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International Journal of Molecular... Oct 2020ADAM9 (A disintegrin and a metalloprotease 9) is a membrane-anchored protein that participates in a variety of physiological functions, primarily through the disintegrin... (Review)
Review
ADAM9 (A disintegrin and a metalloprotease 9) is a membrane-anchored protein that participates in a variety of physiological functions, primarily through the disintegrin domain for adhesion and the metalloprotease domain for ectodomain shedding of a wide variety of cell surface proteins. ADAM9 influences the developmental process, inflammation, and degenerative diseases. Recently, increasing evidence has shown that ADAM9 plays an important role in tumor biology. Overexpression of ADAM9 has been found in several cancer types and is correlated with tumor aggressiveness and poor prognosis. In addition, through either proteolytic or non-proteolytic pathways, ADAM9 promotes tumor progression, therapeutic resistance, and metastasis of cancers. Therefore, comprehensively understanding the mechanism of ADAM9 is crucial for the development of therapeutic anti-cancer strategies. In this review, we summarize the current understanding of ADAM9 in biological function, pathophysiological diseases, and various cancers. Recent advances in therapeutic strategies using ADAM9-related pathways are presented as well.
Topics: ADAM Proteins; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Membrane Proteins; Neoplasms; Neurodegenerative Diseases; Phenylurea Compounds; Pyridines; Retinal Diseases; Sorafenib; Tumor Microenvironment
PubMed: 33096780
DOI: 10.3390/ijms21207790 -
Journal of Biological Regulators and... 2020Matrix metalloproteases (MMPs) are a family of zinc-dependent endopeptidases, produced by numerous cell types including fibroblasts, endothelial cells, osteoblasts,... (Clinical Trial)
Clinical Trial
Matrix metalloproteases (MMPs) are a family of zinc-dependent endopeptidases, produced by numerous cell types including fibroblasts, endothelial cells, osteoblasts, macrophages, lymphocytes and neutrophils, and capable of degrading different components of the extracellular matrix (ECM), but also cytokines, receptors and factors that regulate cell motility (1). MMPs represent the main proteolytic enzymes involved in the remodeling and degradation of the components of the extracellular matrix, in the modifications of interactions between cells, and those between cells and the ECM that regulate, for example, the processes of cell migration (2, 3). Due to these characteristics, the MMPs are involved in numerous physiological processes (angiogenesis, apoptosis, bone remodeling, wound repair, morphogenesis, inflammation, immune response) response to incongruous conservative and endodontic treatments (29-37, 46, 47) and pathological (periodontitis, arthritis, cancer, cardiovascular diseases, neurological diseases, osteoporosis etc.) (5). Metalloproteinase-8 (MMP-8) is an important indicator of tissue decomposition and is present in case of periodontitis in the gingiva and in the sulcular fluid. The concentration of MMP-8 in the sulcular fluid of patients with chronic or aggressive periodontitis is higher than that found in healthy patients (4, 6). MMP-8 was also significantly correlated with gingivitis index, plaque index, probing and clinical attack level. For this reason, the concentration of MMP-8 in the sulcular fluid could constitute a useful index to monitor periodontitis activity and be used to predict disease progression, also because of orthodontic treatments (38-45). Patients with periodontitis had elevated concentrations of MMP-8 salivary compared to patients with gingivitis and healthy tissues. Through this experimentation we wanted to demonstrate the real effectiveness of using this test as a means of preventing peri-implant pathology.
Topics: Endothelial Cells; Gingivitis; Humans; Matrix Metalloproteinase 8; Peri-Implantitis; Periodontitis
PubMed: 32618172
DOI: No ID Found -
Frontiers in Immunology 2022Metalloproteinases (MPs) is a large family of proteinases with metal ions in their active centers. According to the different domains metalloproteinases can be divided... (Review)
Review
Metalloproteinases (MPs) is a large family of proteinases with metal ions in their active centers. According to the different domains metalloproteinases can be divided into a variety of subtypes mainly including Matrix Metalloproteinases (MMPs), A Disintegrin and Metalloproteases (ADAMs) and ADAMs with Thrombospondin Motifs (ADAMTS). They have various functions such as protein hydrolysis, cell adhesion and remodeling of extracellular matrix. Metalloproteinases expressed in multiple types of cancers and participate in many pathological processes involving tumor genesis and development, invasion and metastasis by regulating signal transduction and tumor microenvironment. In this review, based on the current research progress, we summarized the structure of MPs, their expression and especially immunomodulatory role and mechanisms in cancers. Additionally, a relevant and timely update of recent advances and future directions were provided for the diagnosis and immunotherapy targeting MPs in cancers.
