The Role of PTP4A3 Phosphatase in Microvascular Endothelial and Tumor Cells
McQueeney, Kelley, Pharmacology - School of Medicine, University of Virginia
Lazo, John, Department of Pharmacology, University of Virginia
Cancer is a disease caused by errant cell signaling. Targeting the enzymes that control reversible phosphorylation is one strategy for correcting this aberration. The intracellular protein tyrosine phosphatase PTP4A3 is overexpressed in multiple human cancers and this correlates with poor patient prognosis and reduced survival. PTP4A3 also seems to regulate key malignant processes such as invasion, migration, and angiogenesis, suggesting a pivotal role in both cancer and endothelial signaling pathways. In the work presented here, I describe: (1) the creation and characterization of paired colorectal cancer cell lines expressing or lacking PTP4A3 protein, (2) the discovery and evaluation of JMS-053, the most potent PTP4A3 inhibitor known to date, and (3) the interrogation of PTP4A3 function in endothelial cells. In brief, the genetic loss of PTP4A3 or phosphatase inhibition by JMS-053 in tumor cells resulted in reduced colony formation, spheroid formation, migration, and adhesion. These phenotypes led me to uncover a previously unknown effect of this intracellular phosphatase on the expression of cellular adhesion proteins, most notably Emilin 1, which may be important for colorectal cancer. In addition, I show a role for PTP4A3 in promoting VEGF signaling, endothelial cell motility via Src activation and vascular permeability via RhoA activation. Thus, this dissertation presents novel concepts and reagents that facilitated the discovery of a relationship between PTP4A3 phosphatase activity and genes controlling extracellular matrix interactions, along with a contribution to endothelial cell barrier function through enhanced VEGF signaling. This suggests PTP4A3 inhibition may suppress tumor progression through actions on tumor and endothelial cells.
PHD (Doctor of Philosophy)
Phosphatase, PTP4A3, Cancer, Pharmacology