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The aim of this article is to review the exciting and intriguing literature on TIMPs, with special emphasis on their conflicting-paradoxical roles in PCD and their potential" /> <meta name="twitter:image" content="https://0.academia-photos.com/51461427/20315663/20012482/s200_ferdinando.mannello.jpg" /> <meta property="fb:app_id" content="2369844204" /> <meta property="og:type" content="article" /> <meta property="og:url" content="https://www.academia.edu/27346784/Tissue_inhibitors_of_metalloproteinases_and_programmed_cell_death_Conundrums_controversies_and_potential_implications" /> <meta property="og:title" content="Tissue inhibitors of metalloproteinases and programmed cell death: Conundrums, controversies and potential implications" /> <meta property="og:image" content="http://a.academia-assets.com/images/open-graph-icons/fb-paper.gif" /> <meta property="og:description" content="homeostasis in a tissue-specific fashion and its overexpression induces PCD. The aim of this article is to review the exciting and intriguing literature on TIMPs, with special emphasis on their conflicting-paradoxical roles in PCD and their potential" /> <meta property="article:author" content="https://urbinoc.academia.edu/FerdinandoMannello" /> <meta name="description" content="homeostasis in a tissue-specific fashion and its overexpression induces PCD. 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The aim of this article is to review the exciting and intriguing literature on TIMPs, with special emphasis on their conflicting-paradoxical roles in PCD and their potential clinical usefulness.","publication_date":"2001,,","publication_name":"Apoptosis","grobid_abstract_attachment_id":"47601610"},"document_type":"paper","pre_hit_view_count_baseline":null,"quality":"high","language":"en","title":"Tissue inhibitors of metalloproteinases and programmed cell death: Conundrums, controversies and potential implications","broadcastable":true,"draft":null,"has_indexable_attachment":true,"indexable":true,"seo_quality":null}}["work"]; window.loswp.workCoauthors = [51461427]; window.loswp.locale = "en"; window.loswp.countryCode = "SG"; window.loswp.cwvAbTestBucket = ""; window.loswp.designVariant = "ds_vanilla"; window.loswp.fullPageMobileSutdModalVariant = "full_page_mobile_sutd_modal"; window.loswp.useOptimizedScribd4genScript = false; window.loginModal = {}; window.loginModal.appleClientId = 'edu.academia.applesignon'; 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The aim of this article is to review the exciting and intriguing literature on TIMPs, with special emphasis on their conflicting-paradoxical roles in PCD and their potential clinical usefulness.</p></div></div><div class="ds-top-related-works--grid-container"><div class="ds-related-content--container ds-top-related-works--container"><h2 class="ds-related-content--heading">Related papers</h2><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="0" data-entity-id="50146744" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/50146744/Metalloproteinases_of_the_extracellular_matrix_and_their_inhibitors">Metalloproteinases of the extracellular matrix and their inhibitors</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="34245553" href="https://independent.academia.edu/AndreaBaier1">Andrea Baier</a></div><p class="ds-related-work--metadata ds2-5-body-xs">BioTechnologia, 2016</p><p class="ds-related-work--abstract ds2-5-body-sm">The dynamic equilibrium between the synthesis and degradation of the extracellular matrix is to a large extent mediated by matrix metalloproteinase (MMP) enzymes, which are antagonized by tissue inhibitors of metalloproteinases (TIMPs). Tissue-degrading enzymes of the metalloproteinase family have been implicated in the pathogenesis of several conditions involving the extracellular matrix. MMPs are a family of zinc-dependent endopeptidases capable of degrading practically all components of the extracellular matrix. Recent insights suggest that MMPs may also have a broader spectrum of functions, including regulation of the inflammatory response and cytokine signaling. MMPs have been subdivided according to their main degradation activity and the continuously growing list of known substrates. Metalloproteinases are promising drug targets, and they are subjected to pharmacological inhibition by clinically available drugs such as tetracyclines and bisphosphonates. Interest in MMPs has recently increased, because their expression is frequently related to tumor progression. As such, metalloproteinases have diagnostic potential as markers to predict the outcome of disease processes. This review introduces the members of the MMP family and discusses their domain structure and function, their significance in physiology and pathology and the mechanism of inhibition by TIMPs.