Topics: Humans; Neoplasms; Matrix Metalloproteinases; Thrombospondins; Extracellular Matrix; Signal Transduction; Tumor Microenvironment
PubMed: 36591235
DOI: 10.3389/fimmu.2022.1064033 -
The Journal of Clinical Investigation Jul 2022Mitochondrial stress triggers a response in the cell's mitochondria and nucleus, but how these stress responses are coordinated in vivo is poorly understood. Here, we...
Mitochondrial stress triggers a response in the cell's mitochondria and nucleus, but how these stress responses are coordinated in vivo is poorly understood. Here, we characterize a family with myopathy caused by a dominant p.G58R mutation in the mitochondrial protein CHCHD10. To understand the disease etiology, we developed a knockin (KI) mouse model and found that mutant CHCHD10 aggregated in affected tissues, applying a toxic protein stress to the inner mitochondrial membrane. Unexpectedly, the survival of CHCHD10-KI mice depended on a protective stress response mediated by the mitochondrial metalloendopeptidase OMA1. The OMA1 stress response acted both locally within mitochondria, causing mitochondrial fragmentation, and signaled outside the mitochondria, activating the integrated stress response through cleavage of DAP3-binding cell death enhancer 1 (DELE1). We additionally identified an isoform switch in the terminal complex of the electron transport chain as a component of this response. Our results demonstrate that OMA1 was critical for neonatal survival conditionally in the setting of inner mitochondrial membrane stress, coordinating local and global stress responses to reshape the mitochondrial network and proteome.
Topics: Animals; Metalloproteases; Mice; Mitochondria; Mitochondrial Membranes; Mitochondrial Myopathies; Mitochondrial Proteins; Mutation; Protein Folding
PubMed: 35700042
DOI: 10.1172/JCI157504 -
Cancer Metastasis Reviews Sep 2019Changing the characteristics of cells from epithelial states to mesenchymal properties is a key process involved in developmental and physiological processes as well as... (Review)
Review
Changing the characteristics of cells from epithelial states to mesenchymal properties is a key process involved in developmental and physiological processes as well as in many diseases with cancer as the most prominent example. Nowadays, a great deal of work and literature concerns the understanding of the process of epithelial-to-mesenchymal transition (EMT) in terms of its molecular regulation and its implications for cancer. Similar statements can certainly be made regarding the investigation of the more than 500 proteases typically encoded by a mammalian genome. Specifically, the impact of proteases on tumor biology has been a long-standing topic of interest. However, although EMT actively regulates expression of many proteases and proteolytic enzymes are clearly involved in survival, division, differentiation, and movements of cells, information on the diverse roles of proteases in EMT has been rarely compiled. Here we aim to conceptually connect the scientific areas of "EMT" and "protease" research by describing how several important classes of proteolytic enzymes are regulated by EMT and how they are involved in initiation and execution of the EMT program. To do so, we briefly introduce the evolving key features of EMT and its regulation followed by discussion of protease involvement in this process.
Topics: Animals; Deubiquitinating Enzymes; Disease Progression; Epithelial-Mesenchymal Transition; Humans; Metalloproteases; Neoplasms; Peptide Hydrolases
PubMed: 31482486
DOI: 10.1007/s10555-019-09808-2 -
FASEB Journal : Official Publication of... Nov 2023Adamalysins, a family of metalloproteinases containing a disintegrin and metalloproteinases (ADAMs) and ADAM with thrombospondin motifs (ADAMTSs), belong to the...
Adamalysins, a family of metalloproteinases containing a disintegrin and metalloproteinases (ADAMs) and ADAM with thrombospondin motifs (ADAMTSs), belong to the matrisome and play important roles in various biological and pathological processes, such as development, immunity and cancer. Using a liver cancer dataset from the International Cancer Genome Consortium, we developed an extensive in silico screening that identified a cluster of adamalysins co-expressed in livers from patients with hepatocellular carcinoma (HCC). Within this cluster, ADAMTS12 expression was highly associated with recurrence risk and poorly differentiated HCC signatures. We showed that ADAMTS12 was expressed in the stromal cells of the tumor and adjacent fibrotic tissues of HCC patients, and more specifically in activated stellate cells. Using a mouse model of carbon tetrachloride-induced liver injury, we showed that Adamts12 was strongly and transiently expressed after a 24 h acute treatment, and that fibrosis was exacerbated in Adamts12-null mice submitted to carbon tetrachloride-induced chronic liver injury. Using the HSC-derived LX-2 cell line, we showed that silencing of ADAMTS12 resulted in profound changes of the gene expression program. In particular, genes previously reported to be induced upon HSC activation, such as PAI-1, were mostly down-regulated following ADAMTS12 knock-down. The phenotype of these cells was changed to a less differentiated state, showing an altered actin network and decreased nuclear spreading. These phenotypic changes, together with the down-regulation of PAI-1, were offset by TGF-β treatment. The present study thus identifies ADAMTS12 as a modulator of HSC differentiation, and a new player in chronic liver disease.
