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26
An uncleavable uPAR mutant allows dissection of signaling pathways in uPA-dependent cell migration
- Mol. Biol. Cell
, 2006
"... Urokinase-type plasminogen activator (uPA) binding to uPAR induces migration, adhesion, and proliferation through multiple interactions with G proteins-coupled receptor FPRL1, integrins, or the epidermal growth factor (EGF) receptor (EGFR). At least two forms of uPAR are present on the cell surface: ..."
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Urokinase-type plasminogen activator (uPA) binding to uPAR induces migration, adhesion, and proliferation through multiple interactions with G proteins-coupled receptor FPRL1, integrins, or the epidermal growth factor (EGF) receptor (EGFR). At least two forms of uPAR are present on the cell surface: full-length and cleaved uPAR, each specifically interacting with one or more transmembrane proteins. The connection between these interactions and the effects on the signaling pathways activation is not clear. We have exploited an uPAR mutant (hcr, human cleavage resistant) to dissect the pathways involved in uPA-induced cell migration. This mutant is not cleaved by proteases, is glycosylphosphatidylino-sitol anchored, and binds uPA with a normal Kd. Both wild-type (wt) and hcr-uPAR are able to mediate uPA-induced migration, are constitutively associated with the EGFR, and associate with 31 integrin upon uPA binding. However, they engage different pathways in response to uPA. wt-uPAR requires both integrins and FPRL1 to mediate uPA-induced migration, and association of wt-uPAR to 31 results in uPAR cleavage and extracellular signal-regulated kinase (ERK) activation. On the contrary, hcr-uPAR does not activate ERK and does not engage FPRL1 or any other G protein-coupled receptor, but it activates an alternative pathway initiated by the formation of a triple complex (uPAR–31–EGFR) and resulting in the autotyrosine phosphorylation of EGFR.
Regulation of leukocyte adherence and migration by glycosylphosphatidyl-inositol-anchored proteins
"... Abstract Leukocyte extravasation is essential for subsequent inflammation and the immune response. Extravasation can be divided into at least three steps; rolling, firm adhesion, and transendothelial migration. Although the mechanisms involved in the first two steps have been fairly well documented, ..."
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Abstract Leukocyte extravasation is essential for subsequent inflammation and the immune response. Extravasation can be divided into at least three steps; rolling, firm adhesion, and transendothelial migration. Although the mechanisms involved in the first two steps have been fairly well documented, the last step is complex and largely remains to be clarified. This review focuses on the possible role of GPI-anchored proteins on leukocytes in the regulation of their transendothelial migration. In addition to regulation by urokinase and its receptor, which has been regarded as the main modulator, we draw attention to a novel GPI-anchored protein (GPI-80) on human phagocytes that may be involved in regulating leukocyte adhesion and migration. The high degree of homology of GPI-80 with vanin-1, which is expressed on vascular tissues and is involved in prethymic cell homing into the thymus, raises the possibility that there is a family of molecules, including GPI-80 and vanin-1, that may be involved in leukocyte transendothelial migration. The possible role of soluble GPI-anchored proteins in this process is also discussed. J. Leukoc. Biol. 66: 369–374;
Coxiella burnetii avoids macrophage phagocytosis by interfering with spatial distribution of complement receptor 3
- J Immunol
"... Phagocytosis is a highly localized event requiring the formation of spatially and temporally restricted signals. Numerous micro-organisms have taken advantage of this property to invade host cells. Coxiella burnetii, the agent of Q fever, is an obligate intracellular bacterium that has developed a s ..."