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Metalloproteinases of the extracellular matrix and their inhibitors","attachmentId":68242769,"attachmentType":"pdf","work_url":"https://www.academia.edu/50146744/Metalloproteinases_of_the_extracellular_matrix_and_their_inhibitors","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/50146744/Metalloproteinases_of_the_extracellular_matrix_and_their_inhibitors"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="1" data-entity-id="61170265" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/61170265/Selected_Matrix_Metalloproteinases_MMP_2_MMP_7_and_Their_Inhibitor_TIMP_2_in_Adult_and_Pediatric_Cancer">Selected Matrix Metalloproteinases (MMP-2, MMP-7) and Their Inhibitor (TIMP-2) in Adult and Pediatric Cancer</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="58536220" href="https://independent.academia.edu/NataliaMi%C4%99kus">Natalia Miękus</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Diagnostics</p><p class="ds-related-work--abstract ds2-5-body-sm">The tumor microenvironment (TME) consists of numerous biologically relevant elements. One of the most important components of the TME is the extracellular matrix (ECM). The compounds of the ECM create a network that provides structural and biochemical support to surrounding cells. The most important substances involved in the regulation of the ECM degradation process are matrix metalloproteinases (MMPs) and their endogenous inhibitors (tissue inhibitors of metalloproteinases, TIMPs). The disruption of the physiological balance between MMP activation and deactivation could lead to progression of various diseases such as cardiovascular disease, cancer, fibrosis arthritis, chronic tissue ulcers, pathologies of the nervous system (such as stroke and Alzheimer’s disease), periodontitis, and atheroma. MMP-TIMP imbalance results in matrix proteolysis associated with various pathological processes such as tumor invasion. The present review discusses the involvement of two MMPs, MMP-2 and MM...</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Selected Matrix Metalloproteinases (MMP-2, MMP-7) and Their Inhibitor (TIMP-2) in Adult and Pediatric Cancer","attachmentId":74299741,"attachmentType":"pdf","work_url":"https://www.academia.edu/61170265/Selected_Matrix_Metalloproteinases_MMP_2_MMP_7_and_Their_Inhibitor_TIMP_2_in_Adult_and_Pediatric_Cancer","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/61170265/Selected_Matrix_Metalloproteinases_MMP_2_MMP_7_and_Their_Inhibitor_TIMP_2_in_Adult_and_Pediatric_Cancer"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="2" data-entity-id="24732818" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/24732818/Beneficial_and_detrimental_influences_of_tissue_inhibitor_of_metalloproteinase_1_TIMP_1_in_tumor_progression">Beneficial and detrimental influences of tissue inhibitor of metalloproteinase-1 (TIMP-1) in tumor progression</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="47678741" href="https://independent.academia.edu/EliseLambert">Elise Lambert</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Biochimie, 2005</p><p class="ds-related-work--abstract ds2-5-body-sm">Tissue inhibitor of metalloproteinase-1 (TIMP-1) is one representative of the natural matrix metalloproteinase (MMP) inhibitor family, encompassing four members. It inhibits all MMPs, except several MT-MMPs, and a disintegrin with a metalloproteinase domain (ADAM)-10 with Kis < nM. Unexpectedly, its upregulation was associated to poor clinical outcome for several cancer varieties. Such finding might be related to the growth-promoting and survival activities of TIMP-1 for normal and cancer cells. In most cases, such properties are MMPindependent and binding of TIMP-1 to an unknown receptor system can trigger JAK (or FAK)/PI 3 kinase/Akt/bad-bclX 2 (erythroid, myeloid, epithelial cell lines) or Ras/Raf1/FAK (osteosarcoma cell line) signaling pathways. The relationship between viral infection and TIMP-1 expression is here underlined. Thus, TIMP-1 might display a dual influence on tumor progression; either beneficial by inhibiting MMPs as MMP-9 and by impairing angiogenesis or detrimental by favoring cancer cells growth or survival. We consider that the proMMP-9/TIMP-1 balance is of critical importance in early events of tumor progression, and might show promise as diagnostic and prognostic marker of malignancy.