The crosslinked fibrin multimers in a clot are broken down to soluble polypeptides by plasmin, a serine protease. Plasmin can be generated from its inactive precursor plasminogen and recruited to the site of a fibrin clot in two ways, by interaction with tissue plasminogen activator at the surface of a fibrin clot, and by interaction with urokinase plasminogen activator at a cell surface. The first mechanism appears to be the major one responsible for the dissolution of clots within blood vessels. The second, although capable of mediating clot dissolution, may normally play a major role in tissue remodeling, cell migration, and inflammation (Chapman 1997; Lijnen 2001). These other functions of urokinase plasminogen activator will be annotated in future versions of Reactome. Clot dissolution is regulated in two ways. First, efficient plasmin activation and fibrinolysis occur only in complexes formed at the clot surface or on a cell membrane - proteins free in the blood are inefficient catalysts and are rapidly inactivated. Second, both plasminogen activators and plasmin itself are inactivated by specific serpins, proteins that bind to serine proteases to form stable, enzymatically inactive complexes (Kohler and Grant 2000). These events are outlined in the drawing: black arrows connect the substrates (inputs) and products (outputs) of individual reactions, and blue lines connect output activated enzymes to the other reactions that they catalyze.
Shigekiyo T, Yoshida H, Matsumoto K, Azuma H, Wakabayashi S, Saito S, Fujikawa K, Koide T.; ''HRG Tokushima: molecular and cellular characterization of histidine-rich glycoprotein (HRG) deficiency.''; PubMedEurope PMCScholia
Moroi M, Aoki N.; ''Isolation and characterization of alpha2-plasmin inhibitor from human plasma. A novel proteinase inhibitor which inhibits activator-induced clot lysis.''; PubMedEurope PMCScholia
Pohl G, Källström M, Bergsdorf N, Wallén P, Jörnvall H.; ''Tissue plasminogen activator: peptide analyses confirm an indirectly derived amino acid sequence, identify the active site serine residue, establish glycosylation sites, and localize variant differences.''; PubMedEurope PMCScholia
Luo M, Hajjar KA.; ''Annexin A2 system in human biology: cell surface and beyond.''; PubMedEurope PMCScholia
Ploug M, Rønne E, Behrendt N, Jensen AL, Blasi F, Danø K.; ''Cellular receptor for urokinase plasminogen activator. Carboxyl-terminal processing and membrane anchoring by glycosyl-phosphatidylinositol.''; PubMedEurope PMCScholia
Réty S, Sopkova J, Renouard M, Osterloh D, Gerke V, Tabaries S, Russo-Marie F, Lewit-Bentley A.; ''The crystal structure of a complex of p11 with the annexin II N-terminal peptide.''; PubMedEurope PMCScholia
Ellis V, Scully MF, Kakkar VV.; ''Plasminogen activation initiated by single-chain urokinase-type plasminogen activator. Potentiation by U937 monocytes.''; PubMedEurope PMCScholia
Cubellis MV, Nolli ML, Cassani G, Blasi F.; ''Binding of single-chain prourokinase to the urokinase receptor of human U937 cells.''; PubMedEurope PMCScholia
Behrendt N, Rønne E, Ploug M, Petri T, Løber D, Nielsen LS, Schleuning WD, Blasi F, Appella E, Danø K.; ''The human receptor for urokinase plasminogen activator. NH2-terminal amino acid sequence and glycosylation variants.''; PubMedEurope PMCScholia
Koide T, Foster D, Yoshitake S, Davie EW.; ''Amino acid sequence of human histidine-rich glycoprotein derived from the nucleotide sequence of its cDNA.''; PubMedEurope PMCScholia
Cubellis MV, Andreasen P, Ragno P, Mayer M, Danø K, Blasi F.; ''Accessibility of receptor-bound urokinase to type-1 plasminogen activator inhibitor.''; PubMedEurope PMCScholia
Hedhli N, Falcone DJ, Huang B, Cesarman-Maus G, Kraemer R, Zhai H, Tsirka SE, Santambrogio L, Hajjar KA.; ''The annexin A2/S100A10 system in health and disease: emerging paradigms.''; PubMedEurope PMCScholia
Lijnen HR, Zamarron C, Blaber M, Winkler ME, Collen D.; ''Activation of plasminogen by pro-urokinase. I. Mechanism.''; PubMedEurope PMCScholia
Kohler HP, Grant PJ.; ''Plasminogen-activator inhibitor type 1 and coronary artery disease.''; PubMedEurope PMCScholia
Kruithof EK, Vassalli JD, Schleuning WD, Mattaliano RJ, Bachmann F.; ''Purification and characterization of a plasminogen activator inhibitor from the histiocytic lymphoma cell line U-937.''; PubMedEurope PMCScholia
