DOCSLIB.ORG

TNF Cleavage Beyond TACE/ADAM17

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
TNF Cleavage Beyond TACE/ADAM17 OPEN TRANSPARENT Closeup ACCESS PROCESS TNFa cleavage beyond TACE TNFa cleavage beyond TACE/ADAM17: matrix metalloproteinase 13 is a potential therapeutic target in sepsis and colitis Christoph Becker-Pauly, Stefan Rose-John* Keywords: ADAM protease; inflammatory bowel disease; MMP13; protease web; sepsis See related article in EMBO Molecular Medicine http://dx.doi.org/10.1002/emmm.201202100 For decades, matrix metalloproteinases bone and cartilage turnover but little is the intestinal epithelium. Moreover, ele- (MMPs) have been described as rather known about other functions. vated levels of bioactive TNFa affect the unspecific matrix‐ and collagen‐degrad- In this issue, Libert and coworkers intestinal permeability through endocy- ing enzymes. Accordingly, this group of report on a pro‐inflammatory activity of tosis of tight junction proteins, thereby proteases was mainly associated with MMP13 not by ‘simply’ degrading extra- increasing systemic inflammation. All tissue remodeling and pathologic con- cellular matrix but through the release of these events were abolished in MMP13 ditions such as tumour development and biologically active soluble TNFa from its deficient mice, resulting in increased metastasis. However, broad spectrum membrane bound precursor form. Ecto- survival of MMP13 knockout animals, MMP inhibitors completely failed in domain shedding of TNFa is a paracrine when treated with LPS or DSS. The cancer therapy. authors conclude that MMP13 is a Recent studies with gene deficient potential therapeutic target for the treat- mice revealed more specific functions » …pro-inflammatory activi- ment of colitis (Vandenbroucke et al, of MMPs, e.g. the cleavage of chemo- ty of MMP13 not by ‘simply’ 2013). kines, thereby stimulating inflammatory TACE/ADAM17 has been identified by responses (Dufour & Overall, 2013). degrading extracellular ma- its ability to cleave TNFa but later on it Additionally, mass spectrometry‐based trix but through the release of turned out that many more proteins are proteomic techniques allowed for the biologically active soluble processed by this enzyme. TACE/AD- identification of hundreds of new sub- TNFa from its membrane AM17 knockout mice are not viable and strates of MMPs, giving rise to unexpect- bound precursor form. « show a phenotype strikingly similar to ed biological activity of these proteases in mice lacking ligands of the EGF receptor. health and disease. All these ligands are transmembrane MMP13 is known to be one of few proteins and need to be shed from the collagenases capable of cleaving rigid signaling event in inflammation per- cell surface in order to be systemically collagen fibrils. This ability is based on a formed by the metalloprotease tumour active. More than 74 TACE/ADAM17 complex unfolding mechanism of the necrosis factor a converting enzyme substrates have been identified (Scheller triple‐helical collagen structure. There- (TACE, also known as ADAM17) (Schel- et al, 2011). Up to now, TACE/ADAM17 fore, MMP13 biology is well studied in ler et al, 2011). Although TACE/ADAM17 was considered to be the only biologically is believed to be the major sheddase of relevant TNFa cleaving enzyme in vivo TNFa, Vandenbroucke et al demonstrat- although it was clear that also other Biochemical Institute, Christian-Albrechts- ed that after LPS‐induced sepsis and DSS‐ proteases such as proteinase‐3 could University Kiel, Germany induced colitis, MMP13 is up‐regulated generate biologically active TNFa (Rob- Corresponding author: Tel: þ49 431 880 3336; a ‐ ‐ Fax: þ49 431 880 5007; and cleaves TNF . This leads to ER stress ache Gallea et al, 1995). Mice, in which E-mail: [email protected] and mucus depletion resulting in an the TACE/ADAM17 gene was inactivated DOI 10.1002/emmm.201302899 increased interaction of bacteria with only in neutrophils and monocytes/ ß 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO. This is an open access article under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits use, distribution and reproduction 970 in any medium, provided the original work is properly cited. EMBO Mol Med (2013) 5, 970–972 www.embomolmed.org Closeup Christoph Becker-Pauly and Stefan Rose-John macrophages, failed to shed TNFa upon ty of endogenous activators and/or of TACE/ADAM17 within the protease LPS challenge and were largely resistant inhibitors, e.g. TIMP’s, resulting in al- web signalizes no change in cell homeo- against LPS mediated endotoxin shock tered shedding of TNFa when MMP13 or stasis, while the lack of TACE/ADAM17 is (Horiuchi et al, 