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Beneficial and detrimental influences of tissue inhibitor of metalloproteinase-1 (TIMP-1) in tumor progression","attachmentId":45062737,"attachmentType":"pdf","work_url":"https://www.academia.edu/24732818/Beneficial_and_detrimental_influences_of_tissue_inhibitor_of_metalloproteinase_1_TIMP_1_in_tumor_progression","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/24732818/Beneficial_and_detrimental_influences_of_tissue_inhibitor_of_metalloproteinase_1_TIMP_1_in_tumor_progression"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="3" data-entity-id="93412876" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/93412876/Insights_Into_the_Role_of_Matrix_Metalloproteinases_in_Cancer_and_its_Various_Therapeutic_Aspects_A_Review">Insights Into the Role of Matrix Metalloproteinases in Cancer and its Various Therapeutic Aspects: A Review</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="8032288" href="https://independent.academia.edu/sheejakoran">sheeja koran</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Frontiers in Molecular Biosciences</p><p class="ds-related-work--abstract ds2-5-body-sm">Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that regulate the turnover of extracellular matrix (ECM) components. Gross and La Piere discovered MMPs in 1962 during an experiment on tissue samples from a tadpole’s tail. Several subtypes of MMPs have been identified, depending on their substrate specificity and localization. MMPs are involved as essential molecules in multiple and diverse physiological processes, such as reproduction, embryonic development, bone remodeling, tissue repair, and regulation of inflammatory processes. Its activity is controlled at various levels such as at transcription level, pro-peptide activation level and by the activity of a family of tissue inhibitors of metalloproteinase, endogenous inhibitors of MMPs. Cancer metastasis, which is the spread of a tumor to a distant site, is a complex process that is responsible for the majority of cancer-related death It is considered to be an indicator of cancer metastasis. During metastasis, t...</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Insights Into the Role of Matrix Metalloproteinases in Cancer and its Various Therapeutic Aspects: A Review","attachmentId":96157413,"attachmentType":"pdf","work_url":"https://www.academia.edu/93412876/Insights_Into_the_Role_of_Matrix_Metalloproteinases_in_Cancer_and_its_Various_Therapeutic_Aspects_A_Review","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/93412876/Insights_Into_the_Role_of_Matrix_Metalloproteinases_in_Cancer_and_its_Various_Therapeutic_Aspects_A_Review"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="4" data-entity-id="85211007" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/85211007/Intricate_functions_of_matrix_metalloproteinases_in_physiological_and_pathological_conditions">Intricate functions of matrix metalloproteinases in physiological and pathological conditions</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="114933717" href="https://independent.academia.edu/PremChapagain">Prem Chapagain</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Journal of cellular physiology, 2016</p><p class="ds-related-work--abstract ds2-5-body-sm">Matrix metalloproteinases (MMPs) are a diverse group of proteolytic enzymes and play an important role in the degradation and remodeling of the extracellular matrix (ECM). In normal physiological conditions, MMPs are usually minimally expressed. Despite their low expression, MMPs have been implicated in many cellular processes ranging from embryological development to apoptosis. The activity of MMPs is controlled at three different stages: (1) transcription, (2) zymogen activation, and (3) inhibition of active forms by tissue inhibitor metalloproteinases (TIMPs). They can collectively degrade any component of ECM and basement membrane, and their excessive activity has been linked to numerous pathologies mainly including, but not limited to, tumor evasion and metastasis. The lack of information about several MMPs and the steady stream of new discoveries suggest that there is much more to be studied in this field. In particular, there is a need for controlling their expression in dise...