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International Journal of Molecular... Feb 2021The ability of cells to promote plasminogen activation on their surfaces is now well recognized, and several distinct cell surface proteins have been demonstrated to... (Review)
Review
The ability of cells to promote plasminogen activation on their surfaces is now well recognized, and several distinct cell surface proteins have been demonstrated to function as plasminogen receptors. Here, we review studies demonstrating that plasminogen bound to cells, in addition to plasminogen directly bound to fibrin, plays a major role in regulating fibrin surveillance. We focus on the ability of specific plasminogen receptors on eukaryotic cells to promote fibrinolysis in the in vivo setting by reviewing data obtained predominantly in murine models. Roles for distinct plasminogen receptors in fibrin surveillance in intravascular fibrinolysis, immune cell recruitment in the inflammatory response, wound healing, and lactational development are discussed.
Topics: Animals; Fibrin; Fibrinolysis; Humans; Plasminogen; Receptors, Cell Surface
PubMed: 33567773
DOI: 10.3390/ijms22041712 -
Blood May 2021Plasminogen is an abundant plasma protein that exists in various zymogenic forms. Plasmin, the proteolytically active form of plasminogen, is known for its essential... (Review)
Review
Plasminogen is an abundant plasma protein that exists in various zymogenic forms. Plasmin, the proteolytically active form of plasminogen, is known for its essential role in fibrinolysis. To date, therapeutic targeting of the fibrinolytic system has been for 2 purposes: to promote plasmin generation for thromboembolic conditions or to stop plasmin to reduce bleeding. However, plasmin and plasminogen serve other important functions, some of which are unrelated to fibrin removal. Indeed, for >40 years, the antifibrinolytic agent tranexamic acid has been administered for its serendipitously discovered skin-whitening properties. Plasmin also plays an important role in the removal of misfolded/aggregated proteins and can trigger other enzymatic cascades, including complement. In addition, plasminogen, via binding to one of its dozen cell surface receptors, can modulate cell behavior and further influence immune and inflammatory processes. Plasminogen administration itself has been reported to improve thrombolysis and to accelerate wound repair. Although many of these more recent findings have been derived from in vitro or animal studies, the use of antifibrinolytic agents to reduce bleeding in humans has revealed additional clinically relevant consequences, particularly in relation to reducing infection risk that is independent of its hemostatic effects. The finding that many viruses harness the host plasminogen to aid infectivity has suggested that antifibrinolytic agents may have antiviral benefits. Here, we review the broadening role of the plasminogen-activating system in physiology and pathophysiology and how manipulation of this system may be harnessed for benefits unrelated to its conventional application in thrombosis and hemostasis.
Topics: Animals; Antifibrinolytic Agents; Brain; Conjunctivitis; Enzyme Activation; Fibrin; Fibrinolysin; Fibrinolysis; Fibrinolytic Agents; Humans; Immunity; Infections; Inflammation; Mice; Plasminogen; Radiodermatitis; Receptors, Cell Surface; Skin Diseases, Genetic; Thrombosis; Tranexamic Acid; Wound Healing; Wounds and Injuries
PubMed: 33735914
DOI: 10.1182/blood.2020008951 -
Journal of Thrombosis and Haemostasis :... Oct 2020Plg-R is a structurally unique transmembrane plasminogen receptor with both N- and C-terminal domains exposed on the extracellular face of the cell. Its C-terminal... (Review)
Review
Plg-R is a structurally unique transmembrane plasminogen receptor with both N- and C-terminal domains exposed on the extracellular face of the cell. Its C-terminal lysine functions to tether plasminogen to cell surfaces. Overexpression of Plg-R increases cell surface plasminogen binding capacity while genetic deletion of Plg-R decreases plasminogen binding. Plasminogen binding to Plg-R results in promotion of plasminogen activation to the broad spectrum serine protease plasmin. This function is promoted by the physical association of Plg-R with the urokinase receptor (uPAR). Plg-R is broadly expressed in cells and tissues throughout the organism and its sequence is remarkably conserved phylogenetically. Plg-R also is required for lactation and, thus, is necessary for survival of the species. This review provides an overview of established and emerging functions of Plg-R and highlights major roles for Plg-R in both the initiation and resolution of inflammation. While the roles for Plg-R in the inflammatory response are predominantly plasmin(ogen)-dependent, its role in lactation requires both plasminogen-dependent and plasminogen-independent mechanisms. Furthermore, the functions of Plg-R are dependent on sex. In view of the broad tissue distribution of Plg-R , its role in a broad array of physiological and pathological processes should provide a fruitful area for future investigation.
