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)

Annexin A2 (p36) is a highly alpha-helical molecule that consists of two opposing sides, a convex side that contains the phospholipid-binding sites and a concave side, which faces the extracellular milieu and contains multiple ligand-binding sites. The amino-terminal region of annexin A2 extends along the concave side of the protein and contains the binding site for the S100A10 (p11) subunit. The interaction of these subunits results in the formation of the heterotetrameric form of the protein, annexin A2-S100A10 heterotetramer (AIIt). To simulate the orientation of AIIt on the plasma membrane we bound AIIt to a phospholipid bilayer that was immobilized on a BIAcore biosensor chip. Surface plasmon resonance was used to observe in real time the molecular interactions between phospholipid-associated AIIt or its annexin A2 subunit and the ligands, tissue-type plasminogen activator (t-PA), plasminogen, and plasmin. AIIt bound t-PA (Kd = 0.68 microm), plasminogen (Kd = 0.11 microm), and plasmin (Kd = 75 nm) with moderate affinity. Contrary to previous reports, the phospholipid-associated annexin A2 subunit failed to bind t-PA or plasminogen but bound plasmin (Kd = 0.78 microm). The S100A10 subunit bound t-PA (Kd = 0.45 microm), plasminogen (Kd = 1.81 microm), and plasmin (Kd = 0.36 microm). Removal of the carboxyl-terminal lysines from the S100A10 subunit attenuated t-PA and plasminogen binding to AIIt. These results show that the carboxyl-terminal lysines of S100A10 form t-PA and plasminogen-binding sites. In contrast, annexin A2 and S100A10 contain distinct binding sites for plasmin.
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PMID:Phospholipid-associated annexin A2-S100A10 heterotetramer and its subunits: characterization of the interaction with tissue plasminogen activator, plasminogen, and plasmin. 1273 Feb 31

S100A10 is a key plasminogen receptor of the extracellular cell surface that is overexpressed in many cancer cells. Typically, S100A10 is thought to be anchored to the plasma membrane via the phospholipid-binding sites of its binding partner, annexin A2. Here, using the potent and highly sequence-specific mechanism of RNA interference (RNAi), we have stably silenced the expression of the S100A10 gene in colorectal (CCL-222) cancer cells. We show that siRNA expression mediated by the pSUPER vector causes efficient, stable, and specific down-regulation of S100A10 gene expression. The siRNA-mediated down-regulation of S100A10 gene expression resulted in a major decrease in the appearance of extracellular S100A10 protein and correlated with a 45% loss of plasminogen binding, a 65% loss in cellular plasmin generation and a complete loss in plasminogen-dependent cellular invasiveness. We also observed that the CCL-222 cells do not express annexin A2 on their extracellular surface. Thus, the data show that annexin A2 is not required by S100A10 for its association with the plasma membrane, for its colocalization with uPAR, or for its binding and activation of plasminogen.
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PMID:RNA interference-mediated silencing of the S100A10 gene attenuates plasmin generation and invasiveness of Colo 222 colorectal cancer cells. 1457 Aug 93

Annexin 2 is a profibrinolytic co-receptor for plasminogen and tissue plasminogen activator that stimulates activation of the major fibrinolysin, plasmin, at cell surfaces. In human subjects, overexpression of annexin 2 in acute promyelocytic leukemia leads to a bleeding diathesis reflective of excessive cell surface annexin 2-dependent generation of plasmin (Menell, J. S., Cesarman, G. M., Jacovina, A. T., McLaughlin, M. A., Lev, E. A., and Hajjar, K. A. (1999) N. Engl. J. Med. 340, 994-1004). In addition, mice completely deficient in annexin 2 display fibrin accumulation within blood vessels and impaired clearance of injury-induced thrombi (Ling Q., Jacovina, A.T., Deora, A.B., Febbraio, M., Simantov, R., Silverstein, R. L., Hempstead, B. L., Mark, W., and Hajjar, K. A. (2004) J. Clin. Investig. 113, 38-48). Here, we show that endothelial cell annexin 2, a protein that lacks a typical signal peptide, translocates from the cytoplasm to the extracytoplasmic plasma membrane in response to brief temperature stress both in vitro and in vivo in the absence of cell death or cell lysis. This regulated response is independent of new protein or mRNA synthesis and does not require the classical endoplasmic reticulum-Golgi pathway. Temperature stress-induced annexin 2 translocation is dependent on both expression of protein p11 (S100A10) and tyrosine phosphorylation of annexin 2 because annexin 2 release is completely eliminated on depletion of p11, inactivation of tyrosine kinase, or mutation of tyrosine 23. Translocation of annexin 2 to the cell surface dramatically increases tissue plasminogen activator-dependent plasminogen activation potential and may represent a novel stress-induced protein secretion pathway.
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PMID:An annexin 2 phosphorylation switch mediates p11-dependent translocation of annexin 2 to the cell surface. 1530 70

