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Trends in Molecular Medicine Feb 2024Proteolytic processes on cell surfaces and extracellular matrix (ECM) sustain cell behavior and tissue integrity in health and disease. Matrix metalloproteases (MMPs)... (Review)
Review
Proteolytic processes on cell surfaces and extracellular matrix (ECM) sustain cell behavior and tissue integrity in health and disease. Matrix metalloproteases (MMPs) and a disintegrin and metalloproteases (ADAMs) remodel cell microenvironments through irreversible proteolysis of ECM proteins and cell surface bioactive molecules. Pan-MMP inhibitors in inflammation and cancer clinical trials have encountered challenges due to promiscuous activities of MMPs. Systems biology advances revealed that MMPs initiate multifactorial proteolytic cascades, creating new substrates, activating or suppressing other MMPs, and generating signaling molecules. This review highlights the intricate network that underscores the role of MMPs beyond individual substrate-enzyme activities. Gaining insight into MMP function and tissue specificity is crucial for developing effective drug discovery strategies and novel therapeutics. This requires considering the dynamic cellular processes and consequences of network proteolysis.
Topics: Humans; Proteolysis; Metalloproteases; Neoplasms; Extracellular Matrix; Inflammation; Tumor Microenvironment
PubMed: 38036391
DOI: 10.1016/j.molmed.2023.11.001 -
Science Advances Mar 2022Axonal fusion is an efficient means of repair following axonal transection, whereby the regenerating axon fuses with its own separated axonal fragment to restore...
Axonal fusion is an efficient means of repair following axonal transection, whereby the regenerating axon fuses with its own separated axonal fragment to restore neuronal function. Despite being described over 50 years ago, its molecular mechanisms remain poorly understood. Here, we demonstrate that the metalloprotease ADM-4, an ortholog of human ADAM17, is essential for axonal fusion. We reveal that animals lacking ADM-4 cannot repair their axons by fusion, and that ADM-4 has a cell-autonomous function within injured neurons, localizing at the tip of regrowing axon and fusion sites. We demonstrate that ADM-4 overexpression enhances fusion to levels higher than wild type, and that the metalloprotease and phosphatidylserine-binding domains are essential for its function. Last, we show that ADM-4 interacts with and stabilizes the fusogen EFF-1 to allow membranes to merge. Our results uncover a key role for ADM-4 in axonal fusion, exposing a molecular target for axonal repair.
Topics: Animals; ADAM17 Protein; Axons; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Membrane Glycoproteins; Metalloproteases
PubMed: 35294233
DOI: 10.1126/sciadv.abm2882 -
International Journal of Molecular... Aug 2021In the late 1980s, Paul Primakoff and colleagues showed that fertilization could be blocked in an in vitro sperm-egg fusion assay by inoculating them in the presence of...
In the late 1980s, Paul Primakoff and colleagues showed that fertilization could be blocked in an in vitro sperm-egg fusion assay by inoculating them in the presence of a disintegrin and metalloprotease (ADAM)-specific antibody [...].
Topics: ADAM Proteins; Animals; Humans; Inflammation; Neoplasms
PubMed: 34445468
DOI: 10.3390/ijms22168762 -
International Journal of Molecular... Nov 2021Endometrial cancer is one of the most common gynecological malignancies, yet the molecular mechanisms that lead to tumor development and progression are still not fully... (Review)
Review
Endometrial cancer is one of the most common gynecological malignancies, yet the molecular mechanisms that lead to tumor development and progression are still not fully established. Matrix metalloproteinases (MMPs) are a group of enzymes that play an important role in carcinogenesis. They are proteases involved in the degradation of the extracellular matrix (ECM) that surrounds the tumor and the affected tissue allows cell detachment from the primary tumor causing local invasion and metastasis formation. Recent investigations demonstrate significantly increased metalloproteinase and metalloproteinase inhibitor levels in patients with endometrial cancer compared to those with normal endometrium. In this review, we aim to show their clinical significance and possible use in the diagnosis and treatment of patients with endometrial cancer. We have critically summarized and reviewed the research on the role of MMPs in endometrial cancer.