2007). TACE/ADAM17 is deleted. Therefore, it is recognized to stimulate/recruit compen- Since TNFa is involved in the induc- important to study MMP13 and TACE/ satory proteases. Nevertheless, Blobel and tion and maintenance of many inflamma- ADAM17 expression and activity in vivo coworkers provided evidence that long‐ tory diseases and blockade of TNFa is an in corresponding knockout animals with term inhibition of TACE/ADAM17 in- effective treatment for these conditions, regard to substrate cleavage. This can duced compensation by ADAM10. At this TACE/ADAM17 has been considered a be challenging, but it is known that point, however, one should keep in mind therapeutic target. However, due to the protease activity does not necessarily that mice lacking ADAM10 or TACE/ severe phenotypes of mice lacking TACE/ correlate with mRNA or protein levels. ADAM17 are not viable demonstrating ADAM17, treatment of patients seemed to For e.g. ADAM17 mRNA is expressed that compensation is somewhat limited. be critical with regard to side effects. virtually in all cells and is not subject to A protease network does not explain Indeed, knock‐in mice with 95% de- major transcriptional regulation. The why MMP13 does not compensate for the creased levels of TACE/ADAM17 showed protease is, however, mostly located loss of TACE/ADAM17 and vice versa. increased susceptibility to inflammatory within the cell but is transported to the Proteases might be organized in different bowel disease, which again is critical for cell surface mainly in inflamed tissues sub‐clusters, meaning that MMP13 and medical treatment (Chalaris et al, 2010). and in cancer (Scheller et al, 2011). TACE/ADAM17 are not directly linked in Unexpectedly, Blaydon et al identified a Are proteolytic enzymes lone fighters the protease web. To clarify this issue, single patient with no functional TACE/ or do they have guidance to their identification of regulatory molecules that ADAM17 due to a mutation in the substrates in a molecular network that orchestrate such protease networks is Adam17 gene demonstrating that loss builds the protease web? Could it be important. The tetraspanins and iRhoms, of TACE/ADAM17 activity can be com- that groups of proteases are physically the latter being catalytically inactive pensated in humans (Blaydon et al, connected in ‘clusters’, either directly rhomboid proteases, might be key players 2011). or through linker molecules and that in this scenario. It was shown that these Libert and coworkers additionally these networks rule substrate cleavage? transmembrane proteins influence locali- found MMP7 to be up‐regulated in DSS‐ Such a molecular microenvironment has zation and biologic activity of ADAMs induced colitis in MMP13 knockout mice the capacity to register the loss of single and it is likely that other proteases are (Vandenbroucke et al, 2013). MMP7 had players and might then compensate the involved as well (Adrain et al, 2012; previously been shown to induce TNFa‐ lack of activity (Fig 1). Yanez‐Mo et al, 2011). Additionally, for release in a model of herniated disc numerous secreted proteases tethering to resorption. However, it is not clear the extracellular matrix was demonstrat- whether this is a direct proteolytic effect » …analysing proteolytic ed, which further supports the hypothesis on TNFa or if it is mediated through events in health and disease of clusters of proteolytic enzymes. MMP7‐mediated stimulation of other with regard to localization, Interestingly, only few full knockouts proteases. Along the same line, expres- contributing activators, of proteases in animal models lead to sion of ADAM19, which was also identi- severe phenotypes or even lethality. For fied as a TNFa‐releasing enzyme, is inhibitors, or other regulatory example, all MMP knockout mice, except significantly increased in the mucosa of molecules, in one word, the of MMP14, reveal fairly mild phenotypic patients with colitis. These studies pro- protease web, is abnormalities, pointing to compensatory vide evidence for other proteolytic important. « mechanisms on mRNA‐ and/or protein enzymes that might contribute to TNFa levels, implying activators, endogenous cleavage and progression of colitis and inhibitors, enhancers and other regulato- that are possible candidates to compen- An example is the partial compensation ry molecules. This makes it challenging in sate lacking ADAM17 activity. of TACE/ADAM17 activity by ADAM10. these animal models to distinguish be- The crucial point in understanding Blobel and coworkers demonstrated that tween molecular differences that are protease networks in terms of compensa- in embryonic fibroblasts, deletion of specifically due to the loss of the