Petersen TE, Martzen MR, Ichinose A, Davie EW.; ''Characterization of the gene for human plasminogen, a key proenzyme in the fibrinolytic system.''; PubMedEurope PMCScholia
Higgins DL, Vehar GA.; ''Interaction of one-chain and two-chain tissue plasminogen activator with intact and plasmin-degraded fibrin.''; PubMedEurope PMCScholia
Lijnen HR, Hoylaerts M, Collen D.; ''Isolation and characterization of a human plasma protein with affinity for the lysine binding sites in plasminogen. Role in the regulation of fibrinolysis and identification as histidine-rich glycoprotein.''; PubMedEurope PMCScholia
Lijnen HR, Holmes WE, van Hoef B, Wiman B, Rodriguez H, Collen D.; ''Amino-acid sequence of human alpha 2-antiplasmin.''; PubMedEurope PMCScholia
Hoylaerts M, Rijken DC, Lijnen HR, Collen D.; ''Kinetics of the activation of plasminogen by human tissue plasminogen activator. Role of fibrin.''; PubMedEurope PMCScholia
Estreicher A, Mühlhauser J, Carpentier JL, Orci L, Vassalli JD.; ''The receptor for urokinase type plasminogen activator polarizes expression of the protease to the leading edge of migrating monocytes and promotes degradation of enzyme inhibitor complexes.''; PubMedEurope PMCScholia
Ellis V, Behrendt N, Danø K.; ''Plasminogen activation by receptor-bound urokinase. A kinetic study with both cell-associated and isolated receptor.''; PubMedEurope PMCScholia
Wagner OF, de Vries C, Hohmann C, Veerman H, Pannekoek H.; ''Interaction between plasminogen activator inhibitor type 1 (PAI-1) bound to fibrin and either tissue-type plasminogen activator (t-PA) or urokinase-type plasminogen activator (u-PA). Binding of t-PA/PAI-1 complexes to fibrin mediated by both the finger and the kringle-2 domain of t-PA.''; PubMedEurope PMCScholia
Chapman HA.; ''Plasminogen activators, integrins, and the coordinated regulation of cell adhesion and migration.''; PubMedEurope PMCScholia
Boose JA, Kuismanen E, Gerard R, Sambrook J, Gething MJ.; ''The single-chain form of tissue-type plasminogen activator has catalytic activity: studies with a mutant enzyme that lacks the cleavage site.''; PubMedEurope PMCScholia
This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
The uncleaved (one-chain) form of urokinase plasminogen activator associates with urokinase plasminogen activator receptor (uPAR), forming a complex at the cell surface (Cubellis et al. 1986). The complex is anchored to the outer face of the plasma membrane by a glycophosphatidylinositol moiety at the carboxy terminus of uPAR (Behrendt et al. 1990; Ploug et al. 1991).
Activated (two-chain) urokinase plasminogen activator binds plasminogen activator inhibitor 2, a serpin, to form a stable, inactive complex that remains associated with uPAR on the plasma membrane (Estreicher et al. 1990; Kruithof et al. 1986).
Plasminogen bound to fibrin is cleaved and activated by tissue plasminogen activator also bound to the fibrin. The association of both plasminogen and tissue plasminogen activator with a fibrin clot juxtaposes the two molecules, facilitating their interaction (Hoylaerts et al. 1982). Early studies suggested that tissue plasminogen activator itself might require activation (conversion to its two-chain form) before it could catalyze this reaction (e.g., Higgins and Vehar 1987). More recent work (Boose et al. 1989) indicates that the single-chain form of the molecule is catalytically active, although cleavage increases its activity and may thus serve to accelerate the later stages of fibrinolysis.
Once plasmin has been activated, in the initial stage of the fibrinolysis process, it can catalyze the conversion of fibrin-bound tissue plasminogen activator (one-chain) to its more active two-chain form, increasing the rate at which additional plasminogen molecules can be activated.
Plasminogen reversibly binds histidine-rich glycoprotein (HRG). The resulting complex interacts poorly with fibrin, suggesting that HRG might have an anti-fibrinolytic (clot-stabilizing) effect in vivo (Lijnen et al. 1980). Consistent with this suggestion, individuals with chronically reduced plasma HRG concentrations are susceptible to thrombosis (Shigekiyo et al. 1998).
Plasmin binds the serpin alpha-2-antiplasmin, forming a stable and catalytically inactive complex. While several serpin proteins bind and inactivate plasmin in vitro, alpha-2-antiplasmin appears to be the only one with substantial plasmin-neutralizing activity in vivo (Moroi and Aoki 1976; Lijnen et al. 1987).