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Phagocytosis is a highly localized event requiring the formation of spatially and temporally restricted signals. Numerous micro-organisms have taken advantage of this property to invade host cells. Coxiella burnetii, the agent of Q fever, is an obligate intracellular bacterium that has developed a survival strategy in macrophages based on subversion of receptor-mediated phago-cytosis. The uptake of C. burnetii is mediated by v3 integrin and is restricted by impaired cross-talk of v3 integrin and complement receptor 3 (CR3) (CD11b/CD18). In this study, we showed that CR3 molecules remained outside the pseudopodal extensions induced by C. burnetii in THP-1 monocytes, although v3 integrin was present in the pseudopods. Chemoattractants such as RANTES restored CR3 localization to the front of pseudopodal extensions and increased C. burnetii phagocytosis, dem-onstrating that the localization of CR3 is critical for bacterial uptake. In addition, monocyte activation due to the expression of HIV-1 Nef protein also restored CR3-mediated phagocytosis of C. burnetii by allowing CR3 redistribution toward bacterial-induced pseudopods. The redistribution of CR3 and increased C. burnetii phagocytosis in THP-1 cells stimulated by RANTES or expressing Nef were associated with the inhibition of intracellular replication of C. burnetii. Hence, the localization of CR3 is critical for bacterial phagocytosis and also for the control of bacterial replication. This study describes a nonpreviously reported strategy of phagocytosis subversion by intracellular pathogens based on altered localization of monocyte receptors. The Journal of Immunology, 2003, 170: 4217–4225. Coxiella burnetii is an obligate intracellular microorganismclassified in the subdivision of Proteobacteria (1). Itssurvival strategy in monocytes/macrophages is based on
Nonproteolytic role for the urokinase receptor in cellular migration in vivo
- Am. J. Respir. Cell Mol. Biol
"... The urokinase receptor (uPAR) binds and localizes urokinase activity at cellular surfaces, facilitating fibrinolysis and cellular migration at sites of tissue injury. uPAR also participates in cellular signaling and regulates integrin-dependent adhesion and migration in vitro. We now report evidence ..."
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The urokinase receptor (uPAR) binds and localizes urokinase activity at cellular surfaces, facilitating fibrinolysis and cellular migration at sites of tissue injury. uPAR also participates in cellular signaling and regulates integrin-dependent adhesion and migration in vitro. We now report evidence that uPAR occupancy regulates cellular migration in vivo in the absence of functional urokinase. Recombinant murine KC (1.5 �g), a potent neutrophil chemoattractant, was delivered to the lungs of wild-type, urokinase-deficient or uPAR-deficient mice 18 h after intraperitoneal injection of 200 �g human immunoglobulin G (IgG) or a fusion protein composed of an amino-terminal receptor-binding fragment of urokinase and a human IgG Fc fragment (GFD-Fc). Whole lung lavage for recovery of leukocytes was performed 4 h later. KC treatment resulted in a 100-fold increase in lavage neutrophils. GFD-Fc injection resulted in � 50 % reduction in neutrophil influx in both wild-type and urokinase-deficient animals but had no effect on uPAR �/� mice. A concomitant reduction in alveolar protein leakage but no change in numbers of circulating neutrophils accompanied this attenuated inflammatory response. The reduction in neutrophil influx induced by GFD-Fc is thus related to uPAR occupancy and yet not due to disruption of uPAR-mediated proteolysis. These observations verify that protease-independent functions of uPAR operate in vivo and identify uPAR as a potential target for regulation of inflammatory processes characterized by neutrophil-mediated injury.
Ly6 family proteins in neutrophil biology
- J. Leukoc. Biol
, 2013
"... The murine Ly6 complex was identified 35 years ago using antisera to lymphocytes. With advances in mAb development, molecular cloning, and genome sequenc-ing, 20 structurally related genes have been identified within this complex on chromosome 15. All members of the Ly6 family and their human homolo ..."
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The murine Ly6 complex was identified 35 years ago using antisera to lymphocytes. With advances in mAb development, molecular cloning, and genome sequenc-ing, 20 structurally related genes have been identified within this complex on chromosome 15. All members of the Ly6 family and their human homologues share the highly conserved LU domain and most also possess a GPI anchor. Interestingly, many Ly6 proteins are ex-pressed in a lineage-specific fashion, and their expres-sion often correlates with stages of differentiation. As a result, Ly6 proteins are frequently used as surface markers for leukocyte subset identification and targets for antibody-mediated depletion. Murine neutrophils display prominent surface expression of several Ly6 proteins, including Ly6B, Ly6C, and Ly6G. Although the physiology of most Ly6 proteins is not well understood, a role in neutrophil functions, such as migration, is rec-ognized increasingly. In this review, we will provide an overview of the Ly6 complex and discuss, in detail, the specific Ly6 proteins implicated in neutrophil biology. J. Leukoc. Biol. 94: 000–000; 2013.
