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Endocrine Reviews Nov 2023Pregnancy-associated plasma protein-A (PAPP-A) was first identified in the early 1970s as a placental protein of unknown function, present at high concentrations in the... (Review)
Review
Pregnancy-associated plasma protein-A (PAPP-A) was first identified in the early 1970s as a placental protein of unknown function, present at high concentrations in the circulation of pregnant women. In the mid-to-late 1990s, PAPP-A was discovered to be a metzincin metalloproteinase, expressed by many nonplacental cells, that regulates local insulin-like growth factor (IGF) activity through cleavage of high-affinity IGF binding proteins (IGFBPs), in particular IGFBP-4. With PAPP-A as a cell surface-associated enzyme, the reduced affinity of the cleavage fragments results in increased IGF available to bind and activate IGF receptors in the pericellular environment. This proteolytic regulation of IGF activity is important, since the IGFs promote proliferation, differentiation, migration, and survival in various normal and cancer cells. Thus, there has been a steady growth in investigation of PAPP-A structure and function outside of pregnancy. This review provides historical perspective on the discovery of PAPP-A and its structure and cellular function, highlights key studies of the first 50 years in PAPP-A research, and introduces new findings from recent years.
Topics: Pregnancy; Humans; Female; Pregnancy-Associated Plasma Protein-A; Placenta; Metalloproteases; Cell Differentiation; Insulin-Like Growth Factor I
PubMed: 37267421
DOI: 10.1210/endrev/bnad017 -
Archives of Toxicology Jun 2022Tetanus and botulinum neurotoxins cause the neuroparalytic syndromes of tetanus and botulism, respectively, by delivering inside different types of neurons,... (Review)
Review
Tetanus and botulinum neurotoxins cause the neuroparalytic syndromes of tetanus and botulism, respectively, by delivering inside different types of neurons, metalloproteases specifically cleaving the SNARE proteins that are essential for the release of neurotransmitters. Research on their mechanism of action is intensively carried out in order to devise improved therapies based on antibodies and chemical drugs. Recently, major results have been obtained with human monoclonal antibodies and with single chain antibodies that have allowed one to neutralize the metalloprotease activity of botulinum neurotoxin type A1 inside neurons. In addition, a method has been devised to induce a rapid molecular evolution of the metalloprotease domain of botulinum neurotoxin followed by selection driven to re-target the metalloprotease activity versus novel targets with respect to the SNARE proteins. At the same time, an intense and wide spectrum clinical research on novel therapeutics based on botulinum neurotoxins is carried out, which are also reviewed here.
Topics: Botulinum Toxins, Type A; Clostridium botulinum; Humans; Neurotoxins; SNARE Proteins; Tetanus
PubMed: 35333944
DOI: 10.1007/s00204-022-03271-9 -
General and Comparative Endocrinology Dec 2021Changes in expression or activation of various metalloproteases including matrix metalloproteases (Mmp), a disintegrin and metalloprotease (Adam) and a disintegrin and... (Review)
Review
Changes in expression or activation of various metalloproteases including matrix metalloproteases (Mmp), a disintegrin and metalloprotease (Adam) and a disintegrin and metalloprotease with thrombospondin motif (Adamts), and their endogenous inhibitors (tissue inhibitors of metalloproteases, Timp), have been shown to be critical for ovulation in various species from studies in past decades. Some of these metalloproteases such as Adamts1, Adamts9, Mmp2, and Mmp9 have also been shown to be regulated by luteinizing hormone (LH) and/or progestin, which are essential triggers for ovulation in all vertebrate species. Most of these metalloproteases also express broadly in various tissues and cells including germ cells and somatic gonad cells. Thus, metalloproteases likely play roles in gonad formation processes comprising primordial germ cell (PGC) migration, development of germ and somatic cells, and sex determination. However, our knowledge on the functions and mechanisms of metalloproteases in these processes in vertebrates is still lacking. This review will summarize our current knowledge on the metalloproteases in ovulation and gonad formation with emphasis on PGC migration and germ cell development.
Topics: Animals; Female; Germ Cells; Gonads; Luteinizing Hormone; Matrix Metalloproteinases; Ovulation
PubMed: 34606745
DOI: 10.1016/j.ygcen.2021.113924 -
European Journal of Pharmacology Dec 2017Atherosclerosis underlies most cardiovascular diseases, and is accepted as a primary cause of mortality worldwide. Proteases have been implicated in the development and... (Review)
Review
Atherosclerosis underlies most cardiovascular diseases, and is accepted as a primary cause of mortality worldwide. Proteases have been implicated in the development and progression of atherosclerosis, due to their ability to provoke focal destruction of the vascular extracellular matrix. Members of the metalloproteinase family, especially matrix metalloproteinases (MMPs), and their endogenous tissue inhibitors (TIMPs) have been suggested to perform complex dual roles during late-stage progression and rupture of atherosclerotic plaques. Proposed favourable actions of metalloproteinases include the promotion of vascular smooth muscle growth and survival which stabilises plaques, while conversely extracellular matrix destruction alongside interminable monocyte/macrophage accumulation can encourage plaque rupture. This review provides a summary of the cogent evidence connecting the contribution of individual metalloproteinases to atherosclerotic plaque development, progression, and instability. Topics discussed include structural, functional and cell-specific diversity of MMP members; evidence from animal models of atherosclerosis and comparisons with findings in humans; the dual role of MMPs and the requirement to selectively target individual MMPs; and the need for efficient surrogate markers of MMP inhibition. Accordingly, as our knowledge of the complex roles individual MMPs play especially during the progression and rupture of atherosclerotic plaques expands, new impetus is required for clinical trials evaluating the therapeutic potential of selective MMP inhibition, which could limit cardiovascular morbidity and mortality worldwide.