Topics: Cell Membrane; Female; Fibrinolysin; Humans; Inflammation; Plasminogen
PubMed: 32662180
DOI: 10.1111/jth.15014 -
Journal of Biomedicine & Biotechnology 2012Plasminogen and plasmin tether to cell surfaces through ubiquitously expressed and structurally quite dissimilar family of proteins, as well as some nonproteins, that... (Review)
Review
Plasminogen and plasmin tether to cell surfaces through ubiquitously expressed and structurally quite dissimilar family of proteins, as well as some nonproteins, that are collectively referred to as plasminogen receptors. Of the more than one dozen plasminogen receptors that have been identified, many have been shown to facilitate plasminogen activation to plasmin and to protect bound plasmin from inactivation by inhibitors. The generation of such localized and sustained protease activity is utilized to facilitate numerous cellular responses, including responses that depend on cellular migration. However, many cells express multiple plasminogen receptors and numerous plasminogen receptors are expressed on many different cell types. Furthermore, several different plasminogen receptors can be used to support the same cellular response, such as inflammatory cell migration. Here, we discuss the perplexing issue: why are there so many different Plg-Rs?
Topics: Animals; Apoptosis; Endothelial Cells; Histones; Humans; Organ Specificity; Plasminogen; Receptors, Urokinase Plasminogen Activator
PubMed: 23118495
DOI: 10.1155/2012/141806 -
Blood Jan 2021Plasminogen activation rates are enhanced by cell surface binding. We previously demonstrated that exogenous plasminogen binds to phosphatidylserine-exposing and spread...
Plasminogen activation rates are enhanced by cell surface binding. We previously demonstrated that exogenous plasminogen binds to phosphatidylserine-exposing and spread platelets. Platelets contain plasminogen in their α-granules, but secretion of plasminogen from platelets has not been studied. Recently, a novel transmembrane lysine-dependent plasminogen receptor, Plg-RKT, has been described on macrophages. Here, we analyzed the pool of plasminogen in platelets and examined whether platelets express Plg-RKT. Plasminogen content of the supernatant of resting and collagen/thrombin-stimulated platelets was similar. Pretreatment with the lysine analog, ε-aminocaproic acid, significantly increased platelet-derived plasminogen (0.33 vs 0.08 nmol/108 platelets) in the stimulated supernatant, indicating a lysine-dependent mechanism of membrane retention. Lysine-dependent, platelet-derived plasminogen retention on thrombin and convulxin activated human platelets was confirmed by flow cytometry. Platelets initiated fibrinolytic activity in fluorescently labeled plasminogen-deficient clots and in turbidimetric clot lysis assays. A 17-kDa band, consistent with Plg-RKT, was detected in the platelet membrane fraction by western blotting. Confocal microscopy of stimulated platelets revealed Plg-RKT colocalized with platelet-derived plasminogen on the activated platelet membrane. Plasminogen exposure was significantly attenuated in thrombin- and convulxin-stimulated platelets from Plg-RKT-/- mice compared with Plg-RKT+/+ littermates. Membrane exposure of Plg-RKT was not dependent on plasminogen, as similar levels of the receptor were detected in plasminogen-/- platelets. These data highlight Plg-RKT as a novel plasminogen receptor in human and murine platelets. We show for the first time that platelet-derived plasminogen is retained on the activated platelet membrane and drives local fibrinolysis by enhancing cell surface-mediated plasminogen activation.
Topics: Animals; Blood Platelets; Humans; Mice; Plasminogen; Platelet Activation; Receptors, Cell Surface
PubMed: 32842150
DOI: 10.1182/blood.2020007263 -
The Journal of Experimental Medicine Apr 2020Plasminogen and its active form, plasmin, have diverse functions related to the inflammatory response in mammals. Due to these roles in inflammation, plasminogen has... (Review)
Review
Plasminogen and its active form, plasmin, have diverse functions related to the inflammatory response in mammals. Due to these roles in inflammation, plasminogen has been implicated in the progression of a wide range of diseases with an inflammatory component. In this review, we discuss the functions of plasminogen in inflammatory regulation and how this system plays a role in the pathogenesis of diseases spanning organ systems throughout the body.
Topics: Animals; Disease Progression; Fibrinolysin; Humans; Inflammation; Plasminogen
PubMed: 32159743
DOI: 10.1084/jem.20191865 -
Blood May 2022
Topics: Angioedemas, Hereditary; Bradykinin; Fibrinolysis; Glutamic Acid; Humans; Lysine; Plasminogen
PubMed: 35511189
DOI: 10.1182/blood.2022015610 -
Frontiers in Immunology 2022Bovine mycoplasmosis is an important infectious disease of cattle caused by () which poses a serious threat to the breeding industry. Adhesin is involved in the initial... (Review)
Review
Bovine mycoplasmosis is an important infectious disease of cattle caused by () which poses a serious threat to the breeding industry. Adhesin is involved in the initial process of colonization, which is closely related to the infection, cell invasion, immune escape and virulence of this pathogenic microorganism. For the reason that lacks a cell wall, its adhesin is predominantly located on the surface of the cell membrane. The adhesins of are usually identified by adhesion and adhesion inhibition analysis, and more than 10 adhesins have been identified so far. These adhesins primarily bind to plasminogen, fibronectin, heparin and amyloid precursor-like protein-2 of host cells. This review aims to concisely summarize the current knowledge regarding the adhesins of and their target proteins of the host cell. Additionally, the biological characteristics of the adhesin will be briefly analyzed.
