Fourth, tools for deciphering the balance between kinases and phosphatases involved in the Wnt pathway were examined. We demonstrate dsRNAi knockout of endogenous PP2A-C subunit leads to hype rphosphorylation of the Wnt substrates Dsh and dysregulation of the Arm destruction complex in genetically engineered S2R+ cells. This dissertation extended our knowledge of how CKI-specific isoforms can differentiate Wnt signal transduction in the cell. Results from these studies specify specific-CKI[epsilon] residues that may be important targets in the Wnt pathway and ultimately drive development of pharmacological agents specifically attenuating dysregulation of the beta-catenin accumulation in human cancers.
Type Text
Publisher University of Utah
Subject Signal Transduction; Glycoproteins
Subject MESH Protein Kinases; Circadian Rhythm
Dissertation Institution University of Utah
Dissertation Name PhD
Language eng
Relation is Version of Digital reproduction of "The role of casein kinase I epsilon in regulating Wnt signaling". Spencer S. Eccles Health Sciences Library. Print version of "The role of casein kinase I epsilon in regulating Wnt signaling". available at J. Willard Marriott Library Special Collection. QP6.5 2005 .K58.
Rights Management © Laura Kimberly Klimowski.
Format Medium application/pdf
Format Extent 2,781,449 bytes
Identifier undthes,4552
Source Original: University of Utah Spencer S. Eccles Health Sciences Library (no longer available).
Master File Extent 2,781,483 bytes
ARK ark:/87278/s6q81fvr
Setname ir_etd
Date Created 2012-04-24
Date Modified 2012-04-24
ID 190911
Reference URL