Topics: Animals; Atherosclerosis; Humans; Metalloproteases
PubMed: 28893577
DOI: 10.1016/j.ejphar.2017.09.007 -
Cellular and Molecular Life Sciences :... Aug 2019'A disintegrin and metalloproteases' (ADAMs) are a family of transmembrane proteins with diverse functions in multicellular organisms. About half of the ADAMs are active... (Review)
Review
'A disintegrin and metalloproteases' (ADAMs) are a family of transmembrane proteins with diverse functions in multicellular organisms. About half of the ADAMs are active metalloproteases and cleave numerous cell surface proteins, including growth factors, receptors, cytokines and cell adhesion proteins. The other ADAMs have no catalytic activity and function as adhesion proteins or receptors. Some ADAMs are ubiquitously expressed, others are expressed tissue specifically. This review highlights functions of ADAMs in the mammalian nervous system, including their links to diseases. The non-proteolytic ADAM11, ADAM22 and ADAM23 have key functions in neural development, myelination and synaptic transmission and are linked to epilepsy. Among the proteolytic ADAMs, ADAM10 is the best characterized one due to its substrates Notch and amyloid precursor protein, where cleavage is required for nervous system development or linked to Alzheimer's disease (AD), respectively. Recent work demonstrates that ADAM10 has additional substrates and functions in the nervous system and its substrate selectivity may be regulated by tetraspanins. New roles for other proteolytic ADAMs in the nervous system are also emerging. For example, ADAM8 and ADAM17 are involved in neuroinflammation. ADAM17 additionally regulates neurite outgrowth and myelination and its activity is controlled by iRhoms. ADAM19 and ADAM21 function in regenerative processes upon neuronal injury. Several ADAMs, including ADAM9, ADAM10, ADAM15 and ADAM30, are potential drug targets for AD. Taken together, this review summarizes recent progress concerning substrates and functions of ADAMs in the nervous system and their use as drug targets for neurological and psychiatric diseases.
Topics: ADAM Proteins; Animals; Biological Transport; Epilepsy; Humans; Inflammation; Myelin Sheath; Nervous System; Potassium Channels; Proteolysis
PubMed: 31236626
DOI: 10.1007/s00018-019-03173-7 -
Current Protocols in Protein Science Feb 2016Substrate cleavage by metalloproteinases involves nucleophilic attack on the scissile peptide bond by a water molecule that is polarized by a catalytic metal, usually a... (Review)
Review
Substrate cleavage by metalloproteinases involves nucleophilic attack on the scissile peptide bond by a water molecule that is polarized by a catalytic metal, usually a zinc ion, and a general base, usually the carboxyl group of a glutamic acid side chain. The zinc ion is most often complexed by imidazole nitrogens of histidine side chains. This arrangement suggests that the physiological pH optimum of most metalloproteinases is in the neutral range. In addition to their catalytic metal ion, many metalloproteinases contain additional transition metal or alkaline earth ions, which are structurally important or modulate the catalytic activity. As a consequence, these enzymes are generally sensitive to metal chelators. Moreover, the catalytic metal can be displaced by adventitious metal ions from buffers or biological fluids, which may fundamentally alter the catalytic function. Therefore, handling, purification, and assaying of metalloproteinases require specific precautions to warrant their stability.
Topics: Animals; Catalysis; Glutamic Acid; Humans; Hydrogen-Ion Concentration; Metalloproteases; Zinc
PubMed: 26836407
DOI: 10.1002/0471140864.ps2116s83 -
Methods in Molecular Biology (Clifton,... 2020The ADAMTS superfamily comprises secreted metalloproteases (ADAMTS proteases) as well as structurally related secreted glycoproteins that lack catalytic activity... (Review)
Review
The ADAMTS superfamily comprises secreted metalloproteases (ADAMTS proteases) as well as structurally related secreted glycoproteins that lack catalytic activity (ADAMTS-like proteins). Members of both families participate in diverse morphogenetic processes during embryonic development, and connective tissue maintenance and hemostasis in the adult. Several ADAMTS proteins are heavily implicated in genetic and acquired human and animal disorders. Despite these indicators of a profound biological and medical importance, detailed knowledge about their molecular structures, substrates, biological pathways, and biochemical mechanisms is significantly limited by unique intrinsic characteristics, which have led to several technical challenges. As a group, they are larger, more heavily modified, and harder to purify than other secreted proteases. In addition, idiosyncratic aspects of individual members are deserving of further investigation but can complicate their analysis. Here, some of the key concepts, challenges, and prospects in ADAMTS research are discussed in the context of the knowledge accumulated over the past two decades. Individual chapters in this volume of Methods in Molecular Biology provide practical solutions for surmounting these challenges. Since the biology of a protease is actually the biology of its substrates, there is considerable emphasis on purification of recombinant ADAMTS proteins, identification of their substrates and assays for their proteolytic activity.