Topics: Humans; Liver Cirrhosis; Carcinoma, Hepatocellular; Carbon Tetrachloride; Plasminogen Activator Inhibitor 1; Liver Neoplasms; Liver; Metalloproteases; Hepatic Stellate Cells; ADAMTS Proteins
PubMed: 37819632
DOI: 10.1096/fj.202200692RRRR -
Journal of Diabetes Jun 2022As a type 1 transmembrane protein, a disintegrin and metalloprotease 10 (ADAM10) is responsible for the cleavage of a variety of cell surface molecules and has been...
BACKGROUND
As a type 1 transmembrane protein, a disintegrin and metalloprotease 10 (ADAM10) is responsible for the cleavage of a variety of cell surface molecules and has been implicated in the pathogenesis of Alzheimer disease, atherosclerosis, and inflammatory and neoplastic disorders. It has been suggested that systemic ADAM10 concentration may potentially be used as a prognostic biomarker. Since high glucose can upregulate ADAM10 expression in vitro, we investigated whether serum levels of ADAM10 and its substrate, the lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1), can be influenced by type 2 diabetes.
METHODS
A total of 1091 individuals with type 2 diabetes and 358 age-matched healthy control subjects were recruited. Serum concentrations of ADAM10 and the soluble form of LOX-1 (sLOX-1) released by cleavage of LOX-1 by ADAM were measured by enzyme-linked immunosorbent assay kits (ELISA).
RESULTS
Serum ADAM10 was increased in subjects with diabetes compared with control (40.5 ng/mL [22.3-65.7] vs 10.3 ng/mL [7.0-17.9], respectively; P < .01); the highest levels were seen in insulin-treated subjects. On multiple linear regression analysis, glycosylated hemoglobin, age, body mass index, and insulin use were independent determinants of ADAM10 level. The increase in serum ADAM10 levels in diabetes was accompanied by changes in serum sLOX-1. Subjects with diabetes had higher serum sLOX-1 than the control (110 pg/mL [89-153] vs 104 pg/mL [85-138], respectively; P < .01), and there was a significant correlation between serum ADAM10 and sLOX-1 (r = 0.26, P < .01).
CONCLUSIONS
Serum concentration of ADAM10 is increased in type 2 diabetes and is associated with glycemia and insulin therapy, which may potentially affect the specificity of systemic ADAM10 level as a biomarker.
Topics: Biomarkers; Diabetes Mellitus, Type 2; Disintegrins; Humans; Insulins; Metalloproteases; Scavenger Receptors, Class E
PubMed: 35705192
DOI: 10.1111/1753-0407.13287 -
Frontiers in Immunology 2022CD95L (also known as FasL or CD178) is a member of the tumor necrosis family (TNF) superfamily. Although this transmembrane ligand has been mainly considered as a potent... (Review)
Review
CD95L (also known as FasL or CD178) is a member of the tumor necrosis family (TNF) superfamily. Although this transmembrane ligand has been mainly considered as a potent apoptotic inducer in CD95 (Fas)-expressing cells, more recent studies pointed out its role in the implementation of non-apoptotic signals. Accordingly, this ligand has been associated with the aggravation of inflammation in different auto-immune disorders and in the metastatic occurrence in different cancers. Although it remains to decipher all key factors involved in the ambivalent role of this ligand, accumulating clues suggest that while the membrane bound CD95L triggers apoptosis, its soluble counterpart generated by metalloprotease-driven cleavage is responsible for its non-apoptotic functions. Nonetheless, the metalloproteases (MMPs and ADAMs) involved in the CD95L shedding, the cleavage sites and the different stoichiometries and functions of the soluble CD95L remain to be elucidated. To better understand how soluble CD95L triggers signaling pathways from apoptosis to inflammation or cell migration, we propose herein to summarize the different metalloproteases that have been described to be able to shed CD95L, their cleavage sites and the biological functions associated with the released ligands. Based on these new findings, the development of CD95/CD95L-targeting therapeutics is also discussed.
