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Angiogenesis. 2016 Oct;19(4):487-500. doi: 10.1007/s10456-016-9521-x. Epub 2016 Jul 8.

Prostate-specific membrane antigen (PSMA)-mediated laminin proteolysis generates a pro-angiogenic peptide.

Author information

1
Department of Biology, College of Liberal Arts and Science, Lipscomb University, Nashville, TN, 37204, USA.
2
Johns Hopkins Drug Discovery, Johns Hopkins University, Baltimore, MD, 21205, USA.
3
Department of Molecular and Comparative Pathobiology, Johns Hopkins University, Baltimore, MD, 21205, USA.
4
Laboratory of Structural Biology, Institute of Biotechnology, Czech Academy of Sciences, 25250, Vestec, Czech Republic.
5
Center for Vascular Biology, The University of Connecticut Health Center, 263 Farmington Ave, Farmington, CT, 06030, USA.
6
Center for Vascular Biology, The University of Connecticut Health Center, 263 Farmington Ave, Farmington, CT, 06030, USA. lshapiro@uchc.edu.
7
Johns Hopkins Drug Discovery, Johns Hopkins University, Baltimore, MD, 21205, USA. bslusher@jhmi.edu.
8
Department of Neurology, Johns Hopkins University, Baltimore, MD, 21205, USA. bslusher@jhmi.edu.

Abstract

Prostate-specific membrane antigen (PSMA) is a membrane-bound glutamate carboxypeptidase expressed in a number of tissues. PSMA participates in various biological functions depending on the substrate available in the particular tissue; in the brain, PSMA cleaves the abundant neuropeptide N-acetyl-aspartyl-glutamate to regulate release of key neurotransmitters, while intestinal PSMA cleaves polyglutamated peptides to supply dietary folate. PSMA expression is also progressively upregulated in prostate cancer where it correlates with tumor progression as well as in tumor vasculature, where it regulates angiogenesis. The previous research determined that PSMA cleavage of small peptides generated via matrix metalloprotease-mediated proteolysis of the extracellular matrix protein laminin potently activated endothelial cells, integrin signaling and angiogenesis, although the specific peptide substrates were not identified. Herein, using enzymatic analyses and LC/MS, we unequivocally demonstrate that several laminin-derived peptides containing carboxy-terminal glutamate moieties (LQE, IEE, LNE) are bona fide substrates for PSMA. Subsequently, the peptide products were tested for their effects on angiogenesis in various models. We report that LQ, the dipeptide product of PSMA cleavage of LQE, efficiently activates endothelial cells in vitro and enhances angiogenesis in vivo. Importantly, LQE is not cleaved by an inactive PSMA enzyme containing an active site mutation (E424S). Endothelial cell activation by LQ was dependent on integrin beta-1-induced activation of focal adhesion kinase. These results characterize a novel PSMA substrate, provide a functional rationale for the upregulation of PSMA in cancer cells and tumor vasculature and suggest that inhibition of PSMA could lead to the development of new angiogenic therapies.

KEYWORDS:

Angiogenesis; Extracellular matrix; GCPII; Laminin; PSMA; Peptides

PMID:
27387982
DOI:
10.1007/s10456-016-9521-x
[Indexed for MEDLINE]

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