| Description |
Casein kinase I epsilon (CKI?) and casein kinase I delta (CKI?) are members of the CKI serine/threonine protein kinase family. These two highly-related kinases are ubiquitously expressed in mammalian tissues and are implicated in multiple cellular processes, including Wnt signaling transduction, circadian rhythms and Hedgehog pathway. Due to the ability to induce axis duplication and to activate the TCF-dependent reporter, CKI? and CKI? were first reported as positive regulators of the Wnt?-catenin pathway. Biochemical studies in our laboratory demonstrated that CKI? could destabilize the ?-catenin destruction complex, leading to the accumulation of ?-catenin. However, CKI?; is not only involved in the Wnt/?-catenin pathway but is also required for the convergent extension (CE) movements during Xenopus development. CE comprises the morphological polarization and cell migration, regulating the formation of the body axis in a ?-catenin independent manner. Downstream of Wnt, Frizzled (Fz) receptors and Dishevelled (Dvl/Dsh) protein, CE movements can be stimulated by the activation of small GTPases, including Rho and Rac, which facilitate cytoskeleton reorganization and activate the JNK pathway. Although CKI?; activity has been shown to be important for the regulation of CE movements, the molecular mechanism by which CKI?; regulates CE movements has not been addressed yet. In order to find additional roles of CKI?; in the Wnt signaling pathway, my study focuses on understanding how CKI?; regulates CE movements and the ?-catenin-independent Wnt pathway. The characterization of CKI? and CKI? mutants demonstrates that CKI?/? participate in the control of convergent extension (CE) movements through a ?-catenin independent mechanism. Further investigation of CKI?; function uncovered a novel mechanism of CKI?, in which CKI?; activates Rap1, a monomeric GTP binding protein, through regulating the activity of a GAP (GTPase activating protein) of Rap1, E6TP1. Taken together, this dissertation extends the knowledge of CKI?/? in mediating Wnt/PCP (Planer Cell Polarity) signaling. Since the regulation of cell polarity is highly related to the regulation of cell migration and cancer metastasis, results from these studies not only deepen our understanding the CKI?;/? function in embryonic development but also may be applied for understanding of the progression of cancer development in the future. |