deleted tion is, why MMP13 does not cleave TACE/ADAM17 recruits ADAM10 as protease or based on the regulation of TNFa in TACE/ADAM17 negative mice compensatory sheddase for many sub- compensatory enzymes. and why TACE/ADAM17 does not do so strates (Le Gall et al, 2009). This could be Proteolytic systems are obviously flex- in MMP13 negative mice. The most due to the accumulation of uncleaved ible in terms of substrate‐cleavage‐ obvious reason is an activation of substrates, which are then processed by compensation as demonstrated by Libert MMP13 by ADAM17 and vice versa, other proteases. However, at least in short and coworkers for the ectodomain shed- which is rather unlikely due to their term treatment, pharmacological inhibi- ding of TNFa (Vandenbroucke et al, 2013). activation mechanisms and the different tion of TACE/ADAM17 in cells also Next to the shedding of TNFa by TACE/ phenotypes of knockout mice.
Load more

Recommended publications
  • MATRIX METALLOPROTEINASE REQUIREMENTS for NEUROMUSCULAR SYNAPTOGENESIS by Mary Lynn Dear Dissertation Submitted to the Faculty O
    MATRIX METALLOPROTEINASE REQUIREMENTS FOR NEUROMUSCULAR SYNAPTOGENESIS By Mary Lynn Dear Dissertation Submitted to the Faculty of the Graduate School of Vanderbilt University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY in Biological Sciences January 31, 2018 Nashville, Tennessee Approved: Todd Graham, Ph.D. Kendal Broadie, Ph.D. Katherine Friedman, Ph.D. Barbara Fingleton, Ph.D. Jared Nordman, Ph.D. Copyright © 2018 by Mary Lynn Dear All Rights Reserved ACKNOWLEDGEMENTS I would like to acknowledge my advisor, Kendal Broadie, and the entire Broadie laboratory, both past and present, for their endless support, engaging conversations, thoughtful suggestions and constant encouragement. I would also like to thank my committee members both past and present for playing such a pivotal role in my graduate career and growth as a scientist. I thank the Department of Biological Sciences for fostering my graduate education. I thank the entire protease community for their continued support, helpful suggestions and collaborative efforts that helped my project move forward. I would like to acknowledge Dr. Andrea Page-McCaw and her entire laboratory for helpful suggestions, being engaged in my studies and providing many tools that were invaluable to my project. I thank my parents, Leisa Justus and Raymond Dear, my brother Jake Dear and my best friend Jenna Kaufman. Words cannot describe how grateful I am for your support and encouragement. Most importantly, I would like to thank my husband, Jeffrey Thomas, for always believing in me, your unwavering support and for helping me endure all the ups and downs that come with graduate school.
    [Show full text]
  • What Are the Roles of Metalloproteinases in Cartilage and Bone Damage? G Murphy, M H Lee
    iv44 Ann Rheum Dis: first published as 10.1136/ard.2005.042465 on 20 October 2005. Downloaded from REPORT What are the roles of metalloproteinases in cartilage and bone damage? G Murphy, M H Lee ............................................................................................................................... Ann Rheum Dis 2005;64:iv44–iv47. doi: 10.1136/ard.2005.042465 enzyme moiety into an upper and a lower subdomain. A A role for metalloproteinases in the pathological destruction common five stranded beta-sheet and two alpha-helices are in diseases such as rheumatoid arthritis and osteoarthritis, always found in the upper subdomain with a further C- and the irreversible nature of the ensuing cartilage and bone terminal helix in the lower subdomain. The catalytic sites of damage, have been the focus of much investigation for the metalloproteinases, especially the MMPs, have been several decades. This has led to the development of broad targeted for the development of low molecular weight spectrum metalloproteinase inhibitors as potential therapeu- synthetic inhibitors with a zinc chelating moiety. Inhibitors tics. More recently it has been appreciated that several able to fully differentiate between individual enzymes have families of zinc dependent proteinases play significant and not been identified thus far, although a reasonable level of varied roles in the biology of the resident cells in these tissues, discrimination is now being achieved in some cases.7 Each orchestrating development, remodelling, and subsequent family does, however, have other unique domains with pathological processes. They also play key roles in the numerous roles, including the determination of physiological activity of inflammatory cells. The task of elucidating the substrate specificity, ECM, or cell surface localisation (fig 1).
