Reynolds, JP; (2003) Characterisation of Aardvark, a Dictyostelium ß-catenin. Doctoral thesis , University of London.

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Abstract

Wnt signalling is active both in development and the progression of certain disease processes, most notably cancer. Glycogen Synthase Kinase-3 (GSK-3) and ß-catenin both define the canonical Wnt pathway, where GSK-3 negatively regulates ß-catenin, which, in turn, regulates gene expression. Mutations to ß-catenin that prevent GSK-3 phosphorylation are associated with the progression of many different tumour types. In addition to its signalling function, ß-catenin is required structurally at adherens junctions, linking cadherin molecules to the actin cytoskeleton via its interaction with a-catenin. Loss of 1-catenin from adherens junctions is associated with the increased invasiveness and metastasis of tumour cells. Homologues of GSK-3 (GskA) and ß-catenin (Aardvark) have been cloned in the cellular slime mould Dictyostelium discoideum. Aardvark is required for both the expression of the pre-sprore marker gene pspA and the formation of adherens junctions in Dictyostelium. This thesis describes the characterisation of Aardvark, with particular regard to its function and interaction with GskA. This work shows that distinct regions of Aar are required for its signalling and adhesion functions and suggests that two distinct proteins may bind to it to mediate the formation of adherens junctions. A novel protein kinase has been identified that may phosphorylate the N-terminus of Aar to regulate the expression of the pre-spore marker gene pspA. Fulllength Aar is unstable and a `destabilisation' region has been identified within the core of the protein. A novel derepression mechanism is used to explain GskA and Aar function in the expression of pspA. The characterisation of non-canonical Wnt signalling will enhance the understanding of the evolution and function of the core components of the pathway, giving greater insight into their roles in both development and disease processes.

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