Urokinase-deficient and urokinase receptor-deficient mice have impaired neutrophil antimicrobial activation in vitro
"... Abstract: Leukocytes express both urokinasetype plasminogen activator (uPA) and the urokinase receptor (uPAR, CD87). We have shown that neutrophil recruitment to the lung during P. aeruginosa pneumonia is impaired in uPAR-deficient (uPAR�/�) mice but is normal in uPA�/� mice. However, both uPA�/ � m ..."
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Abstract: Leukocytes express both urokinasetype plasminogen activator (uPA) and the urokinase receptor (uPAR, CD87). We have shown that neutrophil recruitment to the lung during P. aeruginosa pneumonia is impaired in uPAR-deficient (uPAR�/�) mice but is normal in uPA�/� mice. However, both uPA�/ � mice and uPAR�/� mice have impaired lung clearance of P. aeruginosa compared with wild-type (WT) mice. To determine the role of uPA and uPAR in antibacterial host defense, we compared neutrophil bacterialphagocytosis, respiratory burst, and degranulation among uPA�/�, uPAR�/�, and WT mice. Neutrophil phagocytosis was significantly diminished comparing uPA�/ � and uPAR�/ � mice with WT mice at all time points. The generation of superoxide by both uPA�/ � and uPAR�/ � neutrophils was about half of that seen in WT neutrophils. Degranulation of azurophilic granules was significantly diminished in uPA�/ � neutrophils compared with either uPAR�/ � or WT neutrophils. By contrast, agonist-stimulated release of specific granules was not diminished in either uPA�/ � or uPAR�/ � mice compared with WT. We conclude that the uPA/uPAR system modulates several of the crucial steps in neutrophil activation that result in bacterial killing and effective innate host defense.
Regulation of leukocyte recruitment by polypeptides derived from high molecular weight kininogen
- FASEB J
, 2001
"... weight kininogen ..."
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unknown title
, 2008
"... Antibody ligation of murine Ly-6G induces neutropenia, blood flow cessation, and death via complement-dependent and independent mechanisms ..."
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Antibody ligation of murine Ly-6G induces neutropenia, blood flow cessation, and death via complement-dependent and independent mechanisms
Absence of Urokinase-Type Plasminogen Activator (uPA) Receptor, but Is Independent of uPA 1
, 2013
"... This article cites 38 articles, 24 of which you can access for free at: ..."
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Glucocorticoid Receptor Activation Reduces CD11b and CD49d Levels on Murine Eosinophils Characterization and Functional Relevance
"... In vitro incubation of mouse blood eosinophils with dexamethasone (DEX) resulted in concentration- and time-dependent reduction in CD11b and CD49d cell-surface expression as detected by flow cytometry. This inhibitory effect ranged between 20 and 40 % for both integrins, and it was not related to al ..."
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In vitro incubation of mouse blood eosinophils with dexamethasone (DEX) resulted in concentration- and time-dependent reduction in CD11b and CD49d cell-surface expression as detected by flow cytometry. This inhibitory effect ranged between 20 and 40 % for both integrins, and it was not related to alteration of cell survival. DEX was maximally effective at 1 �M, and it was prevented by coaddition of the glucocorticoid receptor antagonist RU486 (mifepristone; 10 �M). Budesonide, hydrocortisone, and prednisolone, but not the sex steroids testosterone and progesterone, reduced CD11b and CD49d cell-surface expression to a similar extent. Subchronic treatment of mice with 1 mg/kg DEX again reduced both CD11b and CD49d expression on circulating eosinophils, without alterations in CD11b messenger RNA expression as assessed by polymerase chain reaction analysis. In contrast, membrane but not intracellular protein expression of either CD11b or CD49d was inhibited by eosinophil incubation with DEX in vitro; thus, an interference with exportation of these adhesion molecules to the cell surface is proposed as the mechanism of action of the glucocorticoid. Finally, steroid effects on integrin expression were linked to a reduced eosinophil function as indicated by a lower degree of cell chemotaxis after incubation with DEX, an effect which was again prevented by 10 �M RU486. These observations may explain part of the therapeutic efficacy displayed by glucocorticoid hormones in the clinical control of tissue eosinophilia in allergic disease conditions.
