PhD Graduate: Abdul Qader AL-AIDAROOS
Thesis Title: The Signaling and Regulation of Metastasis-Associated Phosphatase PRL-3 in Human Cancer Cells
Reversible tyrosine phosphorylation is governed by the balanced action of protein tyrosine kinases (PTKs) and protein-tyrosine phosphatases (PTPs). In recent years, increasing evidence link PRL-3, a member of the phosphatase of regenerating liver (PRL) subgroup of PTPs, to the progression of multiple human cancers. However, the signaling mechanism(s) behind PRL-3’s causal role in promoting cancer progression is still unclear. To address this, in the first part of my study, I investigated the influence of PRL-3 on receptor tyrosine kinases (RTKs), important upstream activators of PRL-3-associated mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) oncogenic signaling pathways. Forced expression or depletion of PRL-3 in multiple cell lines resulted in increased or decreased RTK phospho-activation, respectively. Notably, PRL-3 induced dependency on RTK signaling, as evidenced by the dramatic decrease in 1) MAPK and AKT phosphorylation, 2) in vitro cell proliferation and motility, and 3) in vivo xenograft tumor formation upon RTK inhibition. In corollary, my results suggest a novel mechanism to effectively retard PRL-3-driven tumors. In the second part of my study, I describe the PRL-3-driven downregulation of β-catenin, an adherens junction component, in human ovarian cancer cells. The downregulation of β-catenin corresponded with reduced homotypic cell-cell adhesion. β-catenin downregulation by PRL-3 required a functional Axin/APC degradation complex, components of which were also found to be tightly regulated by PRL-3. Importantly, analysis of PRL-3 and β-catenin expression in human cancer patient tissue sections revealed a significant negative correlation between them, suggesting a clinical significance of this result. Finally, I describe a novel mechanism for regulation of PRL-3’s protein-protein interactome by phosphorylation. Ultimately, the better understanding of the pathways and regulatory mechanisms of PRL-3 will facilitate development of better, more focused therapy and diagnosis for tumors overexpressing this phosphatase.