Topics: Endometrial Neoplasms; Endometrium; Extracellular Matrix; Female; Gene Expression Regulation, Neoplastic; Humans; Metalloproteases
PubMed: 34830354
DOI: 10.3390/ijms222212472 -
Journal of Cardiovascular Pharmacology Jul 2017G protein-coupled receptors (GPCRs) comprise the largest family of receptors in humans. Traditional activation of GPCRs involves binding of a ligand to the receptor,... (Review)
Review
G protein-coupled receptors (GPCRs) comprise the largest family of receptors in humans. Traditional activation of GPCRs involves binding of a ligand to the receptor, activation of heterotrimeric G proteins and induction of subsequent signaling molecules. It is now known that GPCR signaling occurs through G protein-independent pathways including signaling through β-arrestin and transactivation of other receptor types. Generally, transactivation occurs when activation of one receptor leads to the activation of another receptor(s). GPCR-mediated transactivation is an essential component of GPCR signaling, as activation of other receptor types, such as receptor tyrosine kinases, allows GPCRs to expand their signal transduction and affect various cellular responses. Several mechanisms have been identified for receptor transactivation downstream of GPCRs, one of which involves activation of extracellular proteases, such as a disintegrin and metalloprotease, and matrix metalloproteases . These proteases cleave and release ligands that are then able to activate their respective receptors. A disintegrin and metalloprotease, and matrix metalloproteases can be activated via various mechanisms downstream of GPCR activation, including activation via second messenger, direct phosphorylation, or direct G protein interaction. Additional understanding of the mechanisms involved in GPCR-mediated protease activation and subsequent receptor transactivation could lead to identification of new therapeutic targets.
Topics: Animals; Extracellular Fluid; Humans; Matrix Metalloproteinases; Peptide Hydrolases; Receptors, G-Protein-Coupled; Signal Transduction; Transcriptional Activation
PubMed: 28195946
DOI: 10.1097/FJC.0000000000000475 -
Frontiers in Immunology 2022ADAM17 is a member of the a disintegrin and metalloproteinase (ADAM) family of transmembrane proteases involved in the shedding of some cell membrane proteins and... (Review)
Review
ADAM17 is a member of the a disintegrin and metalloproteinase (ADAM) family of transmembrane proteases involved in the shedding of some cell membrane proteins and regulating various signaling pathways. More than 90 substrates are regulated by ADAM17, some of which are closely relevant to tumor formation and development. Besides, ADAM17 is also responsible for immune regulation and its substrate-mediated signal transduction. Recently, ADAM17 has been considered as a major target for the treatment of tumors and yet its immunomodulatory roles and mechanisms remain unclear. In this paper, we summarized the recent understanding of structure and several regulatory roles of ADAM17. Importantly, we highlighted the immunomodulatory roles of ADAM17 in tumor development, as well as small molecule inhibitors and monoclonal antibodies targeting ADAM17.
Topics: Humans; Immunomodulation; Metalloproteases; Neoplasms; Antineoplastic Agents, Immunological; Antibodies, Monoclonal; ADAM17 Protein
PubMed: 36466812
DOI: 10.3389/fimmu.2022.1059376 -
Methods in Molecular Biology (Clifton,... 2017Metalloproteases, notably members of the matrix metalloprotease (MMP) and A Disintegrin And Metalloprotease (ADAM) families play crucial roles in tissue remodeling, the...
Metalloproteases, notably members of the matrix metalloprotease (MMP) and A Disintegrin And Metalloprotease (ADAM) families play crucial roles in tissue remodeling, the liberation of growth factors and cytokines from cell membranes (shedding) and cell-cell or cell-matrix interactions. Activity of MMPs or ADAMs must therefore be tightly controlled in time and space by activation of pro-enzymes upon appropriate stimuli and inhibition by endogenous tissue inhibitors of metalloproteases (TIMPs) or α-macroglobulin to prevent irreversible tissue damage due to excessive degradation or uncontrolled release of potent inflammatory mediators, such as tumor necrosis factor-α (TNF-α).Although there is a wide range of methods to measure the amount of metalloproteases based on immunological approaches, relatively little is known about the activation status of a given enzyme at any given time and location. This information is, however, critical in order to understand the function and possible implication of these enzymes in disease. Since metalloproteases use an active-site bound water molecule to cleave the peptide bond, it is not possible to apply known active-site-directed labeling approaches with electrophilic "warheads." We therefore developed novel metalloprotease inhibitors that contain a photoactivatable trifluoromethylphenyldiazirine group and show that such inhibitors are suitable for activity-dependent photoaffinity labeling of MMPs and ADAMs.
