Barbolina, M. V. & Stack, M. S. Membrane type 1-matrix metalloproteinase: substrate diversity in pericellular proteolysis. Semin. Cell Dev. Biol. 19, 24-33

Department of Chemical and Biological Engineering, Northwestern University, Evanston, IL 60208, USA.
Seminars in Cell and Developmental Biology (Impact Factor: 6.27). 03/2008; 19(1):24-33. DOI: 10.1016/j.semcdb.2007.06.008
Source: PubMed


Enzymes in the matrix metalloproteinase (MMP) family have been linked to key events in developmental biology for almost 50 years. Biochemical, cellular and in vivo analyses have established that pericellular proteolysis contributes to numerous aspects of ontogeny including ovulation, fertilization, implantation, cellular migration, tissue remodeling and repair. Surface anchoring of proteinase activity provides spatial restrictions on substrate targeting. This review will utilize membrane type 1 MMP (MT1-MMP) as an example to highlight substrate diversity in pericellular proteolysis catalyzed by a membrane anchored MMP.

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    • "Of note, 3D invasion is a complex multi-step process involving adhesion to matrix, proteolytic cleavage of matrix components, as well as de-adhesion and pulling of the cell body (Friedl and Wolf, 2009). The impact of the identified Rab proteins on this process may thus not only reflect MT1-MMP dependent matrix degradation, but may also involve other MT1-MMP functions such as integrin processing at the cell surface (Barbolina and Stack, 2008) or cleavage of matrix receptors such as syndecan-1 Table 1. Overview for MT1-MMP distribution after various treatments "
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    ABSTRACT: The matrix metalloproteinase MT1-MMP has a decisive impact on invasive cell migration in both physiological and pathological settings such as immune cell extravasation or metastasis of cancer cells. Surface-associated MT1-MMP is able to cleave components of the extracellular matrix, which is a prerequisite for proteolytic invasive migration. However, current knowledge on the molecular mechanisms that regulate MT1-MMP trafficking to and from the cell surface is limited. Here, we identify three members of the RabGTPase family, Rab5a, Rab8a, and Rab14, as critical regulators of MT1-MMP trafficking and function in primary human macrophages. Both overexpressed and endogenous forms show prominent colocalisation with MT1-MMP-positive vesicles, while expression of mutant constructs as well as siRNA-induced knockdown reveal that these RabGTPases critically regulate MT1-MMP surface exposure, contact of MT1-MMP-positive vesicles with podosomes, extracellular matrix degradation in 2D and 3D, as well as 3D proteolytic invasion of macrophages. Collectively, our results identify Rab5a, Rab8a, and Rab14 as major regulators of MT1-MMP trafficking and invasive migration of primary human macrophages, pointing to them as promising potential targets for manipulation of immune cell invasion.
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    • "MMP-14 also cleaves many membrane-anchored proteins such as E- and N-cadherin, integrins, CD44 (a hyaluronan receptor), and several cell surface proteoglycans and their receptors [22]. MMP-15 is a ubiquitously expressed enzyme with largely overlapping substrate specificity with MMP-14 [23]. The profibrotic change in histopathology post-irradiation indicates that all radiation regimens used in the present study resulted in perturbation of normal tissue remodeling and excessive production of collagen. "
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    ABSTRACT: Background Crew members on space missions inevitably are exposed to low background radiation and can receive much higher doses during solar particle events (SPE) that consist primarily of protons. Ionizing radiation could cause lung pathologies. Cell adhesion molecules (CAM) are believed to participate in fibrogenesis. Interactions between CAM and extracellular matrix (ECM) affect epithelial repair mechanisms in the lung. However, there are very limited data on biological effects of protons on normal lung tissue. Numerous reports have shown that exposure to low-dose/low-dose-rate (LDR) radiation can result in radioadaptation that renders cells more resistant to subsequent acute radiation. The goal of this study was to compare expression of genes associated with ECM and CAM, as well as critical profibrotic mediators, in mouse lungs after acute irradiation with photons and protons, and also determine whether pre-exposure to LDR γ-rays induces an adaptive effect. Results Overall, a marked difference was present in the proton vs. photon groups in gene expression. When compared to 0 Gy, more genes were affected by protons than by photons at both time points (11 vs. 6 on day 21 and 14 vs. 8 on day 56), and all genes affected by protons were upregulated. Many genes were modulated by LDR γ-rays when combined with photons or protons. Col1a1, mmp14, and mmp15 were significantly upregulated by all radiation regimens on day 21. Similarly, the change in expression of profibrotic proteins was also detected after acute and combination irradiation. Conclusion These data show that marked differences were present between acutely delivered protons and photons in modulating genes, and the effect of protons was more profound than that of photons. Pre-exposure to LDR γ-rays ‘normalized’ some genes that were modified by acute irradiation.
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    • "Kondo et al62 investigated the targeting of angiogenic endothelium and tumor cells using stearoyl-Gly-Pro-Leu-Pro-Leu-Arg liposomes (GPLPLR-Lip). PLPL was found to be a consensus substrate sequence for MT1-MMP.61 In vitro, GPLPLR-Lip showed a stronger binding to human umbilical vein endothelial cells, as compared to unmodified liposomes.62 "
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    ABSTRACT: Liposomes are biodegradable and can be used to deliver drugs at a much higher concentration in tumor tissues than in normal tissues. Both passive and active drug delivery by liposomal nanoparticles can significantly reduce the toxic side effects of anticancer drugs and enhance the therapeutic efficacy of the drugs delivered. Active liposomal targeting to tumors is achieved by recognizing specific tumor receptors through tumor-specific ligands or antibodies coupled onto the surface of the liposomes, or by stimulus-sensitive drug carriers such as acid-triggered release or enzyme-triggered drug release. Tumors are often composed of tumor cells and nontumor cells, which include endothelial cells, pericytes, fibroblasts, stromal, mesenchymal cells, innate, and adaptive immune cells. These nontumor cells thus form the tumor microenvironment, which could be targeted and modified so that it is unfavorable for tumor cells to grow. In this review, we briefly summarized articles that had taken advantage of liposomal nanoparticles as a carrier to deliver anticancer drugs to the tumor microenvironment, and how they overcame obstacles such as nonspecific uptake, interaction with components in blood, and toxicity. Special attention is devoted to the liposomal targeting of anticancer drugs to the endothelium of tumor neovasculature, tumor associated macrophages, fibroblasts, and pericytes within the tumor microenvironment.
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