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Title: Adenylyl cyclase-associated protein-1/CAP1 as a biological target substrate of gelatinase B/MMP-9

Abstract

Matrix metalloproteinases (MMPs) are classically associated with the turnover of secreted structural and functional proteins. Although MMPs have been shown to process also a kaleidoscope of membrane-associated substrates, little is known about the processing of intracellular proteins by MMPs. Physiological and pathological cell apoptosis, necrosis and tumor lysis by chemotherapy, radiotherapy or immunological cytotoxicity, are examples of conditions in which an overload of intracellular proteins becomes accessible to the action of MMPs. We used a model system of dying human myelomonocytic cells to study the processing of intracellular protein substrates by gelatinase B/MMP-9 in vitro. Adenylyl cyclase-associated protein-1 or CAP1 was identified as a novel and most efficient substrate of gelatinase B/MMP-9. The presence of CAP1 in the extracellular milieu in vivo was documented by analysis of urine of patients with systemic autoimmune diseases. Whereas no active MMP-9 could be detected in urines of healthy controls, all urine samples of patients with clinical parameters of renal failure contained activated MMP-9 and/or MMP-2. In addition, in some of these patients indications of CAP1 cleavage are observed, implying CAP1 degradation in vivo. The high turnover rate of CAP1 by MMP-9, comparable to that of gelatin as the natural extracellular substrate of thismore » enzyme, may be critical to prevent pathological conditions associated with considerable cytolysis.« less

Authors:
; ; ; ;  [1];  [2];  [3]
  1. Department of Microbiology and Immunology, Rega Institute for Medical Research, University of Leuven, Minderbroedersstraat 10, B-3000 Leuven (Belgium)
  2. Department of General Internal Medicine, University Hospital Gasthuisberg, University of Leuven, Minderbroedersstraat 10, B-3000 Leuven (Belgium)
  3. Department of Microbiology and Immunology, Rega Institute for Medical Research, University of Leuven, Minderbroedersstraat 10, B-3000 Leuven (Belgium), E-mail: ghislain.opdenakker@rega.kuleuven.be
Publication Date:
OSTI Identifier:
21128151
Resource Type:
Journal Article
Journal Name:
Experimental Cell Research
Additional Journal Information:
Journal Volume: 314; Journal Issue: 15; Other Information: DOI: 10.1016/j.yexcr.2008.07.008; PII: S0014-4827(08)00273-5; Copyright (c) 2008 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0014-4827
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; ACTIN; CHEMOTHERAPY; ENZYMES; GELATIN; INFLAMMATION; KIDNEYS; NECROSIS; NEOPLASMS; RADIOTHERAPY; SUBSTRATES; URINE

Citation Formats

Cauwe, Benedicte, Martens, Erik, Van den Steen, Philippe E., Proost, Paul, Van Aelst, Ilse, Blockmans, Daniel, and Opdenakker, Ghislain. Adenylyl cyclase-associated protein-1/CAP1 as a biological target substrate of gelatinase B/MMP-9. United States: N. p., 2008. Web. doi:10.1016/j.yexcr.2008.07.008.
Cauwe, Benedicte, Martens, Erik, Van den Steen, Philippe E., Proost, Paul, Van Aelst, Ilse, Blockmans, Daniel, & Opdenakker, Ghislain. Adenylyl cyclase-associated protein-1/CAP1 as a biological target substrate of gelatinase B/MMP-9. United States. doi:10.1016/j.yexcr.2008.07.008.
Cauwe, Benedicte, Martens, Erik, Van den Steen, Philippe E., Proost, Paul, Van Aelst, Ilse, Blockmans, Daniel, and Opdenakker, Ghislain. Wed . "Adenylyl cyclase-associated protein-1/CAP1 as a biological target substrate of gelatinase B/MMP-9". United States. doi:10.1016/j.yexcr.2008.07.008.
@article{osti_21128151,
title = {Adenylyl cyclase-associated protein-1/CAP1 as a biological target substrate of gelatinase B/MMP-9},
author = {Cauwe, Benedicte and Martens, Erik and Van den Steen, Philippe E. and Proost, Paul and Van Aelst, Ilse and Blockmans, Daniel and Opdenakker, Ghislain},
abstractNote = {Matrix metalloproteinases (MMPs) are classically associated with the turnover of secreted structural and functional proteins. Although MMPs have been shown to process also a kaleidoscope of membrane-associated substrates, little is known about the processing of intracellular proteins by MMPs. Physiological and pathological cell apoptosis, necrosis and tumor lysis by chemotherapy, radiotherapy or immunological cytotoxicity, are examples of conditions in which an overload of intracellular proteins becomes accessible to the action of MMPs. We used a model system of dying human myelomonocytic cells to study the processing of intracellular protein substrates by gelatinase B/MMP-9 in vitro. Adenylyl cyclase-associated protein-1 or CAP1 was identified as a novel and most efficient substrate of gelatinase B/MMP-9. The presence of CAP1 in the extracellular milieu in vivo was documented by analysis of urine of patients with systemic autoimmune diseases. Whereas no active MMP-9 could be detected in urines of healthy controls, all urine samples of patients with clinical parameters of renal failure contained activated MMP-9 and/or MMP-2. In addition, in some of these patients indications of CAP1 cleavage are observed, implying CAP1 degradation in vivo. The high turnover rate of CAP1 by MMP-9, comparable to that of gelatin as the natural extracellular substrate of this enzyme, may be critical to prevent pathological conditions associated with considerable cytolysis.},
doi = {10.1016/j.yexcr.2008.07.008},
journal = {Experimental Cell Research},
issn = {0014-4827},
number = 15,
volume = 314,
place = {United States},
year = {2008},
month = {9}
}