    [Show full text]
  • ADAM17 Targets MMP-2 and MMP-9 Via EGFR-MEK-ERK Pathway Activation to Promote Prostate Cancer Cell Invasion
    1714 INTERNATIONAL JOURNAL OF ONCOLOGY 40: 1714-1724, 2012 ADAM17 targets MMP-2 and MMP-9 via EGFR-MEK-ERK pathway activation to promote prostate cancer cell invasion LI-JIE XIAO1,2*, PING LIN1*, FENG LIN1*, XIN LIU1, WEI QIN1, HAI-FENG ZOU1, LIANG GUO1, WEI LIU1, SHU-JUAN WANG1 and XIAO-GUANG YU1 1Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Harbin Medical University, 194 Xuefu Road, Harbin 150081, Heilongjiang; 2College of Life Science and Technology, Heilongjiang Bayi Agricultural University, 2 Xinyang Road, Daqing 163319, Heilongjiang, P.R. China Received September 8, 2011; Accepted November 18, 2011 DOI: 10.3892/ijo.2011.1320 Abstract. ADAM17, also known as tumor necrosis factor-α released and down-regulation of MMP-2, MMP-9. However, converting enzyme (TACE), is involved in proteolytic ectodo- these effects could be reversed by simultaneous addition of main shedding of cell surface molecules and cytokines. TGF-α. These data demonstrated that ADAM17 contributes to Although aberrant expression of ADAM17 has been shown androgen-independent prostate cancer cell invasion by shed- in various malignancies, the function of ADAM17 in prostate ding of EGFR ligand TGF-α, which subsequently activates the cancer has not been clarified. In the present study, we sought EGFR-MEK-ERK signaling pathway, leading finally to over- to elucidate whether ADAM17 contributes to prostate cancer expression of MMP-2 and MMP-9. This study suggests that the cell invasion, as well as the mechanism involved in the process. ADAM17 expression level may be a new predictive biomarker The expression pattern of ADAM17 was investigated in human of invasion and metastasis of prostate cancer, and ADAM17 prostate cancer cells.
    [Show full text]
  • Matrix Metalloproteinases in Angiogenesis: a Moving Target for Therapeutic Intervention
    Matrix metalloproteinases in angiogenesis: a moving target for therapeutic intervention William G. Stetler-Stevenson J Clin Invest. 1999;103(9):1237-1241. https://doi.org/10.1172/JCI6870. Perspective Angiogenesis is the process in which new vessels emerge from existing endothelial lined vessels. This is distinct from the process of vasculogenesis in that the endothelial cells arise by proliferation from existing vessels rather than differentiating from stem cells. Angiogenesis is an invasive process that requires proteolysis of the extracellular matrix and, proliferation and migration of endothelial cells, as well as synthesis of new matrix components. During embryonic development, both vasculogenesis and angiogenesis contribute to formation of the circulatory system. In the adult, with the single exception of the reproductive cycle in women, angiogenesis is initiated only in response to a pathologic condition, such as inflammation or hypoxia. The angiogenic response is critical for progression of wound healing and rheumatoid arthritis. Angiogenesis is also a prerequisite for tumor growth and metastasis formation. Therefore, understanding the cellular events involved in angiogenesis and the molecular regulation of these events has enormous clinical implications. This understanding is providing novel therapeutic targets for the treatment of a variety of diseases, including cancer. Whatever the pathologic condition, an initiating stimulus results in the formation of a migrating solid column of endothelial cells called the vascular sprout. The advancing front of this endothelial cell column presumably focuses proteolytic activity to create a defect in the extracellular matrix, through which the advancing and proliferating column of endothelial […] Find the latest version: https://jci.me/6870/pdf Matrix metalloproteinases in angiogenesis: Perspective a moving target for therapeutic intervention SERIES Topics in angiogenesis David A.
