Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.73 (urokinase-type plasminogen activator)
 10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The gene for CD59 [membrane inhibitor of reactive lysis (MIRL), protectin], a phosphatidylinositol-linked surface glycoprotein that regulates the formation of the polymeric C9 complex of complement and that is deficient on the abnormal hematopoietic cells of patients with paroxysmal nocturnal hemoglobinuria, consists of four exons spanning 20 kilobases. The untranslated first exon is preceded by a G+C-rich promoter region that lacks a consensus TATA or CAAT motif. The second exon encodes the hydrophobic leader sequence of the protein, and the third exon encodes the amino-terminal portion of the mature protein. The fourth exon encodes the remainder of the mature protein, including the hydrophobic sequence necessary for glycosyl-phosphatidylinositol anchor attachment. The structure of the CD59 gene is very similar to that encoding Ly-6, a murine glycoprotein with which CD59 has some structural similarity. The striking similarity in gene structure is further evidence that the two proteins belong to a superfamily of proteins that may also include the urokinase plasminogen-activator receptor and a squid glycoprotein of unknown function.
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PMID:Structure of the CD59-encoding gene: further evidence of a relationship to murine lymphocyte antigen Ly-6 protein. 138 3

The secretion of plasminogen activators has been implicated in the controlled extracellular proteolysis that accompanies cell migration and tissue remodeling. We found that the human plasminogen activator urokinase (Uk) (Mr 55,000 form) binds rapidly, specifically, and with high affinity to fresh human blood monocytes and to cells of the monocyte line U937. Upon binding Mr 55,000 Uk was observed to confer high plasminogen activator activity to the cells. Binding of the enzyme did not require a functional catalytic site (located on the B chain of the protein) but did require the noncatalytic A chain of Mr 55,000 Uk, since Mr 33,000 Uk did not bind. These results demonstrate the presence of a membrane receptor for Uk on monocytes and show a hitherto unknown function for the A chain of Uk: binding of secreted enzyme to its receptor results in Uk acting as a membrane protease. This localizes plasminogen activation near the cell surface, an optimal site to facilitate cell migration.
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PMID:A cellular binding site for the Mr 55,000 form of the human plasminogen activator, urokinase. 388 Jul 60

It has been shown that a 90-kDa protein (90K), with an as yet unknown function, is expressed in the majority of human breast-cancer tissues. In addition, the serum level of this 90K antigen is elevated in a certain proportion of breast-cancer patients, and high serum levels are associated with a poor overall survival. It was therefore of interest to determine whether levels of 90K in tumor tissues could be used as a prognostic variable in breast cancer. In the present study, the levels of 90K in primary breast tumor cytosols were studied with respect to the length of relapse-free or overall survival in 547 patients (median follow-up, 81.4 months), and the relationship with response to first-line tamoxifen therapy and the length of progression-free survival in 184 patients with recurrent disease (median follow-up, 59.8 months). 90K levels in tumor cytosols were determined with an immunoradiometric assay. The cytosolic contents of 90K were not significantly correlated with age, menopausal status, tumor size, nodal status or differentiation grade. On the other hand, the levels of 90K were positively correlated with those of cytosolic estrogen receptor, progesterone receptor, urokinase-type plasminogen activator, its inhibitor PAI-I, cathepsin D and PS2. The cytosolic tumor level of 90K was not associated with the rate of relapse or death in primary breast cancer, nor with response to first-line therapy with tamoxifen or the length of progression-free survival in recurrent disease.
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PMID:Expression of tumor-associated 90K-antigen in human breast cancer: no correlation with prognosis and response to first-line therapy with tamoxifen. 761 55

A hitherto unknown function of midkine (MK) was found in the regulation of fibrinolytic activity of vascular endothelial cells. Recombinant murine MK enhanced plasminogen activator (PA)/plasmin levels in bovine aortic endothelial cells (BAECs) in a dose- and time-dependent manner. After incubation with 10 ng/ml MK for 18 h, PA and plasmin levels increased 6- and 4-fold, respectively. This effect was attributed to a moderate upregulation of urokinase-type PA expression as well as to a significant down-regulation of PA inhibitor-1 (PAI-1) expression. BAECs constitutively synthesized and secreted MK and its production was enhanced 2-fold with 1 microM retinoic acid or 10 microM retinol. It was found that MK served as a substrate for tissue transglutaminase. In the culture medium, MK existed as a transglutaminase-mediated complex of 36 kDa. Addition of anti-MK antibody to BAEC cultures resulted in a decrease of basal PA activity and an increase of basal PAI-1 levels and attenuated the ability of retinol to enhance PA activity 50% and potentiated the ability to increase PAI-1 levels 4-fold. Furthermore, MK and basic fibroblast growth factor (bFGF) acted more than additively in enhancing PA levels. We conclude that in BAECs MK is a novel autocrine factor sustaining the fibrinolytic property. MK functions as a mediator of retinoid and cooperates with bFGF to enhance fibrinolytic activity of BAECs.
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PMID:Midkine enhances fibrinolytic activity of bovine endothelial cells. 772 90

