Peptidase in Regulatory Loop Affecting Angiogenesis

Science's STKE  18 Jul 2006:
Vol. 2006, Issue 344, pp. tw241
DOI: 10.1126/stke.3442006tw241

Prostate-specific membrane antigen (PSMA) is so-named because its expression is enhanced in advanced prostate carcinomas, where its increased presence correlates with a poor prognosis. The protein is also called glutamate carboxypeptidase II and is a transmembrane protein with peptidase activity. PSMA has been found in endothelial cells in tumor vasculature. Given roles of other peptidases in angiogenesis, Conway et al. explored the possibility of such a role for PSMA. They used an in vivo angiogenesis assay in knockout mice lacking PSMA to show that loss of the PSMA protein inhibited formation of new blood vessels. Proteolysis contributes to remodeling of the extracellular matrix that is necessary for angiogenesis, but further studies by the authors suggest that PSMA may instead be part of a complex regulatory loop that controls integrin signaling and activation of the p21-activated kinase 1 (PAK1). In vitro cell invasion studies with PSMA-null cells or with inhibitors of the enzyme showed that PSMA has an important role in cell invasion and in signaling from β1 integrins to focal adhesion kinase (FAK) and PAK1. The authors confirmed that PSMA interacts with the actin-binding protein filamin A. Disruption of this interaction with a peptide designed to compete with PMSA for binding to filamin A decreased the peptidase activity of PMSA and decreased phosphorylation of PAK1 in cultured cells. PAK1 also interacts with filamin A, and the authors propose that it may compete with PMSA for binding to filamin A. The interaction of PMSA and the cytoskeletal protein filamin A may allow a feedback signal from integrin β1 and PAK to keep PMSA activity in check. Inhibition of PAK by expression of a peptide corresponding to its autoinhibitory domain enhanced association of PMSA with filamin A, increasing its peptidase activity. Further understanding of PMSA's roles in control of angiogenesis may allow new strategies to inhibit angiogenesis in cancers and other diseases to which it contributes.

R. E. Conway, N. Petrovic, Z. Li, W. Heston, D. Wu, L. H. Shapiro, Prostate-specific membrane antigen regulates angiogenesis by modulating integrin signal transduction. Mol. Cell. Biol. 26, 5310-5324 (2006). [Abstract] [Full Text]