Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.7 (plasmin)
9,023 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

TM601 is a synthetic form of chlorotoxin, a 36-amino acid peptide derived from the venom of the Israeli scorpion, Leirius quinquestriatus, initially found to specifically bind and inhibit the migration of glioma cells in culture. Subsequent studies demonstrated specific in vitro binding to additional tumor cell lines. Recently, we demonstrated that proliferating human vascular endothelial cells are the only normal cell line tested that exhibits specific binding to TM601. Here, we identify annexin A2 as a novel binding partner for TM601 in multiple human tumor cell lines and human umbilical vein endothelial cell (HUVEC). We demonstrate that the surface binding of TM601 to the pancreatic tumor cell line Panc-1 is dependent on the expression of annexin A2. Identification of annexin A2 as a binding partner for TM601 is also consistent with the anti-angiogenic effects of TM601. Annexin A2 functions in angiogenesis by binding to tissue plasminogen activator and regulating plasminogen activation on vascular endothelial cells. We demonstrate that in HUVECs, TM601 inhibits both vascular endothelial growth factor- and basic fibroblast growth factor-induced tissue plasminogen activator activation, which is required for activation of plasminogen to plasmin. Consistent with inhibition of cell surface protease activity, TM601 also inhibits platelet-derived growth factor-C induced trans-well migration of both HUVEC and U373-MG glioma cells.
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PMID:Annexin A2 is a molecular target for TM601, a peptide with tumor-targeting and anti-angiogenic effects. 2001 98

Recent studies showed that soluble annexin A2 dramatically increases tissue plasminogen activator (tPA)-mediated plasmin generation in vitro, and reduces thrombus formation in vivo. Here, we hypothesize that combining annexin A2 with tPA can significantly enhance thrombolysis efficacy, so that lower doses of tPA can be applied in ischemic stroke to avoid neurotoxic and hemorrhagic complications. In vitro activity assays confirmed tPA-specific amplification of plasmin generation by recombinant annexin A2. In a rat focal embolic stroke model, combination therapy with tPA and recombinant annexin A2 protein at 2 h post-ischemia decreased the effective dose required for tPA by four-fold and reduced brain infarction. Combining annexin A2 with tPA also lengthened the time window for thrombolysis. Compared with tPA (10 mg/kg) alone, the combination of annexin A2 (5 mg/kg) plus low-dose tPA (2.5 mg/kg) significantly enhanced fibrinolysis, attenuated mortality, brain infarction, and hemorrhagic transformation, even when administered at 4 h post-ischemia. Combination with recombinant annexin A2, the effective thrombolytic dose of tPA can be decreased. As a result, brain hemorrhage and infarction are reduced, and the time window for stroke reperfusion prolonged. Our present findings provide a promising new approach for enhancing tPA-based thrombolytic stroke therapy.
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PMID:Annexin A2 combined with low-dose tPA improves thrombolytic therapy in a rat model of focal embolic stroke. 2006 77

Vascular endothelial cell surface expression of annexin A2 and its binding partner p11 is a key element in maintaining fibrinolytic balance on blood vessel surfaces. In the recent decade, investigators have made significant progress toward understanding the mechanisms that regulate heterotetrameric (A2*p11)(2) receptor translocation from the cytoplasm to the outer cell surface. Accumulating evidence now shows that heterotetrameric (A2*p11)(2) cell surface expression is a dynamic process that modulates plasmin activation during periods of vascular stress or injury, and is independent of the classical endoplasmic reticulum-Golgi pathway. Translocation of heterotetrameric (A2*p11)(2) is facilitated both by src-kinase mediated phosphorylation of A2 at tyrosine 23, and by expression of and partnering with p11. In the absence of A2 both in vivo and in vitro, p11 is expressed at very low levels in endothelial cells, because unpartnered p11 is polyubiquitinated and rapidly degraded through a proteasome-dependent mechanism. A2 directly binds and stabilizes intracellular p11 by masking an autonomous polyubiquitination signal on p11. This modulatory role of A2 binding prevents accumulation of unpartnered p11 within the endothelial cell, and ultimately suggests that the regulation of heterotetrameric (A2*p11)(2) receptor surface expression is precisely attuned to the intracellular level of p11.
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PMID:The endothelial cell annexin A2 system and vascular fibrinolysis. 2009 22

