Fibrinolysis — plasminogen activation by tPA on fibrin and uPA/uPAR on cells, plasmin degradation of fibrin, and its serpin and TAFI brakes; PLG/PLAT/PLAU/PLAUR/SERPINE1/SERPINB2/SERPINF2/CPB2

Fibrinolysis dissolves fibrin clots. Its effector is plasmin, the active serine protease formed from the zymogen plasminogen (PLG). Plasminogen activation is catalysed by two serine proteases. Tissue-type plasminogen activator (tPA, PLAT) is a poor enzyme in solution, but on a fibrin surface it binds fibrin and then plasminogen to form a ternary complex, which lowers its Michaelis constant by orders of magnitude. This restricts plasmin formation to the clot. Fibrin is therefore both the substrate of fibrinolysis and the template for its activation step. Urokinase-type plasminogen activator (uPA, PLAU) works mainly on cell surfaces, bound to its GPI-anchored receptor uPAR (PLAUR), which focuses plasminogen activation at the pericellular surface. Plasmin cleaves fibrin into soluble degradation products. Partial digestion exposes C-terminal lysine residues that bind the kringle lysine-binding sites of plasminogen and tPA, a positive feedback that accelerates further activation. The system is held in check at three points. Plasminogen activator inhibitor-1 (PAI-1, SERPINE1) is the main fast-acting serpin inhibitor of tPA and uPA. PAI-2 (SERPINB2), protease nexin-1 (SERPINE2) and protein C inhibitor (SERPINA5) are tissue- or context-restricted plasminogen activator inhibitors. Alpha2-antiplasmin (SERPINF2) inhibits free plasmin almost instantly. Thrombin-activatable fibrinolysis inhibitor (TAFI, CPB2), once activated by the thrombin-thrombomodulin complex, is a basic carboxypeptidase that removes the C-terminal lysines from partly degraded fibrin and so removes fibrin's cofactor function.

Derived from the RGD Pathway Ontology diagram PW:0000481 through the RGD_PATHWAY_ONTOLOGY project's diagram->module route. The RGD diagram supplied the boundary, the seven drawn gene products (Plg, Plat, Plau, Plaur, Serpine1, Serpinf2, Cpb2) and the topology; fibrinogen (FGA, FGB, FGG, drawn as the "fibrin" node) and the serpins the record names in prose (SERPINB2, SERPINE2, SERPINA5) were added as participants. Activation, effector and inhibition are separate parts. Molecular functions were chosen from each protein's experimental GO annotations in QuickGO: PLAT, PLAU and PLG serine-type endopeptidase activity GO:0004252 (IDA; PLG also EXP); PLAUR enzyme activator activity GO:0008047 (IDA, PMID:1689240), chosen over urokinase plasminogen activator receptor activity GO:0030377 (also IDA), because GO:0030377 is defined as initiating a change in cell activity, which is signalling and not the localisation and acceleration of plasminogen activation that this module needs; SERPINE1, SERPINF2, SERPINE2 and SERPINA5 serine-type endopeptidase inhibitor activity GO:0004867 (IDA); SERPINB2 GO:0004867 (IBA and TAS only in GOA; its urokinase inhibition is shown in PMID:3029122); CPB2 metallocarboxypeptidase activity GO:0004181 (TAS and IBA only in GOA; the activity is shown in PMID:7782309 and PMID:9765237). Fibrin's template role was the hardest call. Fibrinogen's own experimental molecular functions are structural molecule activity GO:0005198 (IDA) and contributes_to signaling receptor binding GO:0005102, neither of which is the acceleration of tPA-mediated plasminogen activation, and the generic protein-macromolecule adaptor activity GO:0030674 on FGA is IBA only. No GO molecular function states "cofactor for plasminogen activation", so the fibrin annoton carries no function term; its role is described in prose and carried by its experimental process annotations plasminogen activation GO:0031639 and fibrinolysis GO:0042730 (IDA, PMID:16846481). Fibrinogen is kept as a participant rather than excluded because, as the repository guidance sets out with fibrinolysis as its worked example, fibrin does part of the work: it polymerises and then acts as the template that lowers the Michaelis constant for tPA-mediated plasminogen activation (PMID:7199524) and, once partly degraded, supplies the C-terminal lysines that drive the positive feedback whose removal by TAFIa suppresses lysis (PMID:9765237). Fibrin clot formation itself (thrombin, factor XIII) is out of scope and belongs to modules/coagulation_cascade.yaml; fibrin is this module's input, which the RGD diagram draws as an edge from the coagulation cascade pathway (PW:0000474). Contact-pathway/kallikrein activation of pro-uPA is likewise out of scope and belongs to modules/kallikrein_kinin_cascade.yaml. Extracellular-matrix roles of plasmin are out of scope; the one human GO-CAM that covers these proteins, gomodel:68fac5ed00001527 "Plasminogen/plasmin function in extracellular matrix disassembly", models PLAUR enzyme activator activity, PLAU and PLG serine-type endopeptidase activity in that ECM context, and its PLAU, PLAUR and PLG activities are linked here under gocam_associations because the gene and molecular function match even though the model's process is extracellular matrix disassembly rather than fibrinolysis. No GO-CAM covers the tPA, serpin or TAFI steps, and there are no gene reviews for any of the thirteen gene products, so every molecular function here was taken from QuickGO and the primary literature directly. All cited publications are abstract-only in the publications cache.