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 function of urokinase and its receptor is essential for cell migration in pathological conditions, as shown by the analysis of knockout mice phenotypes. How a protease of a fibrinolytic pathway can induce migration is not understood and no link between this protease and migration-promoting G protein-coupled receptors has been described. We now show that FPRL1/LXA4R, a G protein-coupled receptor for a number of polypeptides and for the endogenous lipoxin A4 (LXA4), is the link between urokinase-type plasminogen activator (uPA) and migration as it directly interacts with an activated, soluble, cleaved form of uPA receptor (uPAR) (D2D3(88-274)) to induce chemotaxis. In this article we show that (i) both uPAR and FPRL1/LXA4R are necessary for the chemotactic activity of uPA whereas FPRL1/LXA4R is sufficient to mediate D2D3(88-274)-induced cell migration. (ii) Inhibition or desensitization of FPRL1/LXA4R by antibodies or specific ligands specifically prevents chemotaxis induced by D2D3(88-274) in THP-1 cells and human peripheral blood monocytes. (iii) Desensitization of FPRL1/LXA4R prevents the activation of tyrosine kinase Hck induced by D2D3(88-274). (iv) D2D3(88-274) directly binds to FPRL1/LXA4R and is competed by two specific FPRL1/LXA4R agonists, the synthetic MMK-1 peptide and a stable analog of LXA4. Thus, a naturally produced cleaved form of uPAR is a unique endogenous chemotactic agonist for FPRL1/LXA4R receptor and its activity can be antagonized by specific ligands. These results provide the first direct link, to our knowledge, between the fibrinolytic machinery and the inflammatory response, demonstrating that uPA-derived peptide fragments can activate a specific chemotactic receptor.
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PMID:The fibrinolytic receptor for urokinase activates the G protein-coupled chemotactic receptor FPRL1/LXA4R. 1181 41

The serine-protease urokinase (uPA) and its specific membrane receptor uPAR controls matrix degradation through the conversion of plasminogen into plasmin and play a crucial role in a number of biological processes including local fibrinolysis, inflammation, angiogenesis, matrix remodelling during wound healing, tumor invasion and metastasis. Most of the cellular responses modulated by the uPA/uPAR system, including migration, cellular adhesion, differentiation, proliferation and apoptosis require transmembrane signaling, which is mediated by direct contacts of uPAR with a variety of extracellular proteins and membrane receptors, such as integrins, EGF receptor, high molecular weight kininogen, caveolin and the G-protein-coupled receptor FPRL1. As a result of these interactions, uPAR activates intracellular signalling molecules such as tyrosine- and serine-protein kinases, Src, focal adhesion kinase (FAK), Rac, extracellular-signal-regulated kinase (ERK)/mitogen- activated protein kinase (MAPK) and JAK/STAT, being part of a large "signalosome" interacting with several molecules on both the outside and inside of the cell. This review is focused on the biochemistry of the pathways affected by uPAR and its partners.
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PMID:The urokinase receptor as an entertainer of signal transduction. 1927 72

ECRG2 is a novel tumor suppressor gene that shows sequence similarity to KAZAL-type serine protease inhibitor. We have previously demonstrated ECRG2 inhibits migration/invasion of lung cancer PG cells. However, the mechanism by which ECRG2 performs these activities remains unknown. In this study, we found that ECRG2 inhibits proteolysis activity of uPA/plasmin and MMP2, and substantially reduces the ability of HT1080 and HCT-116 cells to invade ECM. Moreover, we demonstrated ECRG2 prevents the cleavage of uPAR, disrupts the association of sD2D3 with FPRL1, and that disruption impairs FPRL1 function. Conversely, depletion of ECRG2 not only markedly increased proteolysis activity of uPA/plasmin and MMP2 but also enhanced the association of uPAR with FPRL1, stimulated cell migration/invasion. Together, our results provide evidence that ECRG2 regulates invasion/migration partly through ECM degradation and uPA/uPAR/FPRL1 pathway, and may represent a novel therapeutic target for cancer.
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PMID:ECRG2 regulates ECM degradation and uPAR/FPRL1 pathway contributing cell invasion/migration. 1979 67

The degradation of the extracellular matrix plays an important role in the processes of morphogenesis, angio- and neurogenesis, wound healing, inflammation, carcinogenesis and others. The urokinase receptor uPAR is an important participant in processes that regulate extracellular proteolysis, cell adhesion to the extracellular matrix, cell migration along the chemokine gradient, proliferation and survival involving growth factor receptors. The presence of the GPI anchor and the absence of transmembrane and cytoplasmic domains in uPAR promote involvement of membrane partners for the realization of uPAR signal effects. In some studies, involvement of the fMLP chemokine receptor FPRL in the regulation of uPAR-dependent directed migration has been shown. Moreover, the migration of neural progenitors and their maturation into neurons during the formation of brain structures are regulated by chemokine receptors. Despite the data on the role of uPARin the processes of morphogenesis, little is known about the interactions between uPAR and chemokine receptors in guidance processes during nerve growth and regeneration. In the present work, it was shown for the first time that the soluble form of uPAR (suPAR) regulates the trajectory of axon outgrowth, and this effect does not depend on the presence of urokinase. It was also shown that regulation of the directed axon growth is based on the interaction of suPAR with the chemokine receptor FPRL1. These data show new mechanisms for the participation of the urokinase system in the regulation of axon guidance.
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PMID:[Mechanisms of Participation of the Urokinase Receptor in Directed Axonal Growth]. 3216 94