</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Intricate functions of matrix metalloproteinases in physiological and pathological conditions","attachmentId":89978997,"attachmentType":"pdf","work_url":"https://www.academia.edu/85211007/Intricate_functions_of_matrix_metalloproteinases_in_physiological_and_pathological_conditions","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/85211007/Intricate_functions_of_matrix_metalloproteinases_in_physiological_and_pathological_conditions"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="5" data-entity-id="115941610" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/115941610/Matrix_Metalloproteinases_and_Cancer_Roles_in_Threat_and_Therapy">Matrix Metalloproteinases and Cancer - Roles in Threat and Therapy</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="294997153" href="https://independent.academia.edu/LalitaYadav54">Lalita Yadav</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Asian Pacific Journal of Cancer Prevention, 2014</p><p class="ds-related-work--abstract ds2-5-body-sm">Matrix metalloproteinases (MMPs) are a family of zinc dependent extracellular matrix (ECM) remodelling endopeptidases having the ability to degrade almost all components of extracellular matrix and implicated in various physiological as well as pathological processes. Carcinogenesis is a multistage process in which alteration of the microenvironment is required for conversion of normal tissue to a tumour. Extracellular matrix remodelling proteinases such as MMPs are principal mediators of alterations observed in the microenvironment during carcinogenesis and according to recent concepts not only have roles in invasion or late stages of cancer but also in regulating initial steps of carcinogenesis in a favourable or unfavourable manner. Establishment of relationships between MMP overproduction and cancer progression has stimulated the development of inhibitors that block proteolytic activity of these enzymes. In this review we discuss the MMP general structure, classification, regulation roles in relation to hallmarks of cancer and as targets for therapeutic intervention.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Matrix Metalloproteinases and Cancer - Roles in Threat and Therapy","attachmentId":112208651,"attachmentType":"pdf","work_url":"https://www.academia.edu/115941610/Matrix_Metalloproteinases_and_Cancer_Roles_in_Threat_and_Therapy","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/115941610/Matrix_Metalloproteinases_and_Cancer_Roles_in_Threat_and_Therapy"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="6" data-entity-id="57222311" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/57222311/The_Roles_of_Matrix_Metalloproteinases_and_Their_Inhibitors_in_Human_Diseases">The Roles of Matrix Metalloproteinases and Their Inhibitors in Human Diseases</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="62644655" href="https://independent.academia.edu/ClaudiaCastruitadelaRosa">Claudia Castruita de la Rosa</a></div><p class="ds-related-work--metadata ds2-5-body-xs">International Journal of Molecular Sciences</p><p class="ds-related-work--abstract ds2-5-body-sm">Matrix metalloproteinases (MMPs) are a family of zinc-dependent extracellular matrix (ECM) remodeling endopeptidases that have the capacity to degrade almost every component of the ECM. The degradation of the ECM is of great importance, since it is related to embryonic development and angiogenesis. It is also involved in cell repair and the remodeling of tissues. When the expression of MMPs is altered, it can generate the abnormal degradation of the ECM. This is the initial cause of the development of chronic degenerative diseases and vascular complications generated by diabetes. In addition, this process has an association with neurodegeneration and cancer progression. Within the ECM, the tissue inhibitors of MMPs (TIMPs) inhibit the proteolytic activity of MMPs. TIMPs are important regulators of ECM turnover, tissue remodeling, and cellular behavior. Therefore, TIMPs (similar to MMPs) modulate angiogenesis, cell proliferation, and apoptosis. An interruption in the balance between ...