Title

Prostate specific membrane antigen regulates angiogenesis by influencing integrin signal transduction

Date of Completion

January 2006

Keywords

Biology, Cell

Degree

Ph.D.

Abstract

Prostate Specific Membrane Antigen (PSMA), a transmembrane peptidase classically expressed in prostate cancer, is also up-regulated in the vasculature of solid tumors. However, its functional contribution to angiogenesis has not been previously studied. Therefore, we investigated whether PSMA is required for angiogenesis in vivo. We demonstrate that growth factor-induced neovascularization is drastically reduced in PSMA-null animals compared to wild type littermates in the Matrigel implant model, suggesting that PSMA is necessary during angiogenesis. To elucidate the mechanisms governing this process, we assessed endothelial cell function in response to loss of PSMA activity or expression; we find that PSMA specifically regulates endothelial cell invasion by modulating laminin-specific integrin activity. Signaling pathways downstream of integrins are also modulated by PSMA, including activation of focal adhesion kinase (FAK) and p21-activated kinase (PAK-1). Interestingly, we find that mechanism during endothelial cell invasion. We hypothesize that the actin binding protein filamin A mechanistically links PAK to PSMA regulation; our data support this idea, as PSMA interacts with filamin A in endothelial cells to regulate invasion. Because filamin A is a known substrate of PAK, and phosphorylation of filamin modulates its interaction with cell-surface proteins, we propose that PSMA-activated PAK phosphorylates filamin A. PAK-mediated filamin A phosphorylation could result in reduced interaction with PSMA, thus decreasing PSMA activity and supporting productive motility by carefully modulating activation of the migratory machinery of the cell. The results of the current study implicate PSMA as an important contributor to angiogenesis and describe a novel mechanism for PSMA in this process. ^