    [Show full text]
  • Gent Forms of Metalloproteinases in Hydra
    Cell Research (2002); 12(3-4):163-176 http://www.cell-research.com REVIEW Structure, expression, and developmental function of early diver- gent forms of metalloproteinases in Hydra 1 2 3 4 MICHAEL P SARRAS JR , LI YAN , ALEXEY LEONTOVICH , JIN SONG ZHANG 1 Department of Anatomy and Cell Biology University of Kansas Medical Center Kansas City, Kansas 66160- 7400, USA 2 Centocor, Malvern, PA 19355, USA 3 Department of Experimental Pathology, Mayo Clinic, Rochester, MN 55904, USA 4 Pharmaceutical Chemistry, University of Kansas, Lawrence, KS 66047, USA ABSTRACT Metalloproteinases have a critical role in a broad spectrum of cellular processes ranging from the breakdown of extracellular matrix to the processing of signal transduction-related proteins. These hydro- lytic functions underlie a variety of mechanisms related to developmental processes as well as disease states. Structural analysis of metalloproteinases from both invertebrate and vertebrate species indicates that these enzymes are highly conserved and arose early during metazoan evolution. In this regard, studies from various laboratories have reported that a number of classes of metalloproteinases are found in hydra, a member of Cnidaria, the second oldest of existing animal phyla. These studies demonstrate that the hydra genome contains at least three classes of metalloproteinases to include members of the 1) astacin class, 2) matrix metalloproteinase class, and 3) neprilysin class. Functional studies indicate that these metalloproteinases play diverse and important roles in hydra morphogenesis and cell differentiation as well as specialized functions in adult polyps. This article will review the structure, expression, and function of these metalloproteinases in hydra. Key words: Hydra, metalloproteinases, development, astacin, matrix metalloproteinases, endothelin.
    [Show full text]
  • Functional and Structural Insights Into Astacin Metallopeptidases
    Biol. Chem., Vol. 393, pp. 1027–1041, October 2012 • Copyright © by Walter de Gruyter • Berlin • Boston. DOI 10.1515/hsz-2012-0149 Review Functional and structural insights into astacin metallopeptidases F. Xavier Gomis-R ü th 1, *, Sergio Trillo-Muyo 1 Keywords: bone morphogenetic protein; catalytic domain; and Walter St ö cker 2, * meprin; metzincin; tolloid; zinc metallopeptidase. 1 Proteolysis Lab , Molecular Biology Institute of Barcelona, CSIC, Barcelona Science Park, Helix Building, c/Baldiri Reixac, 15-21, E-08028 Barcelona , Spain Introduction: a short historical background 2 Institute of Zoology , Cell and Matrix Biology, Johannes Gutenberg University, Johannes-von-M ü ller-Weg 6, The fi rst report on the digestive protease astacin from the D-55128 Mainz , Germany European freshwater crayfi sh, Astacus astacus L. – then termed ‘ crayfi sh small-molecule protease ’ or ‘ Astacus pro- * Corresponding authors tease ’ – dates back to the late 1960s (Sonneborn et al. , 1969 ). e-mail: [email protected]; [email protected] Protein sequencing by Zwilling and co-workers in the 1980s did not reveal homology to any other protein (Titani et al. , Abstract 1987 ). Shortly after, the enzyme was identifi ed as a zinc met- allopeptidase (St ö cker et al., 1988 ), and other family mem- The astacins are a family of multi-domain metallopepti- bers emerged. The fi rst of these was bone morphogenetic β dases with manifold functions in metabolism. They are protein 1 (BMP1), a protease co-purifi ed with TGF -like either secreted or membrane-anchored and are regulated growth factors termed bone morphogenetic proteins due by being synthesized as inactive zymogens and also by co- to their capacity to induce ectopic bone formation in mice localizing protein inhibitors.