The plasminogen activation cascade system, directed by urokinase and the urokinase receptor, plays a key role in extracellular proteolysis during tissue remodeling. To identify molecular interaction partners of these trigger proteins on the cell, we combined covalent protein cross-linking with mass spectrometry based methods for peptide mapping and primary structure analysis of electrophoretically isolated protein conjugates. A specific tri-molecular complex was observed upon addition of pro-urokinase to human U937 cells. This complex included the urokinase receptor, pro-urokinase, and an unknown, high molecular weight urokinase receptor-associated protein. The tryptic peptide mixture derived from a cross-linked complex of pro-urokinase and the latter protein was analyzed by nanoelectrospray tandem mass spectrometric sequencing. This analysis identified the novel protein as the human homologue of a murine membrane-bound lectin with hitherto unknown function. The human cDNA was cloned and sequenced. The protein, designated uPARAP, is a member of the macrophage mannose receptor protein family and contains a putative collagen-binding (fibronectin type II) domain in addition to 8 C-type carbohydrate recognition domains. It proved capable of binding strongly to a single type of collagen, collagen V. This collagen binding reaction at the exact site of plasminogen activation on the cell may lead to adhesive functions as well as a contribution to cellular degradation of collagen matrices.
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PMID:A urokinase receptor-associated protein with specific collagen binding properties. 1063 2

The SspB cysteine protease of Staphylococcus aureus is expressed in an operon, flanked by the sspA serine protease, and sspC, encoding a 12.9-kDa protein of unknown function. SspB was expressed as a 40-kDa prepropeptide pSspB, which did not undergo autocatalytic maturation. Activity of pSspB was reduced compared with 22-kDa mature SspB, but it was equivalent to mature SspB after incubation with SspA, which specifically removed the pSspB N-terminal propeptide. SspC abrogated the activity of pSspB when incubated in a 1:1 complex but had no effect on SspA or papain. Activity of the pSspB.SspC complex was restored when incubated with SspA, and SspC was cleaved by SspA but not pSspB. Thus, SspC maintains pSspB as an inert zymogen, and SspA is required for removal of the propeptide and inactivation of SspC. Like the papain protease family, SspB cleaved substrates with a hydrophobic amino acid at P2 but had a strong preference for arginine at P1. It did not cleave casein, serum albumin, IgG, or IgA, but it promoted detachment of cultured keratinocytes and cleaved fibronectin and fibrinogen at sites recognized by urokinase plasminogen activator and plasmin, respectively. It also processed high molecular weight kininogen in a manner resembling plasma kallikrein. Thus, SspB exhibits a novel maturation mechanism and mimics the specificity of plasma serine proteases.
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PMID:Identification of a novel maturation mechanism and restricted substrate specificity for the SspB cysteine protease of Staphylococcus aureus. 1220 24

To improve tumor targeting in a subset of patients, where tumor cells do not express the well-known tumor antigens widely used in immunotherapy, we have developed a novel biotechnological tool. It is useful for tumors of various origins for the identification of tumor-associated proteins, which are differentially expressed in tumor cells with respect to normal tissue, and exposed on the cell surface. For this purpose, a combination of techniques, such as "suppression subtractive hybridization" and "transmembrane trapping," was employed. In applying this novel approach to breast cancer, we identified a large panel of cDNA fragments encoding for the well-known tumor-associated surface antigens, such as erb-B2, erbB3 and the urokinase receptor and, more importantly, for several clones overexpressed in breast cancer, whose cDNA fragments match the sequences of hypothetical transmembrane proteins with unknown function. The latter may represent novel tumor-specific targets.
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PMID:A novel approach for identification of tumor-associated antigens expressed on the surface of tumor cells. 1716 17