The defining characteristic of a tumor cell is its ability to escape the constraints imposed by neighboring cells, invade the surrounding tissue and metastasize to distant sites. This invasive property of tumor cells is dependent on activation of proteinases at the cell surface. The serine proteinase plasmin is one of the key proteinases that participate in the pericellular proteolysis associated with the invasive program of tumor cells. The assembly of plasminogen and tissue plasminogen activator at the endothelial cell surface or on the fibrin clot provides a focal point for plasmin generation and therefore plays an important role in maintaining blood fluidity and promoting fibrinolysis. S100A10, a member of the S100 family of Ca2+-binding proteins, is a dimeric protein composed of two 11 kDa subunits. Typically, S100A10 is found in most cells bound to its annexin A2 ligand as the heterotetrameric (S100A10)2(annexin A2)2 complex, AIIt. In addition to an intracellular distribution, S100A10 is present on the extracellular surface of many cells. The carboxyl-terminal lysines of S100A10 bind tPA and plasminogen resulting in the stimulation of tPA-dependent plasmin production. Carboxypeptidases cleave the carboxyl-terminal lysines of S100A10, resulting in a loss of binding and activity. Plasmin binds to S100A10 at a distinct site and the formation of the S100A10-plasmin complex stimulates plasmin autoproteolysis thereby providing a highly localized transient pulse of plasmin activity at the cell surface. The binding of tPA and plasmin to S100A10 also protects against inhibition by physiological inhibitors, PAI-1 and alpha2-antiplasmin, respectively. S100A10 also colocalizes plasminogen with the uPA-uPAR complex thereby localizing and stimulating uPA-dependent plasmin formation to the surface of cancer cells. The loss of S100A10 from the extracellular surface of cancer cells results in a significant loss in plasmin generation. In addition, S100A10 knock-down cells demonstrate a dramatic loss in extracellular matrix degradation and invasiveness as well as reduced metastasis. Annexin A2 plays an important role in plasminogen regulation by controlling the levels of extracellular S100A10 and by acting as a plasmin reductase. The mechanism by which annexin A2 regulates the extracellular levels of S100A10 is unknown. This review highlights the important part that S100A10 plays in plasmin regulation and the role this protein plays in cancer cell invasiveness and metastasis.
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PMID:S100A10, annexin A2, and annexin a2 heterotetramer as candidate plasminogen receptors. 1557 70

The binding of plasminogen activators and plasminogen to the cell surface results in the rapid generation of the serine protease plasmin. Plasmin is further degraded by an autoproteolytic reaction, resulting in the release of an angiostatin, A61 (Lys78-Lys468). Previously, we demonstrated that the annexin A2-S100A10 heterotetramer (AIIt) stimulates the release of A61 from plasmin by promoting the autoproteolytic cleavage of the Lys468-Gly469 bond and reduction of the plasmin Cys462-Cys541 disulfide (Kwon, M., Caplan, J. F., Filipenko, N. R., Choi, K. S., Fitzpatrick, S. L., Zhang, L., and Waisman, D. M. (2002) J. Biol. Chem. 277, 10903-10911). Mechanistically, it was unclear if AIIt promoted a conformational change in plasmin, resulting in contortion of the plasmin disulfide, or directly reduced the plasmin disulfide. In the present study, we show that AIIt thiols are oxidized during the reduction of plasmin disulfides, establishing that AIIt directly participates in the reduction reaction. Incubation of HT1080 cells with plasminogen resulted in the rapid loss of thiol-specific labeling of AIIt by 3-(N-maleimidopropionyl)biocytin. The plasminogen-dependent oxidation of AIIt could be attenuated by thioredoxin. Thioredoxin reductase catalyzed the transfer of electrons from NADPH to the oxidized thioredoxin, thus completing the flow of electrons from NADPH to AIIt. Therefore, we identify AIIt as a substrate of the thioredoxin system and propose a new model for the role of AIIt in the redox-dependent processing of plasminogen and generation of an angiostatin at the cell surface.
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PMID:Annexin A2-S100A10 heterotetramer, a novel substrate of thioredoxin. 1584 82

