Activation of plasminogen

Zsuzsa Bagoly University of Debrecen, Hungary. The program supports the professional growth of all members of our communities by providing an open forum for discussion and mentoring. Virginia Metrangolo University of Copenhagen, Denmark.

James Whisstock Monash University, Australia. Christoph Hagemeyer Monash University, Australia. Robert Medcalf Monash University, Australia. Conference Links. Similar Conferences. Poster Information. Diversity Funding. Similar Gordon Research Conferences and Seminars. Hemostasis July 31 - August 5, Proteolytic Enzymes and Their Inhibitors June 5 - 10, Contact Us Call Us: Madame Curie Bioscience Database [Internet].

Austin TX : Landes Bioscience; Search term. Introduction Cell invasion requires that motile cells cross tissue barriers through the degradation of basement membranes and extracellular matrices ECM. Plasminogen and Plasminogen Activators Plasminogen Human plasminogen is a aminoacid zymogen which can be activated to the broadspectrum twochain plasmin by a single proteolytic cleavage of ArgVal peptide bond.

The Urokinasetype Plasminogen Activator uPA The single chain prourokinase prouPA is secreted as a aminoacids zymogen form and becomes activated by plasmin cleavage of KI peptide bridge, thus generating uPA, a two-chain molecule held together by a single disulfide bond.

Cell Surface-Associated Plasminogen Activation The concept of pericellular proteolysis through the specific association of plasminogen activation components to the cell surface has received extensive experimental support.

Figure 2 Model for the urokinase-activated, catalytic-independent signaling cascade leading to cell migration, adhesion and growth. Plasminogen Activators and Tissue Remodeling In the emerging picture, plasminogen activators participate in a wide spectrum of biological events, including the remodeling of the normal surrounding tissue induced by cancer cells, as well as the nonneoplastic tissue involution and regeneration processes.

Plasminogen Activators and Invasion in Animal Models A reasonable hypothesis is that permanent alterations in the proteolytic balance of malignant cells may contribute to tumor dissemination. Prognosis and Diagnosis In the treatment of cancer there is a need to select patients at high risk of recurrence for adjuvant therapy. Therapy and Antagonists If cancer dissemination is indeed promoted by unrestrained matrix degradation, one obvious therapeutic approach is to design specific protease inhibitors to be employed as antimetastatic agents.

Acknowledgments I am grateful to F. References 1. Blasi F, Stoppelli MP. Proteases and cancer invasion: from belief to certainty. AACR meeting on proteases and protease inhibitors in cancer. Biochim Biophys Acta. Plasminogen activators, tissue degradation, and cancer. Adv Cancer Res. Control of type IV collagenase activity by components of the urokinaseplasmin system: a regulatory mechanism with cell-bound reactants. EMBO J. J Biol Chem. Proteolytic control of growth factor availability.

Effects of disruption of the plasminogen gene on thrombosis, growth, and health in mice. Impaired wound healing in mice with a disrupted plasminogen gene. Nat Med. Functional overlap between two classes of matrix-degrading proteases in wound healing. Patthy L.

Evolution of proteases of blood coagulation and fibrinolysis by assembly from modules. Different evolutionary histories of kringle and protease domains in serine proteases: a typical example of domain evolution. J Mol Evol. Angiostatin generation by human tumor cell lines: involvement of plasminogen activators. Int J Cancer.

Angiostatin induces and sustains dormancy of human primary tumors in mice. Plasminogenindependent initiation of the prourokinase activation cascade in vivo. Activation of prourokinase by glandular kallikrein mGK6 in plasminogen-deficient mice. Serine phosphorylation of biosynthetic pro-urokinase from human tumor cells. FEBS Lett. J Cell Biology. Structural requirements for the growth factor activity of the aminoterminal domain of urokinase.

Blasi F, Verde P. Urokinase-dependent cell surface proteolysis and cancer. Semin Cancer Biol. The plasminogen activator system: biology and regulation. Cell Mol Life Sci. Fujinaga The Ets1 and Ets2 transcription factors activate the promoters for invasion-associated urokinase and collagenase genes in response to epidermal growth factor. Eur J Biochem.

Physiological consequences of loss of plasminogen activator gene function in mice. Neuronal migration is retarded in mice lacking the tissue plasminogen activator gene. The plasminogen activation system in tumor growth, invasion, and metastasis. Separation and characterization of nonphosphorylated and serinephosphorylated urokinase. Catalytic properties and sensitivity to plasminogen activator inhibitor type 1. Stefansson S, Lawrence DA.

The serpin PAI1 inhibits smooth muscle cell migration by blocking integrin binding to vitronectin. Is plasminogen activator inhibitor1 the molecular switch that governs urokinase receptormediated cell adhesion and release?