Antiphospholipid antibodies (aPL) represent a heterogeneous group of antibodies that recognize various antigenic targets including beta2 glycoprotein I (beta2GPI), prothrombin (PT), activated protein C, tissue plasminogen activator, plasmin and annexin A2. The most commonly used tests to detect aPL are: lupus anticoagulant (LAC), a functional coagulation assay, anticardiolipin antibody (aCL) and anti-beta2GPI antibody (anti-beta2GPI), which are enzyme-linked immunoassay (ELISA). Clinically aPL are associated with thrombosis and/or with pregnancy morbidity. Apparently aPL alone are unable to induce thrombotic manifestations, but they increase the risk of vascular events that can occur in the presence of another thrombophilic condition; on the other hand obstetrical manifestations were shown to be associated not only to thrombosis but mainly to a direct antibody effect on the trophoblast.
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PMID:[Antiphospholipid antibody: laboratory, pathogenesis and clinical manifestations]. 2039 Jan 20

The antiphospholipid syndrome (APS) is characterized by venous and/or arterial thrombosis, or recurrent fetal loss, in the presence of antiphospholipid antibodies (APL). The pathogenesis of APS is multifaceted and involves numerous mechanisms including activation of endothelial cells, monocytes, and/or platelets; inhibition of natural anticoagulant pathways such as protein C, tissue factor inhibitor, and annexin A5; activation of the complement system; and impairment of the fibrinolytic system. Fibrinolysis--the process by which fibrin thrombi are remodeled and degraded--involves the conversion of plasminogen to plasmin by tissue plasminogen activator (tPA) or urokinase-type plasminogen activator, and is tightly regulated. Although the role of altered fibrinolysis in patients with APS is relatively understudied, several reports suggest that deficient fibrinolytic activity may contribute to the pathogenesis of disease in these patients. This article discusses the function of the fibrinolytic system and reviews studies that have reported alterations in fibrinolytic pathways that may contribute to thrombosis in patients with APL. Some of these mechanisms include elevations in plasminogen activator inhibitor-1 levels, inhibitory antibodies against tPA or other components of the fibrinolytic system, antibodies against annexin A2, and finally, antibodies to beta(2)-glycoprotein-I (beta(2)GPI) that block the ability of beta(2)GPI to stimulate tPA-mediated plasminogen activation.
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PMID:Impaired fibrinolysis in the antiphospholipid syndrome. 2042 34

Plasmin is recognized as a potent signaling molecule in particular human monocytes, inducing a pro-inflammatory response. Recently, the annexin A2 heterotetramer, a plasmin receptor, was described at the surface of the human monocytes. Plasmin is initiating a signaling in monocytes by cleavage of the annexin A2 subunit of the receptor and the apparent dissociation of the heterotetramer at the surface of cell. However, the exact mechanism linking this dissociation and the activation of the intracellular pathway remains undefined. Here we report that the molecular mechanism of monocyte activation may rely on a new molecule containing the amino-terminal end of annexin A2 (A2NP) generated by plasmin cleavage of its receptor - the annexin A2 heterotetramer - as in vitro A2NP is able to mimic plasmin activation of the tyrosine kinase JAK1 and STAT3 and the subsequent increase in expression and release of monocyte/macrophage chemoattractant protein (MCP)-1, which is a major chemokine released by monocytes/macrophages. Additionally, we show that plasmin-induced the phosphorylation of STAT3 is similar to that of IL-6 and IL-31, and protease-activated receptor 1 does not affect plasmin-induced cytokine MCP-1 release in human monocytes. Finally, our data demonstrate that plasmin triggers the production of MCP-1 in macrophages in vivo. Thus, A2NP generated by plasmin cleavage of the annexin A2 heterotetramer could serve as a new proteolytically generated signaling molecule activating an associated transmembrane co-receptor, such as type I cytokine receptors.
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PMID:A role for the annexin A2 amino-terminal peptide in the plasmin-induced activation of human peripheral monocytes. 2222 Mar 4

Atherosclerosis is thought to be a chronic inflammatory disease, and many studies show platelets play important role in atherosclerosis formation. Activated platelets adhere to endothelial cells and make leukocyte arrest on endothelial cells. Platelets can interact with both leukocytes and with endothelial cells. Leykocytes or endothelial cells adhere to platelets secrete various inflammatory factors and promote inflammation. On the other hand, inflammation inhibits anti-thrombotic effect on endothelial cells. Annexin A2 is a co-receptor of tissue plasminogen activator and plasminogen and facilitates plasmin generation. We showed annexin A2 can inhibit formation of thrombus in injured blood vessel. Thus, platelets, coagulation, and fibrinolysis may be key factors in inflamed blood wall.
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PMID:[Platelets, coagulation, and fibrinolysis in atherosclerosis formation]. 2122 60

