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Biomolecules Nov 2021The generation of the serine protease plasmin is initiated by the binding of its zymogenic precursor, plasminogen, to cell surface receptors. The proteolytic activity of... (Review)
Review
The generation of the serine protease plasmin is initiated by the binding of its zymogenic precursor, plasminogen, to cell surface receptors. The proteolytic activity of plasmin, generated at the cell surface, plays a crucial role in several physiological processes, including fibrinolysis, angiogenesis, wound healing, and the invasion of cells through both the basement membrane and extracellular matrix. The seminal observation by Albert Fischer that cancer cells, but not normal cells in culture, produce large amounts of plasmin formed the basis of current-day observations that plasmin generation can be hijacked by cancer cells to allow tumor development, progression, and metastasis. Thus, the cell surface plasminogen-binding receptor proteins are critical to generating plasmin proteolytic activity at the cell surface. This review focuses on one of the twelve well-described plasminogen receptors, S100A10, which, when in complex with its regulatory partner, annexin A2 (ANXA2), forms the ANXA2/S100A10 heterotetrameric complex referred to as AIIt. We present the theme that AIIt is the quintessential cellular plasminogen receptor since it regulates the formation and the destruction of plasmin. We also introduce the term to define those plasminogen receptors directly activated during cancer progression. We then discuss the research establishing AIIt as an oncogenic plasminogen receptor-regulated during EMT and activated by oncogenes such as SRC, RAS, HIF1α, and PML-RAR and epigenetically by DNA methylation. We further discuss the evidence derived from animal models supporting the role of S100A10 in tumor progression and oncogenesis. Lastly, we describe the potential of S100A10 as a biomarker for cancer diagnosis and prognosis.
Topics: Annexin A2; Biomarkers, Tumor; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Humans; Multiprotein Complexes; Neoplasms; Prognosis; S100 Proteins
PubMed: 34944416
DOI: 10.3390/biom11121772 -
The Journal of Biological Chemistry Jul 2022Plasmin is a broad-spectrum protease and therefore needs to be tightly regulated. Active plasmin is formed from plasminogen, which is found in high concentrations in the...
Plasmin is a broad-spectrum protease and therefore needs to be tightly regulated. Active plasmin is formed from plasminogen, which is found in high concentrations in the blood and is converted by the plasminogen activators. In the circulation, high levels of α2-antiplasmin rapidly and efficiently inhibit plasmin activity. Certain myeloid immune cells have been shown to bind plasmin and plasminogen on their cell surface via proteins that bind to the plasmin(ogen) kringle domains. Our earlier work showed that T cells can activate plasmin but that they do not themselves express plasminogen. Here, we demonstrate that T cells express several known plasminogen receptors and that they bind plasminogen on their cell surface. We show T cell-bound plasminogen was converted to plasmin by plasminogen activators upon T cell activation. To examine functional consequences of plasmin generation by activated T cells, we investigated its effect on the chemokine, C-C motif chemokine ligand 21 (CCL21). Video microscopy and Western blotting confirmed that plasmin bound by human T cells cleaves CCL21 and increases the chemotactic response of monocyte-derived dendritic cells toward higher CCL21 concentrations along the concentration gradient by increasing their directional migration and track straightness. These results demonstrate how migrating T cells and potentially other activated immune cells may co-opt a powerful proteolytic system from the plasma toward immune processes in the peripheral tissues, where α2-antiplasmin is more likely to be absent. We propose that plasminogen bound to migrating immune cells may strongly modulate chemokine responses in peripheral tissues.
Topics: Antifibrinolytic Agents; Chemokine CCL21; Chemokines; Dendritic Cells; Fibrinolysin; Humans; Ligands; Plasminogen; Plasminogen Activators; T-Lymphocytes; alpha-2-Antiplasmin
PubMed: 35690148
DOI: 10.1016/j.jbc.2022.102112 -
Cells Jan 2023The oral cavity is a unique environment that consists of teeth surrounded by periodontal tissues, oral mucosae with minor salivary glands, and terminal parts of major... (Review)
Review
The oral cavity is a unique environment that consists of teeth surrounded by periodontal tissues, oral mucosae with minor salivary glands, and terminal parts of major salivary glands that open into the oral cavity. The cavity is constantly exposed to viral and microbial pathogens. Recent studies indicate that components of the plasminogen (Plg)/plasmin (Pm) system are expressed in tissues of the oral cavity, such as the salivary gland, and contribute to microbial infection and inflammation, such as periodontitis. The Plg/Pm system fulfills two major functions: (a) the destruction of fibrin deposits in the bloodstream or damaged tissues, a process called fibrinolysis, and (b) non-fibrinolytic actions that include the proteolytic modulation of proteins. One can observe both functions during inflammation. The virus that causes the coronavirus disease 2019 (COVID-19) exploits the fibrinolytic and non-fibrinolytic functions of the Plg/Pm system in the oral cavity. During COVID-19, well-established coagulopathy with the development of microthrombi requires constant activation of the fibrinolytic function. Furthermore, viral entry is modulated by receptors such as TMPRSS2, which is necessary in the oral cavity, leading to a derailed immune response that peaks in cytokine storm syndrome. This paper outlines the significance of the Plg/Pm system for infectious and inflammatory diseases that start in the oral cavity.