Topics: Cattle; Animals; Mycoplasma bovis; Adhesins, Bacterial; Mycoplasma Infections; Cattle Diseases; Plasminogen
PubMed: 36341375
DOI: 10.3389/fimmu.2022.1016641 -
Journal of Biomedicine & Biotechnology 2012The local environment of neurosecretory cells contains the major components of the plasminogen activation system, including the plasminogen activators, tissue... (Review)
Review
The local environment of neurosecretory cells contains the major components of the plasminogen activation system, including the plasminogen activators, tissue plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA), as well as binding sites for t-PA, the receptor for u-PA (uPAR), and also the plasminogen activator inhibitor, PAI-1. Furthermore, these cells express specific binding sites for plasminogen, which is available in the circulation and in interstitial fluid. Colocalization of plasminogen and its activators on cell surfaces provides a mechanism for promoting local plasminogen activation. Plasmin is retained on the cell surface where it is protected from its inhibitor, α(2)-antiplasmin. In neurosecretory cells, localized plasmin activity provides a mechanism for extracellular processing of secreted hormones. Neurotransmitter release from catecholaminergic cells is negatively regulated by cleavage products formed by plasmin-mediated proteolysis. Recently, we have identified a major plasminogen receptor, Plg-R(KT). We have found that Plg-R(KT) is highly expressed in chromaffin cells of the adrenal medulla as well as in other catecholaminergic cells and tissues. Plg-R(KT)-dependent plasminogen activation plays a key role in regulating catecholaminergic neurosecretory cell function.
Topics: Animals; Catecholamines; Feedback, Physiological; Humans; Neurosecretory Systems; Plasminogen; Plasminogen Activators
PubMed: 23097598
DOI: 10.1155/2012/721657 -
Arteriosclerosis, Thrombosis, and... Oct 2023High levels of Lp(a) (lipoprotein(a)) are associated with multiple forms of cardiovascular disease. Lp(a) consists of an apoB-containing particle attached to the...
BACKGROUND
High levels of Lp(a) (lipoprotein(a)) are associated with multiple forms of cardiovascular disease. Lp(a) consists of an apoB-containing particle attached to the plasminogen homologue apo(a). The pathways for Lp(a) clearance are not well understood. We previously discovered that the plasminogen receptor PlgRKT (plasminogen receptor with a C-terminal lysine) promoted Lp(a) uptake in liver cells. Here, we aimed to further define the role of PlgRKT and to investigate the role of 2 other plasminogen receptors, annexin A2 and S100A10 (S100 calcium-binding protein A10) in the endocytosis of Lp(a).
METHODS
Human hepatocellular carcinoma (HepG2) cells and haploid human fibroblast-like (HAP1) cells were used for overexpression and knockout of plasminogen receptors. The uptake of Lp(a), LDL (low-density lipoprotein), apo(a), and endocytic cargos was visualized and quantified by confocal microscopy and Western blotting.
RESULTS
The uptake of both Lp(a) and apo(a), but not LDL, was significantly increased in HepG2 and HAP1 cells overexpressing PlgRKT, annexin A2, or S100A10. Conversely, Lp(a) and apo(a), but not LDL, uptake was significantly reduced in HAP1 cells in which PlgRKT and S100A10 were knocked out. Surface binding studies in HepG2 cells showed that overexpression of PlgRKT, but not annexin A2 or S100A10, increased Lp(a) and apo(a) plasma membrane binding. Annexin A2 and S100A10, on the other hand, appeared to regulate macropinocytosis with both proteins significantly increasing the uptake of the macropinocytosis marker dextran when overexpressed in HepG2 and HAP1 cells and knockout of S100A10 significantly reducing dextran uptake. Bringing these observations together, we tested the effect of a PI3K (phosphoinositide-3-kinase) inhibitor, known to inhibit macropinocytosis, on Lp(a) uptake. Results showed a concentration-dependent reduction confirming that Lp(a) uptake was indeed mediated by macropinocytosis.
CONCLUSIONS
These findings uncover a novel pathway for Lp(a) endocytosis involving multiple plasminogen receptors that enhance surface binding and stimulate macropinocytosis of Lp(a). Although the findings were produced in cell culture models that have limitations, they could have clinical relevance since drugs that inhibit macropinocytosis are in clinical use, that is, the PI3K inhibitors for cancer therapy and some antidepressant compounds.
Topics: Humans; Plasminogen; Lipoprotein(a); Annexin A2; Dextrans; Phosphatidylinositol 3-Kinases; Carrier Proteins; Apolipoproteins A
PubMed: 37589135
DOI: 10.1161/ATVBAHA.123.319344