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Regulation of Cancer Progression by Pseudopodium-Enriched Atypical Kinase 1 (PEAK1)


In a migrating cell, actin polymerization and assembly drive membrane protrusion leading to the formation of pseudopodia. Repeated cycles of membrane extension at the front and tail retraction at the back facilitate cell translocation. Proliferating cancer cells can aberrantly turn on migration signals that activate the actin cytoskeleton machinery to drive cell locomotion. These motile cells are highly dangerous because they can leave the primary tumor site, invade the surrounding tissues, and gain access to the circulation, where they travel to distant organs and form secondary tumors. Unfortunately, there are no therapeutic treatments available that target migrating cancer cells and the majority of cancer patients succumb to metastatic disease. Recently, there has been a drive to uncover proteins associated with cell migration that can be targeted for therapy. In order to understand the spatiotemporal regulation of proteins involved in the migration machinery, our lab has analyzed the proteome of the cell pseudopodia. Of the proteins identified, we chose to further characterize Pseudopodium-Enriched Atypical Kinase 1 (PEAK1). The goal of this thesis was to elucidate the role of PEAK1 in cancer cell migration and metastasis. Here, I report that PEAK1 is upregulated in human malignancies, including human PDACs. Oncogenic KRas induced a PEAK1-dependent kinase amplification loop between Src, PEAK1, and ErbB2 to drive PDAC tumor growth and metastasis in vivo. Surprisingly, blockade of ErbB2 expression increased Src-dependent PEAK1 expression, PEAK1 -dependent Src activation, and tumor growth in vivo, suggesting a mechanism for the therapeutic resistance of patients with PDAC. Importantly, PEAK1 inactivation sensitized PDAC cells to trastuzumab and gemcitabine therapy suggesting that therapeutics that target PEAK1 in combination with gemcitabine may improve patient outcome. To further elucidate the mechanism by which PEAK1 regulates cancer cell migration, I used a mutagenesis approach to study the function of different functional sites in PEAK1. I discovered that the C-terminal proline- rich region of PEAK1 and the phosphorylation status of tyrosine 665 are essential for PEAK1-mediated focal adhesion dynamics and cancer cell migration. Mutation of the C-terminal proline-rich region decreased cancer cell viability and sensitized cells to DNA damage-induced apoptosis. Altogether, these data suggest that PEAK1 is a promising biomarker and therapeutic target in human malignancies

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