J Cell Biol. A two-step recognition of signal sequences determines the translocation efficiency of proteins. Processing of complex between urokinase and its type2 inhibitor on the cell surface. A possible regulatory mechanism of urokinase activity. Characterization of cellular binding sites and interactive regions within reactants required for enhancement of plasminogen activation by tPA on the surface of leukocytic cells.

Thromb Haemost. Inhibition of cell surface receptorbound plasmin by a2-antiplasmin and a2-macroglobulin. Tissue plasminogen activator binds to human vascular smooth muscle cells by a novel mechanism. Evidence for a reciprocal linkage between inhibition of catalytic activity and cellular binding. Receptor-mediated endocytosis of tissue-type plasminogen activator by low density lipoprotein receptor-related protein on human hepatoma HepG2 cells.

A cellular binding site for the M r 55, form of the human plasminogen activator, urokinase. Differentiation-enhanced binding of the aminoterminal fragment of human urokinase plasminogen activator to a specific receptor on U monocytes. The receptor binding sequence of urokinase: biological function for the growth factor module of proteases.

Systematic mutational analysis of the receptorbinding region of the human urokinasetype plasminogen activator. Cloning and expression of the receptor for human urokinase plasminogen activator, a central molecule in cell surface, plasmin-dependent proteolysis.

Cellular receptor for urokinase plasminogen activator. Carboxyl-terminal processing and membrane anchoring by glycosylphosphatidylinositol. The structure of the urokinase-type plasminogen activator receptor gene. Proteolytic cleavage of the urokinase receptor substitutes for the agonist-induced chemotactic effect.

A urokinase-sensitive region of the human urokinase receptor is responsible for its chemotactic activity. Identification of the urokinase receptor as an adhesion receptor for vitronectin. The intact urokinase receptor is required for efficient vitronectin binding: receptor cleavage prevents ligand interaction.

Vitronectin binding to urokinase receptor in human breast cancer. Clin Cancer Res. Binding of high molecular weight kininogen to human endothelial cells is mediated via a site within domains 2 and 3 of the urokinase receptor.

J Clin Invest. Distribution and lateral mobility of the urokinase-receptor complex at the cell surface. J Histochem Cytochem. An alternatively spliced variant of mRNA for the human receptor for urokinase plasminogen activator. A soluble form of the glycolipidanchored receptor for urokinasetype plasminogen activator is secreted from peripheral blood leukocytes from patients with paroxysmal nocturnal hemoglobinuria. The level of urokinase-type plasminogen activator receptor is increased in serum of ovarian cancer patients.

Cancer Res. Cellular glycosylphosphatidylinositol-specific phospholipase D regulates urokinase receptor shedding and cell surface expression. J Cell Physiol. Shedding and cleavage of the urokinase receptor uPAR : identification and characterisation of uPAR fragments in vitro and in vivo.

Autocrine saturation of pro-urokinase receptors on human A cells. In vivo paracrine interaction between urokinase and its receptor: effect on tumor cell invasion. Binding of single-chain pro-urokinase to the urokinase receptor of human U cells. Plasminogen activation by receptor-bound urokinase. A kinetic study with both cell-associated and isolated receptor. Activation of pro-urokinase and plasminogen on human sarcoma cells: a proteolytic system with surface-bound reactants.

Receptor-mediated internalization and degradation of urokinase is caused by its specific inhibitor PAI1. Direct binding of occupied urokinase receptor uPAR to LDL receptor-related protein is required for endocytosis of uPAR and regulation of cell surface urokinase activity. Mol Biol Cell. Urokinase-type plasminogen activator and its receptor synergize to promote pathogenic proteolysis. Cytokines induce urokinase-dependent adhesion of human myeloid cells.

A regulatory role for plasminogen activator inhibitors. Reversible cellular adhesion to vitronectin linked to urokinase receptor occupancy. Stahl A, Mueller BM. Melanoma cell migration on vitronectin: regulation by components of the plasminogen activation system. Kjoller L, Hall A. Rac mediates cytoskeletal rearrangements and increased cell motility induced by urokinase-type plasminogen activator receptor binding to vitronectin. Urokinase plasminogen activator receptor, beta 2-integrins, and Src-kinases within a single receptor complex of human monocytes.

J Exp Med. Regulation of integrin function by the urokinase receptor. Identification of a urokinase receptor-integrin interaction site. Promiscuous regulator of integrin function. Urokinase-type plasminogen activator receptor CD87 is a ligand for integrins and mediates cell-cell interaction.

Interaction of urokinase with specific receptors stimulates mobilization of bovine adrenal capillary endothelial cells. Exp Cell Res. The urokinase receptor is required for human monocyte chemotaxis in vitro. Urokinase receptor and integrin partnership: coordination of signaling for cell adhesion, migration and growth. Curr Opin Cell Biol. Urokinase receptor-deficient mice have impaired neutrophil recruitment in response to pulmonary Pseudomonas aeruginosa infection.