Topics: Humans; COVID-19; Fibrinolysin; Inflammation; Mouth; Plasminogen; Tissue Plasminogen Activator
PubMed: 36766787
DOI: 10.3390/cells12030445 -
Microbiology and Molecular Biology... May 2021The spp. are tick-borne pathogenic spirochetes that include the agents of Lyme disease and relapsing fever. As part of their life cycle, the spirochetes traffic between... (Review)
Review
The spp. are tick-borne pathogenic spirochetes that include the agents of Lyme disease and relapsing fever. As part of their life cycle, the spirochetes traffic between the tick vector and the vertebrate host, which requires significant physiological changes and remodeling of their outer membranes and proteome. This crucial proteome resculpting is carried out by a diverse set of proteases, adaptor proteins, and related chaperones. Despite its small genome, has dedicated a large percentage of its genome to proteolysis, including a full complement of ATP-dependent proteases. Energy-driven proteolysis appears to be an important physiological feature of this dual-life-cycle bacterium. The proteolytic arsenal of is strategically deployed for disposal of proteins no longer required as they move from one stage to another or are transferred from one host to another. Likewise, the spp. are systemic organisms that need to break down and move through host tissues and barriers, and so their unique proteolytic resources, both endogenous and borrowed, make movement more feasible. Both the Lyme disease and relapsing fever spp. bind plasminogen as well as numerous components of the mammalian plasminogen-activating system. This recruitment capacity endows the spirochetes with a borrowed proteolytic competency that can lead to increased invasiveness.
Topics: Animals; Bacterial Proteins; Borrelia burgdorferi; Humans; Lyme Disease; Plasminogen; Proteolysis; Relapsing Fever
PubMed: 33980587
DOI: 10.1128/MMBR.00217-20 -
International Journal of Molecular... Sep 2022The coronavirus disease 2019 (COVID-19) pandemic has claimed the lives of millions of people around the world. Severe vitamin D deficiency can increase the risk of death... (Review)
Review
The coronavirus disease 2019 (COVID-19) pandemic has claimed the lives of millions of people around the world. Severe vitamin D deficiency can increase the risk of death in people with COVID-19. There is growing evidence that acute kidney injury (AKI) is common in COVID-19 patients and is associated with poorer clinical outcomes. The kidney effects of SARS-CoV-2 are directly mediated by angiotensin 2-converting enzyme (ACE2) receptors. AKI is also caused by indirect causes such as the hypercoagulable state and microvascular thrombosis. The increased release of soluble urokinase-type plasminogen activator receptor (suPAR) from immature myeloid cells reduces plasminogen activation by the competitive inhibition of urokinase-type plasminogen activator, which results in low plasmin levels and a fibrinolytic state in COVID-19. Frequent hypercoagulability in critically ill patients with COVID-19 may exacerbate the severity of thrombosis. Versican expression in proximal tubular cells leads to the proliferation of interstitial fibroblasts through the C3a and suPAR pathways. Vitamin D attenuates the local expression of podocyte uPAR and decreases elevated circulating suPAR levels caused by systemic inflammation. This decrease preserves the function and structure of the glomerular barrier, thereby maintaining renal function. The attenuated hyperinflammatory state reduces complement activation, resulting in lower serum C3a levels. Vitamin D can also protect against COVID-19 by modulating innate and adaptive immunity, increasing ACE2 expression, and inhibiting the renin-angiotensin-aldosterone system. We hypothesized that by reducing suPAR levels, appropriate vitamin D supplementation could prevent the progression and reduce the severity of AKI in COVID-19 patients, although the data available require further elucidation.
Topics: Acute Kidney Injury; Angiotensin-Converting Enzyme 2; Angiotensins; COVID-19; Fibrinolysin; Humans; Plasminogen; Receptors, Urokinase Plasminogen Activator; SARS-CoV-2; Thrombosis; Urokinase-Type Plasminogen Activator; Versicans; Vitamin D; Vitamins; COVID-19 Drug Treatment
PubMed: 36142634
DOI: 10.3390/ijms231810725 -
Journal of Thrombosis and Haemostasis :... Feb 2022To reestablish blood flow in vessels occluded by clots, tissue plasminogen activator (tPA) can be used; however, its efficacy is limited by transport to and into a clot...