    [Show full text]
  • MMP-9) on the Metastatic Behavior of Oropharyngeal Cancer
    ANTICANCER RESEARCH 25: 4129-4134 (2005) Influence of Matrix Metalloproteinase 9 (MMP-9) on the Metastatic Behavior of Oropharyngeal Cancer A.A. DÜNNE1, A. GRÖBE1, A.M. SESTERHENN1, P. BARTH2, C. DALCHOW1 and J.A. WERNER1 1Department of Otolaryngology, Head and Neck Surgery and 2Department of Pathology, Philipps University of Marburg, Marburg, Germany Abstract. Background: The role of the single matrix molecular biological factors have been proposed for their metalloproteinases (MMPs) in the metastatic process of possible impact on the lymphogenic metastatic process. squamous cell carcinomas (SCC) is still obscure. Materials In this context, special interest is being paid to a better and Methods: The MMP-9 expression was described knowledge of the matrix metalloproteinases (MMPs) (5), immunohistochemically in 105 patients (40-79 years of age, that are involved in the physiology of reconstruction and mean: 57.84 years; 84 male, 21 female) suffering from renewal processes of surrounding tissue. In particular, MMP- oropharyngeal cancer (22x T1, 31x T2, 24x T3, 28x T4) with 2 and -9, originating from the subfamily of gelatinases, seem different neck stages (41x N0, 6x N1, 54x N2, 4x N3 neck). to play important roles in the metastatic process of several Results: A significant correlation between MMP-9 expression carcinomas (6, 7), including not only SCC of the head and and T stage (p<0.05), N stage (r=0.55, p<0.01) and UICC neck (8), but also malignant tumors of the lung (9), the stage (r=0.55, p<0.01) was revealed. Most remarkable was the prostate (10), the colon (11) and the bladder (12).
    [Show full text]
  • Identification of the Membrane-Type Matrix Metalloproteinase MT1-MMP
    Journal of Cell Science 110, 589-596 (1997) 589 Printed in Great Britain © The Company of Biologists Limited 1997 JCS9564 Identification of the membrane-type matrix metalloproteinase MT1-MMP in osteoclasts Takuya Sato1, Maria del Carmen Ovejero1, Peng Hou1, Anne-Marie Heegaard1, Masayoshi Kumegawa2, Niels Tækker Foged1 and Jean-Marie Delaissé1,* 1Department of Basic Research, Center for Clinical & Basic Research, Ballerup Byvej 222, DK-2750 Ballerup, Denmark 2The First Department of Oral Anatomy, Meikai University School of Dentistry, Keyakidai 1-1, Sakado, Saitama 350-02, Japan *Author for correspondence SUMMARY The osteoclasts are the cells responsible for bone resorp- on bone sections showed that MT1-MMP is expressed also tion. Matrix metalloproteinases (MMPs) appear crucial in osteoclasts in vivo. Antibodies recognizing MT1-MMP for this process. To identify possible MMP expression in reacted with specific plasma membrane areas corre- osteoclasts, we amplified osteoclast cDNA fragments sponding to lamellipodia and podosomes involved, respec- having homology with MMP genes, and used them as a tively, in migratory and attachment activities of the osteo- probe to screen a rabbit osteoclast cDNA library. We clasts. These observations highlight how cells might bring obtained a cDNA of 1,972 bp encoding a polypeptide of MT1-MMP into contact with focal points of the extracel- 582 amino acids that showed more than 92% identity to lular matrix, and are compatible with a role of MT1- human, mouse, and rat membrane-type 1 MMP (MT1- MMP in migratory and attachment activities of the osteo- MMP), a cell surface proteinase believed to trigger cancer clast. cell invasion. By northern blotting, MT1-MMP was found to be highly expressed in purified osteoclasts when compared with alveolar macrophages and bone stromal Key words: Osteoclast, MMP-14, MT1-MMP, Membrane proteinase, cells, as well as with various tissues.