Topics: Animals; Cell Line, Tumor; Culture Media; Enzyme Activation; Humans; Inhibitory Concentration 50; Metalloproteases; Mice; Photoaffinity Labels; Tissue Inhibitor of Metalloproteinase-1; Tumor Necrosis Factor-alpha
PubMed: 27778284
DOI: 10.1007/978-1-4939-6439-0_8 -
Biochemical Society Transactions Aug 2017By interacting directly with partner proteins and with one another, tetraspanins organize a network of interactions referred to as the tetraspanin web. ADAM10 (A... (Review)
Review
By interacting directly with partner proteins and with one another, tetraspanins organize a network of interactions referred to as the tetraspanin web. ADAM10 (A Disintegrin And Metalloprotease 10), an essential membrane-anchored metalloprotease that cleaves off the ectodomain of a large variety of cell surface proteins including cytokines, adhesion molecules, the precursor of the β-amyloid peptide APP or Notch, has emerged as a major component of the tetraspanin web. Recent studies have shown that ADAM10 associates directly with all members (Tspan5, Tspan10, Tspan14, Tspan15, Tspan17 and Tspan33) of a subgroup of tetraspanins having eight cysteines in the large extracellular domain and referred to as TspanC8. All TspanC8 regulate ADAM10 exit from the endoplasmic reticulum, but differentially regulate its subsequent trafficking and its function, and have notably a different impact on Notch signaling. TspanC8 orthologs in invertebrates also regulate ADAM10 trafficking and Notch signaling. It may be possible to target TspanC8 tetraspanins to modulate in a tissue- or substrate-restricted manner ADAM10 function in pathologies such as cardiovascular diseases, cancer or Alzheimer's disease.
Topics: ADAM10 Protein; Amyloid Precursor Protein Secretases; Animals; Cysteine; Humans; Membrane Proteins; Models, Molecular; Mutation; Protein Interaction Domains and Motifs; Protein Multimerization; Protein Transport; Substrate Specificity; Tetraspanins
PubMed: 28687716
DOI: 10.1042/BST20160296 -
FEBS Letters Mar 2022Systemic inflammatory disorders (SIDs) comprise a broad range of diseases characterized by dysregulated excessive innate immune responses. Severe forms of SIDs can lead... (Review)
Review
Systemic inflammatory disorders (SIDs) comprise a broad range of diseases characterized by dysregulated excessive innate immune responses. Severe forms of SIDs can lead to organ failure and death, and their increasing incidence represents a major issue for the healthcare system. Protease-mediated ectodomain shedding of cytokines and their receptors represents a central mechanism in the regulation of inflammatory responses. The metalloprotease A disintegrin and metalloproteinase (ADAM) 17 is the best-characterized ectodomain sheddase capable of releasing TNF-α and soluble IL-6 receptor, which are decisive factors of systemic inflammation. Recently, meprin metalloproteases were also identified as IL-6 receptor sheddases and activators of the pro-inflammatory cytokines IL-1β and IL-18. In different mouse models of SID, particularly those mimicking a sepsis-like phenotype, ADAM17 and meprins have been found to promote disease progression. In this review, we summarize the role of ADAM10, ADAM17, and meprins in the onset and progression of sepsis and discuss their potential as therapeutic targets.
Topics: Animals; Mice; ADAM10 Protein; ADAM17 Protein; Amyloid Precursor Protein Secretases; Cytokines; Inflammation; Metalloproteases; Receptors, Interleukin-6; Sepsis; Tiopronin
PubMed: 34762736
DOI: 10.1002/1873-3468.14225 -
ELife Sep 2023The amyloid beta (Aβ) plaques found in Alzheimer's disease (AD) patients' brains contain collagens and are embedded extracellularly. Several collagens have been...
The amyloid beta (Aβ) plaques found in Alzheimer's disease (AD) patients' brains contain collagens and are embedded extracellularly. Several collagens have been proposed to influence Aβ aggregate formation, yet their role in clearance is unknown. To investigate the potential role of collagens in forming and clearance of extracellular aggregates in vivo, we created a transgenic strain that expresses and secretes human Aβ. This secreted Aβ forms aggregates in two distinct places within the extracellular matrix. In a screen for extracellular human Aβ aggregation regulators, we identified different collagens to ameliorate or potentiate Aβ aggregation. We show that a disintegrin and metalloprotease a disintegrin and metalloprotease 2 (ADM-2), an ortholog of ADAM9, reduces the load of extracellular Aβ aggregates. ADM-2 is required and sufficient to remove the extracellular Aβ aggregates. Thus, we provide in vivo evidence of collagens essential for aggregate formation and metalloprotease participating in extracellular Aβ aggregate removal.
Topics: Animals; Humans; Amyloid beta-Peptides; Caenorhabditis elegans; Peptide Hydrolases; Disintegrins; Alzheimer Disease; Endopeptidases; Plaque, Amyloid; Metalloproteases; Membrane Proteins; ADAM Proteins
PubMed: 37728486
DOI: 10.7554/eLife.83465