BACKGROUND
To reestablish blood flow in vessels occluded by clots, tissue plasminogen activator (tPA) can be used; however, its efficacy is limited by transport to and into a clot and by the depletion of its substrate, plasminogen.
OBJECTIVES
To overcome these rate limitations, a platform was designed to co-deliver tPA and plasminogen based on microwheels (µwheels), wheel-like assemblies of superparamagnetic colloidal beads that roll along surfaces at high speeds.
METHODS
The biochemical speed limit was determined by measuring fibrinolysis of plasma clots at varying concentrations of tPA (10-800 nM) and plasminogen (1-6 µM). Biotinylated magnetic mesoporous silica nanoparticles were synthesized and bound to streptavidin-coated superparamagnetic beads to make studded beads. Studded beads were loaded with plasminogen and tPA was immobilized on their surface. Plasminogen release and tPA activity were measured on the studded beads. Studded beads were assembled into µwheels with rotating magnetic fields and fibrinolysis of plasma clots was measured in a microfluidic device.
RESULTS
The biochemical speed limit for plasma clots was ~15 µm/min. Plasminogen-loaded, tPA-immobilized µwheels lyse plasma clots at rates comparableto the biochemical speed limit. With the addition of a corkscrew motion, µwheels penetrate clots, thereby exceeding the biochemical speed limit (~20 µm/min) and achieving lysis rates 40-fold higher than 50 nM tPA.
CONCLUSIONS
Co-delivery of an immobilized enzyme and its substrate via a microbot capable of mechanical work has the potential to target and rapidly lyse clots that are inaccessible by mechanical thrombectomy devices or recalcitrant to systemic tPA delivery.
Topics: Drug Delivery Systems; Fibrin Clot Lysis Time; Fibrinolysis; Humans; Magnetic Iron Oxide Nanoparticles; Plasminogen; Thrombosis; Tissue Plasminogen Activator
PubMed: 34882946
DOI: 10.1111/jth.15617 -
Journal of Thrombosis and Haemostasis :... Mar 2022Plg-R , a unique transmembrane plasminogen receptor, enhances the activation of plasminogen to plasmin, and localizes the proteolytic activity of plasmin on the cell...
BACKGROUND
Plg-R , a unique transmembrane plasminogen receptor, enhances the activation of plasminogen to plasmin, and localizes the proteolytic activity of plasmin on the cell surface.
OBJECTIVES
We investigated the role of Plg-R in adipose function, metabolic homeostasis, and obesity.
METHODS
We used adipose tissue (AT) sections from bariatric surgery patients and from high fat diet (HFD)-induced obese mice together with immunofluorescence and real-time polymerase chain reaction to study adipose expression of Plg-R . Mice genetically deficient in Plg-R and littermate controls fed a HFD or control low fat diet (LFD) were used to determine the role of Plg-R in insulin resistance, glucose tolerance, type 2 diabetes, and associated mechanisms including adipose inflammation, fibrosis, and ectopic lipid storage. The role of Plg-R in adipogenesis was determined using 3T3-L1 preadipocytes and primary cultures established from Plg-R -deficient and littermate control mice.
RESULTS
Plg-R was highly expressed in both human and mouse AT, and its levels dramatically increased during adipogenesis. Plg-R -deficient mice, when fed a HFD, gained more weight, developed more hepatic steatosis, and were more insulin resistant/glucose intolerant than HFD-fed wild-type littermates. Mechanistically, these metabolic defects were linked with increased AT inflammation, AT macrophage and T-cell accumulation, adipose and hepatic fibrosis, and decreased insulin signaling in the AT and liver. Moreover, Plg-R regulated the expression of PPARγ and other adipogenic molecules, suggesting a novel role for Plg-R in the adipogenic program.
CONCLUSIONS
Plg-R coordinately regulates multiple aspects of adipose function that are important to maintain efficient metabolic homeostasis.
Topics: Adipose Tissue; Animals; Diabetes Mellitus, Type 2; Dietary Fats; Fibrosis; Glucose Tolerance Test; Homeostasis; Humans; Inflammation; Insulin Resistance; Mice; Plasminogen; Receptors, Cell Surface
PubMed: 34897983
DOI: 10.1111/jth.15622 -
Veterinary Research Mar 2022Mycoplasma hyorhinis may cause systemic inflammation of pigs, typically polyserositis and arthritis, and is also associated with several types of human cancer. However,...
