TIMP-2 is released as an intact molecule following binding to MT1-MMP on the cell surface

Zucker, Stanley; Hymowitz, Michelle; Conner, Cathleen; DeClerck, Yves A.; Cao, Jian

doi:10.1016/j.yexcr.2003.10.007

Cited by 28 publications

(28 citation statements)

References 36 publications

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“…1B). Furin inhibition with the synthetic furin inhibitor decanoyl-Arg-Val-Lys-Arg-chloromethyl ketone confirmed the nature of the active MT1-MMP build-up (data not shown) as reported previously (33). Because pro-MMP-2 activation is thought to interfere with cell survival and proliferation (34,35), we also sought to investigate the effect of ConA on BMSC cell cycle progression.…”

Section: Mt1-mmp-mediated Activation Of Latent Pro-mmp-2 By Concanavasupporting

confidence: 84%

MT1-MMP Down-regulates the Glucose 6-Phosphate Transporter Expression in Marrow Stromal Cells

Currie¹,

Fortier²,

Sina³

et al. 2007

Journal of Biological Chemistry

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Recent advances in the understanding of stem cell mobilization, cell-matrix interaction, and biodistribution have enabled the development of new therapeutic strategies (1, 2). Although locally transplanted bone marrow-derived stromal cells (BMSC) 2 have already been used clinically (3-5), less invasive routes of BMSC transplantation have become the focus of recent attention (6 -8). In fact, several clinical applications now use intravenous administration of genetically engineered BMSC either as an ideal vehicle for gene transfer or as a platform for the systemic delivery of therapeutic recombinant proteins in vivo (6,9,10). This implies that these circulating, systemically infused cells must respond to serum-derived cues that direct their ultimate biodistribution. The molecular players regulating cellular mobilization, chemotaxis, and cell survival of BMSC have received little attention.Among the mediators known to exert potent cellular chemotactic effects, sphingosine 1-phosphate (S1P) is one of the most important bioactive lysophospholipids secreted in blood plasma either upon platelet activation (11) or from brain tumor-derived glioma cells (12). In fact, we have demonstrated that BMSC chemotaxis was very strong in response to S1P (13) and required reorganization of the actin cytoskeleton and remodeling of the extracellular matrix (ECM) through a complex, cooperative signal transduction network involving cell surface matrix metalloproteinase (MMP) activity (14). Currently, the molecular characterization and the nature of that MMP, regulating both BMSC chemotaxis and interaction with the ECM protein microenvironment, remain poorly understood. Recently, we highlighted functional cross-talk between the membrane type-1 MMP (MT1-MMP) and the S1P receptor EDG-1-mediated signaling in BMSC chemotaxis (13). Interestingly, aside from its classical role in ECM proteolysis, MT1-MMP is also involved in transducing crucial intracellular signaling that may control several processes related to BMSC mobilization and cell survival (13)(14)(15)(16).Given that impaired chemotaxis was recently observed in bone marrow cells isolated from a microsomal glucose 6-phos-* This work was supported by a grant of the Natural Sciences and EngineeringResearch Council of Canada (NSERC) (to B. A.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 2 The abbreviations used are: BMSC, bone marrow-derived stromal cell(s); ConA, concanavalin A; ECM, extracellular matrix; G6P, glucose 6-phosphate; G6Pase, glucose-6-phosphatase; G6PT, G6P transporter; MMP, matrix metalloproteinase; MT1-MMP, membrane type-1 MMP; PI, propidium iodine; siRNA, small interfering RNA; S1P, sphingosine 1-phosphate; PBS, phosphate-buffered saline; Wt, wild type; GFP, green fluorescent protein.

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Section: Mt1-mmp-mediated Activation Of Latent Pro-mmp-2 By Concanavasupporting

confidence: 84%

MT1-MMP Down-regulates the Glucose 6-Phosphate Transporter Expression in Marrow Stromal Cells

Currie¹,

Fortier²,

Sina³

et al. 2007

Journal of Biological Chemistry

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“…Remacle et al (30) reported that MT1-MMP mediates TIMP-2 internalization by concomitant clathrin-dependent and -independent pathways. In contrast, Zucker et al (31) reported that, following binding to MT1-MMP on the cell surface, internalized TIMP-2 is released primarily as an intact functional molecule.…”

Section: Discussionmentioning

confidence: 92%

Low Density Lipoprotein Receptor-related Protein Mediates Endocytic Clearance of Pro-MMP-2·TIMP-2 Complex through a Thrombospondin-independent Mechanism

Emonard

Bellon

Troeberg

et al. 2004

Journal of Biological Chemistry

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“…Cell surface biotinylation and MT1-MMP detection Cell surface biotinylation was performed as described previously (Zucker et al, 2002(Zucker et al, , 2004. Cell lysates were centrifugated at 13 000 g for 15 min at 41C.…”

Section: Cell Surface Fluorescent Immunocytochemistrymentioning

confidence: 99%

Hypoxia stimulates breast carcinoma cell invasion through MT1-MMP and MMP-2 activation

et al. 2005

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The process of cancer cell invasion involves degradation of the extracellular matrix (ECM) by proteases, integrin adhesion and cell motility. The role of ECM degrading proteases on the hypoxia-induced invasion of breast carcinoma cells was investigated. Hypoxia markedly increased the invasion capacity of MDA-MB-231 and MDA-MB-435 breast carcinoma cell lines. Matrix metalloproteinase (MMP) inhibitors blocked the hypoxia-induced invasion, whereas other protease inhibitors had no effect. Antibodies or siRNAs blocking either membrane type-1 MMP (MT1-MMP) or MMP-2 were effective in reducing the hypoxia-induced invasion. Serumfree reconstitution experiments confirmed the involvement of the MT1-MMP/MMP-2/tissue inhibitor of metalloproteinase-2 complex in this hypoxia-induced response. Overexpression of MT1-MMP in a poorly invasive breast cancer cell line, T47-D, promoted hypoxia-induced invasion and MMP-2 activation. Cell surface accumulation and activation of MT1-MMP without apparent regulation at the mRNA or protein levels indicated a post-translational adaptive response to hypoxia. Inhibition of the small GTPase RhoA eliminated the hypoxiainduced invasion and blocked the localization of MT1-MMP to the plasma membrane. Zymographic and molecular analysis of human breast tumors showed a strong correlation between hypoxic microenvironments and MMP-2 activation without changes in MT1-MMP expression. Our studies suggest that hypoxic tumor microenvironments promote breast cancer invasion through an MT1-MMP-dependent mechanism.

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TIMP-2 is released as an intact molecule following binding to MT1-MMP on the cell surface

Cited by 28 publications

References 36 publications

MT1-MMP Down-regulates the Glucose 6-Phosphate Transporter Expression in Marrow Stromal Cells

MT1-MMP Down-regulates the Glucose 6-Phosphate Transporter Expression in Marrow Stromal Cells

Low Density Lipoprotein Receptor-related Protein Mediates Endocytic Clearance of Pro-MMP-2·TIMP-2 Complex through a Thrombospondin-independent Mechanism

Hypoxia stimulates breast carcinoma cell invasion through MT1-MMP and MMP-2 activation

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