A Peptidase Affecting Angiogenesis

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Science  28 Jul 2006:
Vol. 313, Issue 5786, pp. 413
DOI: 10.1126/science.313.5786.413c

Prostate-specific membrane antigen (PSMA) got its name because its expression is enhanced in advanced prostate carcinomas. It is also called glutamate carboxypeptidase II and is a transmembrane protein with peptidase activity. PSMA has been found in endothelial cells in tumor vasculature, and, given the involvement of other peptidases in angiogenesis, Conway et al. explored such a possibility for PSMA. They used an angiogenesis assay in mice lacking PSMA to show that loss of PSMA inhibited formation of new blood vessels. Proteolysis contributes to a remodeling of the extracellular matrix that is necessary for angiogenesis, but 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). Cell invasion studies with PSMA-null cells showed that PSMA has an important role in cell invasion and in signaling from β1 integrins to focal adhesion kinase (FAK) and PAK1. They confirmed that PSMA interacts with the actin-binding protein filamin A, and disruption of this interaction decreased the peptidase activity of PMSA and decreased phosphorylation of PAK1 in cultured cells. 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 the association of PMSA with filamin A, increasing its peptidase activity. Further understanding of how PMSA affects angiogenesis may lead to strategies to inhibit angiogenesis in cancers and other diseases. — LBR

Mol. Cell Biol. 26, 5310 (2006).

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