Pericellular activation of proMMP-7 (promatrilysin-1) through interaction with CD151

Abstract

Matrix metalloproteinase-7 (MMP-7) (also known as matrilysin-1) is secreted as a proenzyme (proMMP-7) and plays a key role in the degradation of various extracellular matrix (ECM) and non-ECM molecules after activation. To identify the binding proteins related to proMMP-7 activation, a human lung cDNA library was screened by yeast two-hybrid system using proMMP-7 as bait. We identified a candidate molecule CD151, which is a member of the transmembrane 4 superfamily. Complex formation of proMMP-7 with CD151 was demonstrated by immunoprecipitation of the molecules from CaR-1 cells, a human rectal carcinoma cell line, expressing both proMMP-7 and CD151, and CD151 stable transfectants incubated with proMMP-7. Yeast twohybrid assays using deletion mutants of proMMP-7 and CD151 suggested an interaction between the propeptide of proMMP-7 and the COOH-terminal extracellular loop of CD151. The binding activity of 125 I-labeled proMMP-7 to CD151 on the cell membranes was shown with CD151 stable transfectants. Laser-scanning confocal microscopy demonstrated that proMMP-7 colocalizes with CD151 on the cell membranes of CD151 stable transfectants and CaR-1 cells. In situ zymography using crosslinked carboxymethylated transferrin, a substrate of MMP-7, demonstrated proteinase activity on and around CD151 stable transfectants and CaR-1 cells, while the activity was abolished by their treatment with MMP inhibitors, anti-MMP-7 antibody or anti-CD151 antibody. In human lung adenocarcinoma tissues, colocalization of MMP-7 and CD151 was demonstrated on the carcinoma cells. Metalloproteinase activity was present in these tissues and could be inhibited by antibodies to MMP-7 or CD151. These data demonstrate for the first time that proMMP-7 is captured and activated on the cell membranes through interaction with CD151, and suggest the possibility that similar to the MT1-MMP/MMP-2 system, MMP-7 is involved in the pericellular activation mechanism mediated by CD151, a crucial step in proteolysis on the cell membranes under various pathophysiological conditions including cancer invasion and metastasis.

A novel nonsynonymous variant of matrix metalloproteinase-7 confers risk of liver cirrhosis

“…These include CD44 heparan sulfate proteoglycan (HSPG), cholesterol sulfate, and CD151. [18][19][20] Cholesterol sulfate is a component of lipid raft and CD151 is a transmembrane 4 superfamily protein that appears in a detergent-insoluble lipid-containing microdomain. To learn the possible docking mechanism of MMP-7, the behavior of the membrane-associated MMP-7(Asp-137) variant was analyzed in the presence of detergent.…”

“…19 In contrast, CD151 anchors latent proMMP-7 onto the cell surface, but its affinity to interact with the active form of MMP-7 is relatively low. 20 Therefore, we hypothesized that association of the pro-form of MMP-7(Asp-137) variant to CD151 at the cell surface provides the opportunity for MMP-7 activation. The hypothesis was first examined by confocal microscopy to learn the distribution patterns of MMP-7 and CD151 in HSCs under nonpermeabilized conditions.…”

Control of matrix metalloproteinase catalytic activity

“…Rather, proteinases, such as MMPs, would likely be anchored to the cell membrane, thereby maintaining a locally high enzyme concentration and targeting their catalytic activity to specific substrates within the pericellular space. In addition to the membrane-bound MMPs, several examples of specific cell-MMP interactions have been reported, such as the binding of MMP-2 to the α v β 3 integrin (Brooks et al, 1996), MMP-1 to the α 2 β 1 integrin Stricker et al, 2001), MMP-9 to CD44 (Yu and Stamenkovic, 2000), and MMP-7 to surface proteoglycans (Yu and Woessner, 2000;Yu et al, 2002), cholesterol (Yamamoto et al, 2006), and CD151 (Shiomi et al, 2005). As suggested for CD44 (Yu and Stamenkovic, 2000) and the α 2 β 1 integrin ), these membrane anchors may act as accessory factors that mediate both pro-enzyme activation and binding of both substrate and proteinase, thereby increasing the probability of proteolysis (Fig.…”

“…3). For example, Shiomi et al (2005) reported that CD151, a tetraspanin, binds and activates proMMP-7. The authors speculate that CD151 causes a conformational change in proMMP-7, thus facilitating a spontaneous activation of proMMP-7 on a pericellular level.…”

“…The authors speculate that CD151 causes a conformational change in proMMP-7, thus facilitating a spontaneous activation of proMMP-7 on a pericellular level. Interestingly, activated MMP-7 was only detected in the presence of carboxylmethylated transferrin, a preferred in vitro substrate of MMP-7 (Shiomi et al, 2005). Thus, membrane anchors may function by facilitating the interaction between substrate and proteinase, and in the presence of substrate, the allosteric release of the cysteine switch may be more favored.…”