Abstract

Cancer is a set of varied and diverse diseases that share common characteristics, such as active proliferation, increased replicative potential, and tissue invasion or metastasis. One protein, 14-3-3ζ, is shown to be upregulated in a number of different cancers and also correlates with poor patient prognosis, recurrence, and mortality. This protein comes from a family of adapter proteins known for their scaffolding ability, pro- and anti-oncogenic capabilities, and affinity for phosphorylated substrates. It has been shown previously to participate in cancer progression, subversion of apoptosis, and to increase chemoresistance. Herein we will discuss the ability of 14-3-3ζ to promote distant-site metastasis and we propose that it does so through a variety of different mechanisms including the MAPK signaling cascade, HER2/ErbB2 pathway, and by mediation of cell adhesion through regulation of LAR. Liprin-β was identified as a novel 14-3-3ζ interactor in a mass spectrometry-based interactomics analysis. 14-3-3ζ was found to co-immunoprecipitate with both Liprin-α and Liprin-β. We will discuss the identification and mutation of putative 14-3-3ζ binding sites on both Liprins, the effect these have on the binding of both Liprins to 14-3-3ζ and of Liprin-α to LAR, and the possible downstream consequences of these interactions. The results described herein are inconclusive due in part to our inability to obtain a reliable Liprin-β pulldown and in part our inability to identify the 14-3-3ζ-binding sites on Liprin-α and Liprin-β. The concluding chapter contains a discussion of the possible future directions, including the creation of further Liprin mutants as well as fluorescent imaging of LAR localization and focal adhesion turnover.

Degree

College and Department

Physical and Mathematical Sciences; Chemistry and Biochemistry

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