We have previously demonstrated that plasmin acts as a potent proinflammatory activator of human peripheral monocytes. Here we identify the annexin A2 heterotetramer, composed of annexin A2 and S100A10, as a receptor for the plasmin-induced signaling in human monocytes. Monocytes express the annexin A2 heterotetramer on the cell surface as shown by flow cytometry, fluorescence microscopy, and coimmunoprecipitation of biotinylated cell surface proteins. Binding of plasmin to annexin A2 and S100A10 on monocytes was verified by biotin transfer from plasmin labeled with a trifunctional cross-linker. Antibodies directed against annexin A2 or S100A10 inhibited the chemotaxis elicited by plasmin, but not that induced by fMLP. Further, down-regulation of annexin A2 or S100A10 in monocytes by antisense oligodeoxynucleotides impaired the chemotactic response to plasmin, but not that to fMLP. Antisense oligodeoxynucleotides similarly decreased the TNF-alpha release by plasmin-stimulated, but not by LPS-stimulated, monocytes. At the molecular level, stimulation with plasmin, but not with catalytically inactivated plasmin, induced cleavage of annexin A2 and dissociation of the heterotetramer complex. Substitution of lysine to alanine in position 27 abolished the cleavage of recombinant annexin A2 in vitro. Together, these data identify the annexin A2 heterotetramer as a signaling receptor activated by plasmin via proteolysis.
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PMID:Identification of the annexin A2 heterotetramer as a receptor for the plasmin-induced signaling in human peripheral monocytes. 1637 65

Chronic inflammatory diseases are associated with connective tissue turnover that involves a series of proteases, which include the plasminogen activation system and the family of matrix metalloproteinases (MMPs). Urokinase-type plasminogen activator (uPA) and plasmin, in addition to their role in fibrinolysis and activation of pro-MMPs, have been shown to transduce intracellular signals through specific receptors. The potential for uPA and plasmin to also contribute to connective tissue turnover by directly regulating MMP production was examined in human monocytes. Both catalytically active high m.w. uPA, which binds to the uPAR, and low m.w. uPA, which does not, significantly enhanced MMP-1 synthesis by activated human monocytes. In contrast, the N-terminal fragment of uPA, which binds to uPAR, but lacks the catalytic site, failed to induce MMP-1 production, indicating that uPA-stimulated MMP-1 synthesis was plasmin dependent. Endogenous plasmin generated by the action of uPA or exogenous plasmin increased MMP-1 synthesis by signaling through annexin A2, as demonstrated by inhibition of MMP-1 production with Abs against annexin A2 and S100A10, a dimeric protein associated with annexin A2. Interaction of plasmin with annexin A2 resulted in the stimulation of ERK1/2 and p38 MAPK, cyclooxygenase-2, and PGE(2), leading to increased MMP-1 production. Furthermore, binding of inactive plasmin to annexin A2 inhibited plasmin induction of MMP-1, suggesting that inactive plasmin may be useful in suppressing inflammation.
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PMID:Urokinase-type plasminogen activator stimulation of monocyte matrix metalloproteinase-1 production is mediated by plasmin-dependent signaling through annexin A2 and inhibited by inactive plasmin. 1770 46