Topics: Humans; Fas Ligand Protein; Ligands; fas Receptor; Metalloproteases; Signal Transduction; Neoplasms; Inflammation
PubMed: 36544756
DOI: 10.3389/fimmu.2022.1074099 -
Cancer Letters Dec 2019ADAM proteases are multi domain transmembrane metalloproteases that cleave a range of cell surface proteins and activate signaling pathways implicated in tumor... (Review)
Review
ADAM proteases are multi domain transmembrane metalloproteases that cleave a range of cell surface proteins and activate signaling pathways implicated in tumor progression, including those mediated by Notch, EFGR, and the Eph receptors. Consequently, they have emerged as key therapeutic targets in the efforts to inhibit tumor initiation and progression. To that end, two main approaches have been taken to develop ADAM antagonists: (i) small molecule inhibitors, and (ii) monoclonal antibodies. In this mini-review we describe the distinct features of ADAM proteases, particularly of ADAM10 and ADAM17, their domain organization, conformational rearrangements, regulation, as well as their emerging importance as therapeutic targets in cancer. Further, we highlight an anti-ADAM10 monoclonal antibody that we have recently developed, which has shown significant promise in inhibiting Notch signaling and deterring growth of solid tumors in pre-clinical settings.
Topics: ADAM Proteins; ADAM10 Protein; ADAM17 Protein; Animals; Antineoplastic Agents, Immunological; Catalytic Domain; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; Protein Conformation; Protein Domains
PubMed: 31593799
DOI: 10.1016/j.canlet.2019.10.003 -
Toxins Jan 2020The active components of snake venoms encompass a complex and variable mixture of proteins that produce a diverse, but largely stereotypical, range of pharmacologic... (Review)
Review
The active components of snake venoms encompass a complex and variable mixture of proteins that produce a diverse, but largely stereotypical, range of pharmacologic effects and toxicities. Venom protein diversity and host susceptibilities determine the relative contributions of five main pathologies: neuromuscular dysfunction, inflammation, coagulopathy, cell/organ injury, and disruption of homeostatic mechanisms of normal physiology. In this review, we describe how snakebite is not only a condition mediated directly by venom, but by the amplification of signals dysregulating inflammation, coagulation, neurotransmission, and cell survival. Although venom proteins are diverse, the majority of important pathologic events following envenoming follow from a small group of enzyme-like activities and the actions of small toxic peptides. This review focuses on two of the most important enzymatic activities: snake venom phospholipases (svPLA) and snake venom metalloproteases (svMP). These two enzyme classes are adept at enabling venom to recruit homologous endogenous signaling systems with sufficient magnitude and duration to produce and amplify cell injury beyond what would be expected from the direct impact of a whole venom dose. This magnification produces many of the most acutely important consequences of envenoming as well as chronic sequelae. Snake venom PLAs and MPs enzymes recruit prey analogs of similar activity. The transduction mechanisms that recruit endogenous responses include arachidonic acid, intracellular calcium, cytokines, bioactive peptides, and possibly dimerization of venom and prey protein homologs. Despite years of investigation, the precise mechanism of svPLA-induced neuromuscular paralysis remains incomplete. Based on recent studies, paralysis results from a self-amplifying cycle of endogenous PLA activation, arachidonic acid, increases in intracellular Ca and nicotinic receptor deactivation. When prolonged, synaptic suppression supports the degeneration of the synapse. Interaction between endothelium-damaging MPs, sPLAs and hyaluronidases enhance venom spread, accentuating venom-induced neurotoxicity, inflammation, coagulopathy and tissue injury. Improving snakebite treatment requires new tools to understand direct and indirect effects of envenoming. Homologous PLA and MP activities in both venoms and prey/snakebite victim provide molecular targets for non-antibody, small molecule agents for dissecting mechanisms of venom toxicity. Importantly, these tools enable the separation of venom-specific and prey-specific pathological responses to venom.
Topics: Animals; Blood Coagulation; Humans; Inflammation; Metalloproteases; Phospholipases A2, Secretory; Reptilian Proteins; Signal Transduction; Snake Venoms
PubMed: 31979014
DOI: 10.3390/toxins12020068