Topics: ADAMTS Proteins; Animals; Humans; Mice; Proteolysis; Substrate Specificity
PubMed: 31463898
DOI: 10.1007/978-1-4939-9698-8_1 -
Nature Reviews. Nephrology Aug 2021Matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinases (ADAMs) belong to the metzincin family of zinc-containing multidomain molecules, and can act as... (Review)
Review
Matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinases (ADAMs) belong to the metzincin family of zinc-containing multidomain molecules, and can act as soluble or membrane-bound proteases. These enzymes inactivate or activate other soluble or membrane-expressed mediator molecules, which enables them to control developmental processes, tissue remodelling, inflammatory responses and proliferative signalling pathways. The dysregulation of MMPs and ADAMs has long been recognized in acute kidney injury and in chronic kidney disease, and genetic targeting of selected MMPs and ADAMs in different mouse models of kidney disease showed that they can have detrimental and protective roles. In particular, MMP-2, MMP-7, MMP-9, ADAM10 and ADAM17 have been shown to have a mainly profibrotic effect and might therefore represent therapeutic targets. Each of these proteases has been associated with a different profibrotic pathway that involves tissue remodelling, Wnt-β-catenin signalling, stem cell factor-c-kit signalling, IL-6 trans-signalling or epidermal growth factor receptor (EGFR) signalling. Broad-spectrum metalloproteinase inhibitors have been used to treat fibrotic kidney diseases experimentally but more targeted approaches have since been developed, including inhibitory antibodies, to avoid the toxic side effects initially observed with broad-spectrum inhibitors. These advances not only provide a solid foundation for additional preclinical studies but also encourage further translation into clinical research.
Topics: ADAM Proteins; Animals; Humans; Kidney; Kidney Diseases; Matrix Metalloproteinases; Metabolic Networks and Pathways; Metalloproteases
PubMed: 33879883
DOI: 10.1038/s41581-021-00415-5 -
Trends in Immunology Nov 2019Hematopoietic stem cells (HSCs) self-renew or differentiate into blood cell lineages following extrinsic cues propagated in specialized niches. Support cells and soluble... (Review)
Review
Hematopoietic stem cells (HSCs) self-renew or differentiate into blood cell lineages following extrinsic cues propagated in specialized niches. Support cells and soluble factors in the niche respond to stress and enable progenitor activity. Metalloproteases (MMPs, ADAMs, ADAMTSs) and their inhibitors (TIMPs) control certain physical and biochemical features of the niche by altering protease-dependent bioavailability of local niche factors (e.g., CXCL12, SCF, TGFβ, VEGF), matrix turnover, and cellular interactions. With over 40 examples of diverse metalloprotease substrates known to trigger fate-changing decisions, the spatially confined activity of this multi-member protease family is ideally positioned to constitute a higher order control over hematopoiesis. Comprehension of regulated proteolysis in the bone marrow may fuel innovative strategies to harness HSC fate and function.
Topics: Animals; Cell Differentiation; Cell Self Renewal; Extracellular Matrix; Hematopoiesis; Hematopoietic Stem Cells; Humans; Metalloproteases; Proteolysis; Stem Cell Niche
PubMed: 31645297
DOI: 10.1016/j.it.2019.09.006 -
Journal of Neuroscience Research Apr 2018The brain extracellular matrix (ECM) plays a crucial role in both the developing and adult brain by providing structural support and mediating cell-cell interactions. In... (Review)
Review
The brain extracellular matrix (ECM) plays a crucial role in both the developing and adult brain by providing structural support and mediating cell-cell interactions. In this review, we focus on the major constituents of the ECM and how they function in both normal and injured brain, and summarize the changes in the composition of the ECM as well as how these changes either promote or inhibit recovery of function following traumatic brain injury (TBI). Modulation of ECM composition to facilitates neuronal survival, regeneration and axonal outgrowth is a potential therapeutic target for TBI treatment.
Topics: Brain Injuries, Traumatic; Extracellular Matrix; Extracellular Matrix Proteins; Metalloproteases; Proteoglycans; Tenascin
PubMed: 29344975
DOI: 10.1002/jnr.24151