In mammalian cells, specific aminoacyl-transfer RNA (tRNA) synthetases have cytokine functions that require interactions with partners outside of the translation apparatus. Little is known about these interactions and how they facilitate expanded functions that link protein translation to other cellular pathways. For example, an alternative splice fragment of tryptophanyl-tRNA synthetase (TrpRS) and a similar natural proteolytic fragment are potent angiostatic factors that act through the vascular endothelial-cadherin receptor and Akt signaling pathway. Here we demonstrate mobilization of TrpRS for exocytosis from endothelial cells and the potential for plasmin to activate the cytokine function of the extracellular synthetase. Direct physical evidence showed that the annexin II-S100A10 complex, which regulates exocytosis, forms a ternary complex with TrpRS. Functional studies demonstrate that both annexin II and S100A10 regulate trafficking of TrpRS. Thus, complexes of mammalian tRNA synthetases with seemingly disparate proteins may in general be relevant to understanding how their expanded functions are implemented.
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PMID:Evidence for annexin II-S100A10 complex and plasmin in mobilization of cytokine activity of human TrpRS. 1799 56

The annexin A2 (A2) heterotetramer, consisting of two copies of A2 and two copies of S100A10/p11, promotes fibrinolytic activity on the surface of vascular endothelial cells by assembling plasminogen and tissue plasminogen activator (tPA) and accelerating the generation of plasmin. In humans, overexpression of A2 by acute promyelocytic leukemia cells is associated with excessive fibrinolysis and hemorrhage, whereas anti-A2 autoantibodies appear to accentuate the risk of thrombosis in patients with anti-phospholipid syndrome. Complete deficiency of A2 in mice leads to a lack of tPA cofactor activity, accumulation of intravascular fibrin, and failure to clear arterial thrombi. Within the endothelial cell, p11 is required for Src kinase-mediated tyrosine phosphorylation of A2, which signals translocation of both proteins to the cell surface. Here we show that p11 is expressed at very low levels in the absence of A2 both in vitro and in vivo. We demonstrate further that unpartnered p11 becomes polyubiquitinated and degraded via a proteasome-dependent mechanism. A2 stabilizes intracellular p11 through direct binding, thus masking an autonomous p11 polyubiquitination signal that triggers proteasomal degradation. This interaction requires both the p11-binding N-terminal domain of A2 and the C-terminal domain of p11. This mechanism prevents accumulation of free p11 in the endothelial cell and suggests that regulation of tPA-dependent cell surface fibrinolytic activity is precisely tuned to the intracellular level of p11.
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PMID:Endothelial cell annexin A2 regulates polyubiquitination and degradation of its binding partner S100A10/p11. 1843 2

Annexin A2 (ANXA2) was reported as the receptor, activator, expression enhancer, or cooperator for plasmin, S100A10, and others. To delineate the effect of ANXA2 on the proteins that are probably associated with tumor development and metastasis by a credible experimental method, we generated an ANXA2 gene knockout tumor cell line, ANXA2(-/-) L5178Y, and compared the expression levels of plasmin, S100A10 and fascin in the generated cell line with in wild type of L5178Y at mRNA and protein levels. The results showed that the mRNA level of plasminogen (PLG) was not substantially changed in cultured ANXA2(-/-) cells, but the protein level of plasmin was significantly lower in the cultured ANXA2(-/-) cells than in cultured ANXA2(+/+) cells. For S100A10 and fascin, their mRNA and protein levels were significantly lower in the cultured ANXA2(-/-) cells than in cultured ANXA2(+/+) cells. Results indicate that ANXA2 introduces the generation or expression of plasmin, S100A10, and fascin in tumor cells. ANXA2 affects PLG/plasmin level by a way post transcription and may be an inducer or enhancer to fascin expression at transcription level. By the regulations, ANXA2 enhances the development, invasion, and metastasis of tumor. The detailed mechanism for the regulations above remains to be further investigated, but our results show the potential of ANXA2 as a new target molecule for the strategies of tumor biotherapy or tumor gene therapy.
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PMID:Annexin A2 regulates the levels of plasmin, S100A10 and Fascin in L5178Y cells. 1860 16


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