Adenylyl cyclase-associated protein-1/CAP1 as a biological target substrate of gelatinase B/MMP-9.
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.
Cauwe
Bénédicte
B
Department of Microbiology and Immunology, Rega Institute for Medical Research, University of Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
Martens
Erik
E
Van den Steen
Philippe E
PE
Proost
Paul
P
Van Aelst
Ilse
I
Blockmans
Daniel
D
Opdenakker
Ghislain
G
D000293:Adolescent; D000328:Adult; D000368:Aged; D017209:Apoptosis; D001327:Autoimmune Diseases / Q000201:enzymology* / Q000652:urine; D018797:Cell Cycle Proteins / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D002460:Cell Line; D003593:Cytoplasm / Q000201:enzymology*; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D045604:Extracellular Fluid / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000652:urine*; D008875:Middle Aged; D009000:Monocytes / Q000201:enzymology; D009336:Necrosis / Q000201:enzymology / Q000652:urine; D051437:Renal Insufficiency / Q000201:enzymology / Q000652:urine
C489549:CAP1 protein, human; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D020780:Matrix Metalloproteinase 9