Mycoplasma hyorhinis may cause systemic inflammation of pigs, typically polyserositis and arthritis, and is also associated with several types of human cancer. However, the pathogenesis of M. hyorhinis colonizing and breaching the respiratory barrier to establish systemic infection is poorly understood. Glycolytic enzymes are important moonlighting proteins and virulence-related factors in various bacteria. In this study, we investigated the functions of a glycolytic critical enzyme, enolase in the infection and systemic spread of M. hyorhinis. Bacterial surface localization of enolase was confirmed by flow cytometry and colony hybridization assay. Recombinant M. hyorhinis enolase (rEno) was found to adhere to pig kidney (PK-15) cells, and anti-rEno serum significantly decreased adherence. The enzyme was also found to bind host plasminogen and fibronectin, and interactions were specific and strong, with dissociation constant (K) values of 1.4 nM and 14.3 nM, respectively, from surface plasmon resonance analysis. Activation of rEno-bound plasminogen was confirmed by its ability to hydrolyze plasmin-specific substrates and to degrade a reconstituted extracellular matrix. To explore key sites during these interactions, C-terminal lysine residues of enolase were replaced with leucine, and the resulting single-site and double-site mutants show significantly reduced interaction with plasminogen in far-Western blotting and surface plasmon resonance tests. The binding affinities of all mutants to fibronectin were reduced as well. Collectively, these results imply that enolase moonlights as an important adhesin of M. hyorhinis, and interacts with plasminogen and fibronectin. The two lysine residues in the C-terminus are important binding sites for its multiple binding activities.
Topics: Adhesins, Bacterial; Animals; Fibronectins; Mycoplasma hyorhinis; Phosphopyruvate Hydratase; Plasminogen; Swine
PubMed: 35337383
DOI: 10.1186/s13567-022-01041-0 -
Biochemical and Biophysical Research... Apr 2023Alzheimer's disease (AD) is the most common neurodegenerative disorder in the world. The aggregation of both amyloid beta (Aβ) peptides extracellularly and Tau proteins...
Alzheimer's disease (AD) is the most common neurodegenerative disorder in the world. The aggregation of both amyloid beta (Aβ) peptides extracellularly and Tau proteins intracellularly plays key roles in the pathological consequences of AD, which lead to cholinergic neurodegeneration and eventually death. Currently, there are no effective methods to stop the progression of AD. Using ex vivo, in vivo and clinical approaches, we investigated the functional effects of plasminogen on the widely used FAD, Aβ42 oligomer or Tau intracranial injection-induced AD mouse model and explored its therapeutic effects on patients with AD. The results show that intravenously injected plasminogen rapidly crosses the blood‒brain barrier (BBB); increases plasmin activity in the brain; colocalizes with and effectively promotes the clearance of Aβ42 peptide and Tau protein deposits ex vivo and in vivo; increases the choline acetyltransferase (ChAT) level and decreases the acetylcholinesterase (AChE) activity; and improves the memory functions. Clinically, when GMP-level plasminogen was administered to 6 AD patients for 1-2 weeks, their average scores on the Minimum Mental State Examination (MMSE), which is a standard scoring system used to measure the memory loss and cognitive deficits, were extremely significantly improved by 4.2 ± 2.23 points, e.g., an average increase from 15.5 ± 8.22 before treatment to 19.7 ± 7.09 after treatment. The preclinical study and pilot clinical study suggest that plasminogen is effective in treating AD and may be a promising drug candidate.
Topics: Humans; Mice; Animals; Alzheimer Disease; Amyloid beta-Peptides; tau Proteins; Plasminogen; Acetylcholinesterase; Peptide Fragments
PubMed: 36905760
DOI: 10.1016/j.bbrc.2023.02.078 -
Journal of Translational Medicine Mar 2022Urokinase-type plasminogen activator receptor (uPAR) is an attractive target for the treatment of cancer, because it is expressed at low levels in healthy tissues but at... (Review)
Review
Urokinase-type plasminogen activator receptor (uPAR) is an attractive target for the treatment of cancer, because it is expressed at low levels in healthy tissues but at high levels in malignant tumours. uPAR is closely related to the invasion and metastasis of malignant tumours, plays important roles in the degradation of extracellular matrix (ECM), tumour angiogenesis, cell proliferation and apoptosis, and is associated with the multidrug resistance (MDR) of tumour cells, which has important guiding significance for the judgement of tumor malignancy and prognosis. Several uPAR-targeted antitumour therapeutic agents have been developed to suppress tumour growth, metastatic processes and drug resistance. Here, we review the recent advances in the development of uPAR-targeted antitumor therapeutic strategies, including nanoplatforms carrying therapeutic agents, photodynamic therapy (PDT)/photothermal therapy (PTT) platforms, oncolytic virotherapy, gene therapy technologies, monoclonal antibody therapy and tumour immunotherapy, to promote the translation of these therapeutic agents to clinical applications.
Topics: Humans; Neoplasms; Prognosis; Receptors, Urokinase Plasminogen Activator; Signal Transduction; Urokinase-Type Plasminogen Activator
PubMed: 35303878
DOI: 10.1186/s12967-022-03329-3