</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"The Roles of Matrix Metalloproteinases and Their Inhibitors in Human Diseases","attachmentId":72225779,"attachmentType":"pdf","work_url":"https://www.academia.edu/57222311/The_Roles_of_Matrix_Metalloproteinases_and_Their_Inhibitors_in_Human_Diseases","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/57222311/The_Roles_of_Matrix_Metalloproteinases_and_Their_Inhibitors_in_Human_Diseases"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="7" data-entity-id="13498480" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/13498480/Tissue_Inhibitor_of_Metalloproteinases_4_The_road_less_traveled">Tissue Inhibitor of Metalloproteinases-4. The road less traveled</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="32748156" href="https://independent.academia.edu/PozoLuisDel">Luis Del Pozo</a><span>, </span><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="32702825" href="https://inmegen.academia.edu/GiselaCeballos">Gisela Ceballos</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Molecular Cancer, 2008</p><p class="ds-related-work--abstract ds2-5-body-sm">Tissue inhibitors of metalloproteinases (TIMPs) regulate diverse processes, including extracellular matrix (ECM) remodeling, and growth factors and their receptors' activities through the inhibition of matrix metalloproteinases (MMPs). Recent evidence has shown that this family of four members (TIMP-1 to TIMP-4) can also control other important processes, such as proliferation and apoptosis, by a mechanism independent of their MMP inhibitory actions. Of these inhibitors, the most recently identified and least studied is TIMP-4. Initially cloned in human and, later, in mouse, TIMP-4 expression is restricted to heart, kidney, pancreas, colon, testes, brain and adipose tissue. This restricted expression suggests specific and different physiological functions. The present review summarizes the information available for this protein and also provides a putative structural model in order to propose potential relevant directions toward solving its function and role in diseases such as cancer.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Tissue Inhibitor of Metalloproteinases-4. The road less traveled","attachmentId":45266429,"attachmentType":"pdf","work_url":"https://www.academia.edu/13498480/Tissue_Inhibitor_of_Metalloproteinases_4_The_road_less_traveled","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/13498480/Tissue_Inhibitor_of_Metalloproteinases_4_The_road_less_traveled"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="8" data-entity-id="29918319" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/29918319/Molecular_mechanisms_of_tissue_inhibitor_of_metalloproteinase_2_in_the_tumor_microenvironment">Molecular mechanisms of tissue inhibitor of metalloproteinase 2 in the tumor microenvironment</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="56693857" href="https://independent.academia.edu/SandraJensentaubman">Sandra M Jensen</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Molecular and Cellular Therapies, 2014</p><p class="ds-related-work--abstract ds2-5-body-sm">There has been a recent paradigm shift in the way we target cancer, drawing a greater focus on the role of the tumor microenvironment (TME) in cancer development, progression and metastasis. Within the TME, there is a crosstalk in signaling and communication between the malignant cells and the surrounding extracellular matrix. Matrix metalloproteinases (MMPs) are zinc-dependent endoproteases that have the ability to degrade the matrix surrounding a tumor and mediate tumor growth, angiogenesis and metastatic disease. Their endogenous inhibitors, the Tissue Inhibitors of Metalloproteinases (TIMPs), primarily function to prevent degradation of the ECM via inhibition of MMPs. However, recent studies demonstrate that TIMP family members also possess MMP-independent functions. One TIMP member in particular, TIMP-2, has many distinct properties and functions, that occur independent of MMP inhibition, including the inhibition of tumor growth and reduction of angiogenesis through decreased endothelial cell proliferation and migration. The MMP-independent molecular mechanisms and signaling pathways elicited by TIMP-2 in the TME are described in this review.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Molecular mechanisms of tissue inhibitor of metalloproteinase 2 in the tumor microenvironment","attachmentId":50377968,"attachmentType":"pdf","work_url":"https://www.academia.edu/29918319/Molecular_mechanisms_of_tissue_inhibitor_of_metalloproteinase_2_in_the_tumor_microenvironment","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/29918319/Molecular_mechanisms_of_tissue_inhibitor_of_metalloproteinase_2_in_the_tumor_microenvironment"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="9" data-entity-id="20975120" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/20975120/Tissue_Inhibitor_of_Metalloproteinase_TIMP_2_Acts_Synergistically_with_Synthetic_Matrix_Metalloproteinase_MMP_Inhibitors_but_Not_with_TIMP_4_to_Enhance_the_Membrane_Type_1_MMP_dependent_Activation_of_Pro_MMP_2">Tissue