Franz, Clemens Martin; (2003) Phosphorylation and intercellular localization of p120 catenin. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

p120 catenin (p120ctn) is an ARM-repeat protein and a component of cadherin adhesion complexes. In contrast to its role in mediating cell-cell adhesion at the plasma membrane, overexpression of p120ctn in the cytoplasm stimulates cell migration and causes actin cytoskeleton rearrangement via the regulation of Rho family GTPases. In addition, p120ctn localizes to the nucleus where it may regulate transcription by binding to the transcription factor Kaiso. p120ctn thus has different functions depending on the cellular compartment. The identification of mechanisms regulating the intracellular localization of p120ctn will be crucial for gaining a better understanding of how the diverse functions of p120ctn are coordinated. The state of p120ctn serine/threonine phosphorylation varies between different cellular compartments, but the relevance of these phosphorylation events for p120ctn function and localization are unclear. A number of novel serine/threonine phosphorylation sites were identified and their involvement in regulating p120ctn localization was investigated using phospho/non-phospho-mimicking mutants. In addition, a panel of kinase and phosphatase inhibitors was tested for their effects on p120ctn phosphorylation and localization. The ARM-repeat domain of p120ctn mediates the interaction with cadherins and is involved in the regulation of Rho GTPases. Several point mutations in this region were identified that target p120ctn to microtubules, leading to microtubule reorganization and stabilization. Binding of p120ctn to microtubules was inversely related to its ability to regulate Rho GTPases. Mutant p120ctn also localized to the mitotic spindle and centrosomes, implicating p120ctn in the regulation of mitosis. Hepatocyte growth factor (HGF) treatment of MDCK cells induces adherens junction disassembly and stimulates cell migration. HGF stimulation caused relocalization of p120ctn from adherens junctions into the cytoplasm and led to a transient accumulation of p120ctn in the nucleus. The identification of HGF as a physiological stimulus of p120ctn nuclear translocation suggests a role for p120ctn in HGF-induced transcriptional changes. Finally, a novel interaction of p120ctn with the tight junction protein ZO-1 was identified, pointing towards a more complex role of p120ctn in modulating intercellular adhesion.

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