    [Show full text]
  • Matrix Metalloproteinase -9, Human Recombinant, Expressed in Transfected Cells
    Matrix Metalloproteinase -9, human recombinant, expressed in transfected cells Catalog Number M4809 Storage Temperature –70 °C EC 3.4.24.35 All MMPs are synthesized as proenzymes, and most of Synonyms: MMP-9; Gelatinase-B; 95 kDa Gelatinase them are secreted from the cells as proenzymes. Thus, the activation of these proenzymes is a critical step that Product Description leads to extracellular matrix breakdown. Human Matrix Metalloproteinase-9 (MMP-9) is a matrix metalloproteinase that has been substrate-affinity MMPs are considered to play an important role in purified from transfected cells (pro and active forms). wound healing, apoptosis, bone elongation, embryo development, uterine involution, angiogenesis,5 and Matrix Metalloproteinase-9 (MMP-9) may be used in tissue remodeling, and in diseases such as multiple various immunochemical techniques such as sclerosis,3,6 Alzheimer’s,3 malignant gliomas,3 lupus, immunoblotting, ELISA, enzyme kinetics assays, and arthritis, periodontis, glomerulonephritis, athero- substrate assays. This preparation consists primarilay sclerosis, tissue ulceration, and in cancer cell invasion of the proenzyme form, with a small amount of active and metastasis.7 Numerous studies have shown that enzyme and TIMP present. The following bands may be there is a close association between expression of detected: various members of the MMP family by tumors and MMP-9 Proenzyme (>85%) at ~88 kDa non-reduced their proliferative and invasive behavior and metastatic and 92 kDa reduced potential. minor band (MMP-9 dimer) at ~180 kDa intermediate active form (very small amounts) at The tissue inhibitors of metalloproteinases (TIMPs) are ~84 kDa non-reduced naturally occurring proteins that specifically inhibit mature active form (very small amounts) at 82 kDa matrix metalloproteinases and regulate extracellular non-reduced matrix turnover and tissue remodeling by forming tight - TIMP-1 (~10%) at 28 kDa binding inhibitory complexes with the MMPs.
    [Show full text]
  • Expression of Matrix Metalloproteinase (MMP)-2 and MMP-9 in Breast Cancer with a Special Reference to Activator Protein-2, HER2, and Prognosis
    Vol. 10, 7621–7628, November 15, 2004 Clinical Cancer Research 7621 Expression of Matrix Metalloproteinase (MMP)-2 and MMP-9 in Breast Cancer with a Special Reference to Activator Protein-2, HER2, and Prognosis Johanna M. Pellikainen,1,2,3 Kirsi M. Ropponen,2 positive disease. In the univariate survival analysis, positive Vesa V. Kataja,3 Jari K. Kellokoski,4 stromal MMP-9 predicted shorter recurrence-free survival and breast cancer-related survival (0.0389 ؍ RFS; P) 1,2,3,6 5 ؉ ؍ Matti J. Eskelinen, and Veli-Matti Kosma 1 (BCRS; P 0.0081) in ER disease, especially in the sub- ؍ > Department of Pathology and Forensic Medicine, University of ؉ 2 3 group of ER tumors of 2 cm in diameter (T1; P 0.0031 ؍ ,Kuopio, Kuopio, Finland; Departments of Pathology, Oncology 4Otorhinolaryngology, Oral and Maxillofacial Unit, and 5Surgery, for RFS, and P 0.0089 for BCRS). High MMP-9 expres- in the (0.0351 ؍ Kuopio University Hospital, Kuopio, Finland; and 6Department of sion in cancer cells predicted longer RFS (P Pathology, Centre for Laboratory Medicine, University of Tampere whole patient group. In the multivariate analysis of the and Tampere University Hospital, Tampere, Finland whole patient group, the independent predictors of shorter RFS were reduced MMP-9 expression in carcinoma cells ؍ ؍ ABSTRACT (P 0.0248), HER2 overexpression (P 0.0001), and ad- -Shorter BCRS was pre .(0.0002 ؍ vanced-stage disease (P Purpose: In the present study, we investigated the ex- dicted by advanced-stage disease (P < 0.0001). pression and prognostic value of matrix metalloproteinase Conclusions: Expression of MMP-2 and MMP-9 in (MMP)-2 and MMP-9 in breast cancer as well as their breast cancer seems to be partly related to expression of relation to transcription factor activator protein (AP)-2 AP-2 and HER2.
