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Prostate-specific membrane antigen (PSMA)-mediated laminin proteolysis generates a pro-angiogenic peptide
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SYSNO ASEP 0467212 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Prostate-specific membrane antigen (PSMA)-mediated laminin proteolysis generates a pro-angiogenic peptide Author(s) Conway, R. E. (US)
Rojas, C. (US)
Alt, J. (US)
Nováková, Zora (BTO-N) ORCID, RID
Richardson, S. M. (US)
Rodrick, T. C. (US)
Fuentes, J. L. (US)
Richardson, N. H. (US)
Attalla, J. (US)
Stewart, S. (US)
Fahmy, B. (US)
Bařinka, Cyril (BTO-N) RID, ORCID
Ghosh, M. (US)
Shapiro, L. H. (US)
Slusher, B. S. (US)Number of authors 15 Source Title Angiogenesis - ISSN 0969-6970
Roč. 19, č. 4 (2016), s. 487-500Number of pages 14 s. Language eng - English Country NL - Netherlands Keywords TUMOR-ASSOCIATED NEOVASCULATURE ; BASEMENT-MEMBRANE ; DISTINCT ANTITUMOR PROPERTIES Subject RIV FA - Cardiovascular Diseases incl. Cardiotharic Surgery R&D Projects GAP301/12/1513 GA ČR - Czech Science Foundation (CSF) ED1.1.00/02.0109 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Institutional support BTO-N - RVO:86652036 UT WOS 000384411900003 DOI 10.1007/s10456-016-9521-x Annotation 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. Workplace Institute of Biotechnology Contact Monika Kopřivová, Monika.Koprivova@ibt.cas.cz, Tel.: 325 873 700 Year of Publishing 2017
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