Inhibitor of Metalloproteinase (TIMP)-2 Acts Synergistically with Synthetic Matrix Metalloproteinase (MMP) Inhibitors but Not with TIMP-4 to Enhance the (Membrane Type 1)-MMP-dependent Activation of Pro-MMP-2</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="42225466" href="https://independent.academia.edu/PaulSoloway">Paul Soloway</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Journal of Biological Chemistry, 2000</p><p class="ds-related-work--abstract ds2-5-body-sm">The membrane-type 1 matrix metalloproteinase (MT1-MMP) has been shown to be a key enzyme in tumor angiogenesis and metastasis. MT1-MMP hydrolyzes a variety of extracellular matrix components and is a physiological activator of pro-MMP-2, another MMP involved in malignancy. Pro-MMP-2 activation by MT1-MMP involves the formation of an MT1-MMP⅐tissue inhibitors of metalloproteinases 2 (TIMP-2)⅐pro-MMP-2 complex on the cell surface that promotes the hydrolysis of pro-MMP-2 by a neighboring TIMP-2-free MT1-MMP. The MT1-MMP⅐TIMP-2 complex also serves to reduce the intermolecular autocatalytic turnover of MT1-MMP, resulting in accumulation of active MT1-MMP (57 kDa) on the cell surface. Evidence shown here in Timp2-null cells demonstrates that pro-MMP-2 activation by MT1-MMP requires TIMP-2. In contrast, a C-terminally deleted TIMP-2 (⌬-TIMP-2), unable to form ternary complex, had no effect. However, ⌬-TIMP-2 and certain synthetic MMP inhibitors, which inhibit MT1-MMP autocatalysis, can act synergistically with TIMP-2 in the promotion of pro-MMP-2 activation by MT1-MMP. In contrast, TIMP-4, an efficient MT1-MMP inhibitor, had no synergistic effect. These studies suggest that under certain conditions the pericellular activity of MT1-MMP in the presence of TIMP-2 can be modulated by synthetic and natural (TIMP-4) MMP inhibitors. . 1 The abbreviations used are: ECM, extracellular matrix; MMP, matrix metalloproteinase; MT-MMP, membrane type MMP; MMPI, MMP inhibitor; TIMP, tissue inhibitor of metalloproteinase; PAGE, polyacrylamide gel electrophoresis; pAb, polyclonal antibody; pfu, plaque-forming units; DMEM, Dulbecco's modified Eagle's medium.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Tissue Inhibitor of Metalloproteinase (TIMP)-2 Acts Synergistically with Synthetic Matrix Metalloproteinase (MMP) Inhibitors but Not with TIMP-4 to Enhance the (Membrane Type 1)-MMP-dependent Activation of Pro-MMP-2","attachmentId":41653714,"attachmentType":"pdf","work_url":"https://www.academia.edu/20975120/Tissue_Inhibitor_of_Metalloproteinase_TIMP_2_Acts_Synergistically_with_Synthetic_Matrix_Metalloproteinase_MMP_Inhibitors_but_Not_with_TIMP_4_to_Enhance_the_Membrane_Type_1_MMP_dependent_Activation_of_Pro_MMP_2","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/20975120/Tissue_Inhibitor_of_Metalloproteinase_TIMP_2_Acts_Synergistically_with_Synthetic_Matrix_Metalloproteinase_MMP_Inhibitors_but_Not_with_TIMP_4_to_Enhance_the_Membrane_Type_1_MMP_dependent_Activation_of_Pro_MMP_2"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div></div></div><div class="ds-sticky-ctas--wrapper js-loswp-sticky-ctas hidden"><div class="ds-sticky-ctas--grid-container"><div class="ds-sticky-ctas--container"><button class="ds2-5-button js-swp-download-button" data-signup-modal="{"location":"continue-reading-button--sticky-ctas","attachmentId":47601610,"attachmentType":"pdf","workUrl":null}">See full PDF</button><button class="ds2-5-button ds2-5-button--secondary js-swp-download-button" data-signup-modal="{"location":"download-pdf-button--sticky-ctas","attachmentId":47601610,"attachmentType":"pdf","workUrl":null}"><span class="material-symbols-outlined" style="font-size: 20px" translate="no">download</span>Download PDF</button></div></div></div><div class="ds-below-fold--grid-container"><div class="ds-work--container js-loswp-embedded-document"><div class="attachment_preview" data-attachment="Attachment_47601610" style="display: none"><div class="js-scribd-document-container"><div class="scribd--document-loading js-scribd-document-loader" style="display: block;"><img alt="Loading..." src="//a.academia-assets.com/images/loaders/paper-load.gif" /><p>Loading Preview</p></div></div><div style="text-align: center;"><div class="scribd--no-preview-alert js-preview-unavailable"><p>Sorry, preview is currently unavailable. 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