    [Show full text]
  • Methods for Detection of Matrix Metalloproteinases As Biomarkers in Cardiovascular Disease Viorica Lopez-Avila
    The University of San Francisco USF Scholarship: a digital repository @ Gleeson Library | Geschke Center Biology Faculty Publications Biology 2008 Methods for Detection of Matrix Metalloproteinases as Biomarkers in Cardiovascular Disease Viorica Lopez-Avila Juliet Spencer University of San Francisco, [email protected] Follow this and additional works at: http://repository.usfca.edu/biol_fac Part of the Biology Commons, and the Cardiovascular Diseases Commons Recommended Citation Lopez-Avila, V and Spencer, JV. Methods for Detection of Matrix Metalloproteinases as Biomarkers in Cardiovascular Disease. Clinical Medicine Insights: Cardiology 2008:2 75-87. This Article is brought to you for free and open access by the Biology at USF Scholarship: a digital repository @ Gleeson Library | Geschke Center. It has been accepted for inclusion in Biology Faculty Publications by an authorized administrator of USF Scholarship: a digital repository @ Gleeson Library | Geschke Center. For more information, please contact [email protected]. REVIEW Methods for Detection of Matrix Metalloproteinases as Biomarkers in Cardiovascular Disease Viorica Lopez-Avila1 and Juliet V. Spencer2 1Agilent Technologies, Santa Clara, CA 95051, U.S.A. 2University of San Francisco, San Francisco, CA 94403, U.S.A. Abstract: Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteolytic enzymes that degrade extracel- lular matrix (ECM) components like collagen, fi bronectin, and laminin. While this activity is important for normal develop- ment, morphogenesis, and wound healing, deregulation of MMP activity has been implicated in a number of cardiovascular diseases, including congenital heart defects, atherosclerosis, myocardial infarction, and congestive heart failure. MMPs are good potential diagnostic indicators of cardiovascular disease, but current detection methods are time consuming and quite laborious.
    [Show full text]
  • Matrix Metalloproteinase-3, Catalytic Domain (M9320)
    Matrix Metalloproteinase-3, Catalytic Domain human, recombinant expressed in E. coli Catalog Number M9320 Storage Temperature -70 °C EC 3.4.24.17 Matrix Metalloproteinase-3 (MMP-3) degrades a wide range of substrates, including gelatin, type IV, V, IX, Synonyms: MMP-3; Stromelysin-1; Transin; and X collagens, elastin, laminin, vitronectin, casein, Proteoglycanase fibronectin, proteoglycans, aggrecan, myelin basic protein, and a-1-antitrypsin.8,9 MMP-3 can be induced Product Description by cytokines IL-1b and TNF-a, by growth factors EGF, The matrix metalloproteinases (MMPs) are a family of PDGF, and IGFBP-3, and by the tumor promotor PMA. at least eighteen secreted and membrane-bound zinc- Its expression is inhibited by TGF-b and by all-trans endopeptidases. Collectively, these enzymes can retinoic acid (RA). The MMP-3 substrate repertoire degrade all the components of the extracellular matrix, extends beyond the extracellular matrix proteins and including fibrillar and non-fibrillar collagens, fibro- suggests that MMP-3 has additional roles other than in nectin, laminin and basement membrane glyco- direct tissue remodeling (i.e., enzyme cascades and proteins. In general, a signal peptide, a propeptide, cytokine regulation). and a catalytic domain containing the highly conserved zinc-binding site characterize the structure of the MMP-3 does not cleave the triple helical region of the MMPs. In addition, fibronectin-like repeats, a hinge interstitial collagens, which is a characteristic that region, and a C-terminal hemopexin-like domain allow distinguishes the stromelysins from the collagenases. categorization of MMPs into the collagenase, gela- Structurally, MMP-3 is divided into several distinct tinase, stomelysin and membrane-type MMP sub- domains: a pro-domain which is cleaved upon 1-4 families.
    [Show full text]