Jilani 1 ; Abdul H. Siddiqui 2. Tissue plasminogen activator tPA is classified as a serine protease enzymes that cleave peptide bonds in proteins. It is thus one of the essential components of the dissolution of blood clots. Its primary function includes catalyzing the conversion of plasminogen to plasmin, the primary enzyme involved in dissolving blood clots. Examples of these drugs include alteplase, reteplase, and tenecteplase.

Indications for the use of tPA include ischemic stroke most common in patients presenting to treating facility within 3 hours 4. This activity outlines the indications, mechanism of action, methods of administration, important adverse effects, contraindications, toxicity, and monitoring, of tPA agents so providers can direct patient therapy where they are indicated as part of the interprofessional team.

Objectives: Review the mechanism of action of tissue plasminogen activators. Identify the indications for initiating therapy with a tPA agent, differentiating between individual agents where appropriate.

Summarize the contraindications of tPA medications. Describe interprofessional team strategies for improving care coordination and communication to properly use tPA agents to improve patient outcomes in the varied scenarios where it can be effective. Access free multiple choice questions on this topic. Recombinant biotechnology has allowed tPA to be manufactured in labs, and these synthetic products are called recombinant tissue plasminogen activators rtPA.

These drugs have undergone various modifications to amplify their pharmacokinetic and pharmacodynamic properties, especially to prolong their short half-life in the circulation and further increase their fibrin specificity to prevent an unwanted fibrinolytic state. More specifically, it cleaves the zymogen plasminogen at its ArgVal peptide bond to form the serine protease, plasmin.

Plasmin, an endogenous fibrinolytic enzyme, breaks the cross-links between fibrin molecules, which are the structural support of the blood clot, and its activity is extremely short-lived. This short duration is because alpha 2-antiplasmin, an abundant inhibitor of plasmin, quickly inactivates it and restricts the action of plasmin to the vicinity of the clot. Alteplase administration is via the intravenous route. However, for catheter clearance, it is administered directly into the catheter.

To manage acute myocardial infarction in adults, administer alteplase as soon as possible after the onset of symptoms. After 30 minutes of dwell time, assess the function of the catheter by attempting to aspirate blood; if one cannot aspirate blood minutes after dwell time, a second dose may be administered, and repeat the process. If there is a restoration of catheter function, aspirate around 4 to 5 mL of blood in patients who weigh 10 kg or more aspirate around 3 mL if the patient weighs less than 10 kg to remove the drug and the residual clot.

Then gently irrigate with 0. The most common adverse effect is bleeding, and the most serious is a stroke. The most common is minor bleeding. Reteplase: As with other tPAs, the most common adverse effect seen with reteplase is bleeding. Do not administer tPA for the treatment of acute ischemic stroke in the following scenarios [18] [19] [20] :. Do not administer tPA in the management of acute myocardial infarction or pulmonary embolism in the following:. Do not administer tPA in any patient who had a hypersensitivity reaction to a previous dose of tPA urticarial or anaphylactic reactions [18] [21].

The drug used to reverse tPA toxicity is aminocaproic acid, an FDA-approved drug for managing acute bleeding caused by increased fibrinolytic activity. It acts as an effective inhibitor for proteolytic enzymes like plasmin, which is the primary enzyme responsible for fibrinolysis. Monitor closely with any drug that causes anticoagulation as there is an increased risk of bleeding. An interprofessional team consisting of the nurses, pharmacists, and clinicians exercising open lines of communication should monitor patients receiving this drug to provide the safest care and best patient outcome.

Interprofessional collaboration and open communication can lead to improved patient outcomes with fewer adverse effects. This book is distributed under the terms of the Creative Commons Attribution 4. Turn recording back on. National Center for Biotechnology Information , U. StatPearls [Internet]. Search term. Tissue Plasminogen Activator Talha N. Author Information Authors Talha N. Continuing Education Activity Tissue plasminogen activator tPA is classified as a serine protease enzymes that cleave peptide bonds in proteins.

Indications Tissue plasminogen activator tPA is classified as a serine protease enzymes that cleave peptide bonds in proteins. Indications for the use of tPA include the following: Ischemic stroke most common in patients presenting to the treating facility within 3 hours 4. Myocardial Infarction would be a delay of more than 1 to 2 hours before percutaneous transluminal coronary angioplasty.

Pulmonary embolism in massive pulmonary embolisms, causing severe instability due to high pressure on the heart. Reteplase is a modified form of human tPA with similar effects but a faster onset and longer duration of action. It is currently FDA-approved for the management of acute myocardial infarction. Preferred over alteplase due to its longer half-life, allowing it to be given as a bolus injection rather than through an infusion like alteplase.