Optimal fibrin balance requires precisely controlled plasmin generation on the surface of endothelial cells, which line the blood vessel wall. As a co-receptor for plasminogen and tissue plasminogen activator (tPA), which are key factors in plasmin generation, the annexin A2 (A2) complex promotes vascular fibrinolysis. The intracellular A2 complex is a heterotetramer of two A2 monomers and two copies of the associated protein, p11. In response to endothelial cell activation, A2 is phosphorylated by src-kinase, and translocated to the cell surface in a highly regulated manner. Over-expression of A2 is seen in acute promyelocytic leukemia during the early hemorrhagic phase, while high titer antibodies to A2, as in antiphospholipid syndrome or cerebral venous thrombosis, are associated with thrombosis. In experimental hyperhomocysteinemia, moreover, derivatization of A2 by homocysteine leads to intravascular fibrin accumulation and dysangiogenesis, features that phenocopy the Anxa2(-/-) mouse. Exogenous A2 may also offer a novel therapeutic approach to ischemic thrombotic stroke, as administration of A2 in conjunction with conventional tPA-based thrombolytic therapy improved outcome in an animal model. Here, we discuss the role of the A2 system in vascular homeostasis, the molecular interactions that regulate its profibrinolytic activity, and its potential role in the pathogenesis and treatment of vascular disease.
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PMID:The annexin A2 system and vascular homeostasis. 2144 88

Differential expression of secretory leukocyte protease inhibitor (SLPI) impacts on tumor progression. SLPI directly inhibits elastase and other serine proteases, and regulates matrix metalloproteinases, plasminogen activation, and plasmin downstream targets to influence invasion. We examined tissues from human oral squamous cell carcinoma (OSCC) for SLPI expression in parallel with proteases associated with tumor progression and evaluated their relationships using tumor cell lines. Significantly decreased SLPI was detected in OSCC compared to normal oral epithelium. Furthermore, an inverse correlation between SLPI and histological parameters associated with tumor progression, including stage of invasion, pattern of invasion, invasive cell grade, and composite histological tumor score was evident. Conversely, elevated plasmin and elastase were positively correlated with histological parameters of tumor invasion. In addition to its known inhibition of elastase, we identify SLPI as a novel inhibitor of plasminogen activation through its interaction with annexin A2 with concomitant reduced plasmin generation by macrophages and OSCC cell lines. In an in vitro assay measuring invasive activity, SLPI blocked protease-dependent tumor cell migration. Our data suggest that SLPI may possess antitumorigenic activity by virtue of its ability to interfere with multiple requisite proteolytic steps underlying tumor cell invasion and may provide insight into potential stratification of oral cancer according to risk of occult metastasis, guiding treatment strategies.
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PMID:Secretory leukocyte protease inhibitor (SLPI) expression and tumor invasion in oral squamous cell carcinoma. 2164 6

Endothelial cells form the inner lining of vascular networks and maintain blood fluidity by inhibiting blood coagulation and promoting blood clot dissolution (fibrinolysis). Plasmin, the primary fibrinolytic enzyme, is generated by the cleavage of the plasma protein, plasminogen, by its activator, tissue plasminogen activator. This reaction is regulated by plasminogen receptors at the surface of the vascular endothelial cells. Previous studies have identified the plasminogen receptor protein S100A10 as a key regulator of plasmin generation by cancer cells and macrophages. Here we examine the role of S100A10 and its annexin A2 binding partner in endothelial cell function using a homozygous S100A10-null mouse. Compared with wild-type mice, S100A10-null mice displayed increased deposition of fibrin in the vasculature and reduced clearance of batroxobin-induced vascular thrombi, suggesting a role for S100A10 in fibrinolysis in vivo. Compared with wild-type cells, endothelial cells from S100A10-null mice demonstrated a 40% reduction in plasminogen binding and plasmin generation in vitro. Furthermore, S100A10-deficient endothelial cells demonstrated impaired neovascularization of Matrigel plugs in vivo, suggesting a role for S100A10 in angiogenesis. These results establish an important role for S100A10 in the regulation of fibrinolysis and angiogenesis in vivo, suggesting S100A10 plays a critical role in endothelial cell function.
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PMID:Regulation of fibrinolysis by S100A10 in vivo. 2176 97


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