Plau codes for the urokinase-type plasminogen activator (uPA), critical in cancer metastasis. While the mechanisms driving its overexpression in tumorigenic processes are unknown, it is regulated by the AP-1 transcriptional complex in diverse situations. The AP-1 component Fra-1 being overexpressed in aggressive breast cancers, we have addressed its role in the overexpression of Plau in the highly metastatic breast cancer model cell line MDA-MB231 using ChIP, pharmacological and RNAi approaches. Plau transcription appears controlled by 2 AP-1 enhancers located -1.9 (ABR-1.9) and -4.1 kb (ABR-4.1) upstream of the transcription start site (TSS) of the uPA-coding mRNA, Plau-001, that bind Fra-1. Surprisingly, RNA Pol II is not recruited only at the Plau-001 TSS but also upstream in the ABR-1.9 and ABR-4.1 region. Most Pol II molecules transcribe short and unstable RNAs while tracking down toward the TSS, where there are converted into Plau-001 mRNA-productive species. Moreover, a minority of Pol II molecules transcribes a low abundance mRNA of unknown function called Plau-004 from the ABR-1.9 domain, whose expression is tempered by Fra-1. Thus, we unveil a heretofore-unsuspected transcriptional complexity at Plau in a reference metastatic breast cancer cell line with pleiotropic effects for Fra-1, providing novel information on AP-1 transcriptional action.
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PMID:Transcriptional complexity and roles of Fra-1/AP-1 at the uPA/Plau locus in aggressive breast cancer. 2520 76

Quebec Platelet disorder (QPD) is a unique bleeding disorder that markedly increases urokinase plasminogen activator (uPA) in megakaryocytes and platelets but not in plasma or urine. The cause is tandem duplication of a 78 kb region of chromosome 10 containing PLAU (the uPA gene) and C10orf55, a gene of unknown function. QPD increases uPA in platelets and megakaryocytes >100 fold, far more than expected for a gene duplication. To investigate the tissue-specific effect that PLAU duplication has on gene expression and transcript structure in QPD, we tested if QPD leads to: 1) overexpression of normal or unique PLAU transcripts; 2) increased uPA in leukocytes; 3) altered levels of C10orf55 mRNA and/or protein in megakaryocytes and leukocytes; and 4) global changes in megakaryocyte gene expression. Primary cells and cultured megakaryocytes from donors were prepared for quantitative reverse polymerase chain reaction analyses, RNA-seq and protein expression analyses. Rapidly isolated blood leukocytes from QPD subjects showed only a 3.9 fold increase in PLAU transcript levels, in keeping with the normal to minimally increased uPA in affinity purified, QPD leukocytes. All subjects had more uPA in granulocytes than monocytes and minimal uPA in lymphocytes. QPD leukocytes expressed PLAU alleles in proportions consistent with an extra copy of PLAU on the disease chromosome, unlike QPD megakaryocytes. QPD PLAU transcripts were consistent with reference gene models, with a much higher proportion of reads originating from the disease chromosome in megakaryocytes than granulocytes. QPD and control megakaryocytes contained minimal reads for C10orf55, and C10orf55 protein was not increased in QPD megakaryocytes or platelets. Finally, our QPD megakaryocyte transcriptome analysis revealed a global down regulation of the interferon type 1 pathway. We suggest that the low endogenous levels of uPA in blood are actively regulated, and that the regulatory mechanisms are disrupted in QPD in a megakaryocyte-specific manner.
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PMID:The duplication mutation of Quebec platelet disorder dysregulates PLAU, but not C10orf55, selectively increasing production of normal PLAU transcripts by megakaryocytes but not granulocytes. 2830 87

Pathogenic Leptopira is the etiological agent of leptospirosis, the most widespread zoonotic infection in the world. The disease represents a major public health problem, especially in tropical countries. The present work focused on two hypothetical proteins of unknown function, encoded by the genes LIC13059 and LIC10879, and predicted to be surface-exposed proteins. The genes were cloned and the proteins expressed using E. coli as a host system. We report that the recombinant proteins interacted with extracellular matrix (ECM) laminin, in a dose-dependent fashion and are novel potential adhesins. The recombinant proteins were called Lsa25.6 (rLIC13059) and Lsa16 (rLIC10879), for Leptospiral surface adhesins, followed by the respective molecular masses. The proteins attached to plasminogen (PLG), generating plasmin, in the presence of PLG-activator uPA. Both proteins bind to fibrinogen (Fg), but only Lsa25.6 inhibited fibrin clotting by thrombin-catalyzed reaction. Moreover, Lsa16 interacts with the mammalian cell receptor E-cadherin, and could contribute to bacterial attachment to epithelial cells. The proteins were recognized by confirmed leptospirosis serum samples, suggesting that they are expressed during infection. The corresponding leptospiral proteins are surface exposed based on proteinase K accessibility assay, being LIC10879 most probably exposed in its dimer form. The data of this study extend the spectrum of surface-exposed proteins of L. interrogans and indicate a possible role of the originally annotated hypothetical proteins in infection processes.
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PMID:Multifunctional and Redundant Roles of Leptospira interrogans Proteins in Bacterial-Adhesion and fibrin clotting inhibition. 2860 Jan 23


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