At the beginning of this reaction, 1 molecule of 'fibrin multimer, crosslinked:tissue plasminogen activator (two-chain):plasminogen' is present. At the end of this reaction, 1 molecule of 'plasmin', and 1 molecule of 'fibrin multimer, crosslinked:tissue plasminogen activator (two-chain)' are present.
This reaction takes place in the 'extracellular region' and is mediated by the 'plasminogen activator activity' of 'fibrin multimer, crosslinked:tissue plasminogen activator (two-chain):plasminogen'.
Extracellular plasminogen binds with high affinity to histidine-rich glycoprotein on the plasma membrane. Binding requires Zn++ in concentrations higher than those found in normal plasma, but that can be generated, e.g., by platelet activation (Jones et al. 2004).
Plasminogen activator inhibitor 1, a serpin, binds to fibrin-associated tissue plasminogen activator. The resulting stable complex remains associated with fibrin but cannot activate plasminogen (Wagner et al. 1989). The importance of this step in the regulation of clot dissolution in vivo is indicated by the occurence of thrombosis in individuals with abnormally little tissue plasminogen activator or abnormally much plasminogen activator inhibitor (Juhan-Vague et al. 1987).
The small amount of plasmin generated by the activity of the one-chain form of urokinase plasminogen activator in turn cleaves urokinase plasminogen activator, converting it to its substantially more active two-chain form (Cubellis et al. 1986; Lijnen et al. 1991).
Plasminogen, tethered to the cell surface by its association with histidine-rich glycoprotein, is rapidly cleaved and activated to plasmin by the action of urokinase plasminogen activator(two-chain form) bound to uPAR, its cell-surface receptor. The association of both substrate and enzyme with the cell surface is necessary for the reaction to proceed efficiently (Ellis et al. 1989, 1991).
Plasmin, generated at the surfaces of the fibrin clot by tissue plasminogen activator or at the surfaces of cells by urokinase plasminogen activator, catalyzes the hydrolysis of fibrin to soluble fragments (Chapman 1997).
Plasminogen, tethered to the cell surface by its association with histidine-rich glycoprotein, is cleaved and activated to plasmin by the action of urokinase plasminogen activator bound to uPAR, its cell-surface receptor. The association of both substrate and enzyme with the cell surface is necessary for the reaction to proceed efficiently (Ellis et al. 1991). While the one-chain form of urokinase plasminogen activator is lower than that of the two-chain form, it is still sufficient to initiate the process of plasmin activation (Ellis et al. 1989; Lijnen et al. 1986).
Plasminogen reversibly binds histidine-rich glycoprotein (HRG). The resulting complex interacts poorly with fibrin, suggesting that HRG might have an anti-fibrinolytic (clot-stabilizing) effect in vivo (Lijnen et al. 1980). Consistent with this suggestion, individuals with chronically reduced plasma HRG concentrations are susceptible to thrombosis (Shigekiyo et al. 1998).
Plasminogen activator inhibitor 1, a serpin, binds to fibrin-associated tissue plasminogen activator. The resulting stable complex remains associated with fibrin but cannot activate plasminogen (Wagner et al. 1989). The importance of this step in the regulation of clot dissolution in vivo is indicated by the occurence of thrombosis in individuals with abnormally little tissue plasminogen activator or abnormally much plasminogen activator inhibitor (Juhan-Vague et al. 1987).
At the beginning of this reaction, 1 molecule of 'plasminogen', and 1 molecule of 'fibrin multimer, crosslinked:tissue plasminogen activator (two-chain)' are present. At the end of this reaction, 1 molecule of 'fibrin multimer, crosslinked:tissue plasminogen activator (two-chain):plasminogen' is present.
This reaction takes place in the 'extracellular region'.
Activated (two-chain) urokinase plasminogen activator binds plasminogen activator inhibitor 1, a serpin, to form a stable, inactive complex that remains associated with uPAR on the plasma membrane (Cubellis et al. 1989).
Clot dissolution is regulated in two ways. First, efficient plasmin activation and fibrinolysis occur only in complexes formed at the clot surface or on a cell membrane - proteins free in the blood are inefficient catalysts and are rapidly inactivated. Second, both plasminogen activators and plasmin itself are inactivated by specific serpins, proteins that bind to serine proteases to form stable, enzymatically inactive complexes (Kohler and Grant 2000).
These events are outlined in the drawing: black arrows connect the substrates (inputs) and products (outputs) of individual reactions, and blue lines connect output activated enzymes to the other reactions that they catalyze.
Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=75205
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This reaction takes place in the 'extracellular region' and is mediated by the 'plasminogen activator activity' of 'fibrin multimer, crosslinked:tissue plasminogen activator (two-chain):plasminogen'.
This reaction takes place in the 'extracellular region'.