1,721,048 research outputs found
Multiple activities of a multifaceted receptor: roles of cleaved and soluble uPAR.
No full textThe urokinase-type plasminogen activator receptor (uPAR) is a GPI-anchored cell-surface receptor involved in many physiological and pathological events that include cell migration and tissue invasion. uPAR traditional role was considered the focusing of uPA proteolytic activity on the cell surface; however, different uPAR activities have been demonstrated in the last years. In fact, cell surface uPAR functionally interacts with integrins, fMLP-receptors (fMLP-Rs) and growth factor receptors, thus regulating cell adhesion, migration and proliferation. uPAR also exists in a soluble form (suPAR) that has been detected in human body fluids. Both cell surface and suPAR can be proteolytically cleaved, thus generating truncated forms lacking the N-terminal domain and exposing the specific sequence able to interact with the fMLP-Rs. The cleaved form of suPAR binds and activates the fMLP-Rs and regulates the activity of MCP-1, RANTES and SDF1 receptors. Here, we review the role that shedding and cleavage could play in regulating uPAR structural/functional interaction with other cell-surface receptors and in uPAR-mediated biological and pathological processes
The N-formyl peptide receptors: much more than chemoattractant receptors. Relevance in health and disease
No full textPattern Recognition Receptors (PRRs) are a superfamily of receptors that detect molecular structures typical for pathogens and damaged cells and play a crucial role in the proper function of the innate immune system. A particular subgroup of membrane-bound PRRs is represented by the N-formyl peptide receptors (FPRs) that consist of transmembrane G-protein coupled receptors involved in inflammatory responses. FPRs were initially described in immune cells as transducers of chemotactic signals in phagocytes that react to tissue injury. Subsequently, FPRs were also identified in a wide variety of cell types, including cancer cells. Beyond broad cellular distribution, FPRs are also characterized by the ability to bind a variety of ligands with different chemical and biological properties, ranging from natural peptides to synthetic compounds. The binding of FPRs to specific agonists induces a cascade of functional biological events, such as cell proliferation, migration, angiogenesis, and oxidative stress. From all this evidence, it becomes clear that FPRs are multifaceted receptors involved in several pathophysiological processes associated with inflammation. In this review, we provide a comprehensive molecular description of structure-function relationship of FPRs and their pivotal role in the host defense, highlighting the regulatory functions in both the initiation and resolution of inflammation. In addition to their activity as PRRs during innate immune response, we focus on their involvement in pathological conditions, including chronic inflammatory disease, neurodegenerative disorders, and cancer, with special emphasis on FPR targeting as promising therapeutic strategies in the era of precision medicine
Urokinase-type plasminogek-activator receptor associates with a cell surface molecule in monocytic cells
No full textThe urokinase-type plasminogen activator (uPA) is a specific protease which, by converting plasminogen into plasmin, can promote the degradation of the extracellular matrix. uPA and its specific cellular receptor (uPA-R) are involved in cell migration and in tissue remodelling process. The urokinase-type plasminogen-activator receptor (uPA-R) cross-linked to its possible ligands, in THP-1 cells, appears to have a molecular wheight 10-15 kDa higher than the same molecular species in the epithelial thyroid cell line TAD-2. The same difference is observed comparing peripheral monocytes and primary cultures of thyroid. Molecular wheight of not cross-linked receptors is about 50 kDa and appears to be identical in these two cell types. These results suggest that, in monocytic cells, uPA-R associates with a 10-15 kDa molecule. This molecule is probably linked to the cell surface by a glyco-phospho-inositol anchor because it is eluted with the urokinase-type plasminogen activator receptor from THP-1 cells by phospholipase-C treatment
The urokinase-receptor in infectious diseases.
No full textCell migration through the extracellular matrix (ECM) or endothelial cells is a basic process in several physiological and pathological events, including the immune host response to pathogens, both in the case of innate and adaptive immunity. The urokinase-type plasminogen activator (uPA) receptor (uPAR) is a GPI-anchored cell-surface receptor largely expressed on most of leukocytes, including monocytes/macrophages, granulocytes, immature dendritic cells. uPAR has been detected also in soluble and cleaved forms, which are increased in several pathologies. uPAR focuses the proteolytic activity of its ligand, the serine-protease uPA, on the cell membrane, thus promoting localized plasminogen activation and allowing the cell to degrade surrounding ECM and to move across physical barriers. However, the discovery that uPAR can bind with high affinity a component of the ECM, vitronectin (VN), and associates to cell surface molecules to activate signalling pathways inside the cells, largely expanded the role that uPAR can play in cell proliferation/survival and adhesion/migration, which are crucial events for an efficient immune response to infectious agents. This review is focused on the expression and possible functions of the various forms of uPAR in infectious diseases
Post-transcriptional regulation of gene expression in the plasminogen activation system.
No full textThe urokinase-mediated plasminogen activation (PA) system has been shown to play a key role in cell migration and tissue invasion by regulating both cell-associated proteolysis and cell-cell and cell-matrix interactions. The expression and activity of the components of this complex system are strictly regulated. The control of the expression occurs both at transcriptional and post-transcriptional levels. This review is focused on the post-transcriptional regulation of gene expression of all components of the PA system
The value of flow cytometry clonality in large granular lymphocyte leukemia
No full textLarge granular lymphocyte (LGL) leukemia is a lymphoproliferative disorder of mature T or NK cells frequently associated with autoimmune disorders and other hematological conditions, such as myelodysplastic syndromes. Immunophenotype of LGL cells is similar to that of effector memory CD8+ T cells with T-cell receptor (TCR) clonality defined by molecular and/or flow cytometric analysis. Vβ usage by flow cytometry can identify clonal TCR rearrangements at the protein level, and is fast, sensitive, and almost always available in every Hematology Center. Moreover, Vβ usage can be associated with immunophenotypic characterization of LGL clone in a multiparametric staining, and clonal kinetics can be easily monitored during treatment and follow-up. Finally, Vβ usage by flow cytometry might identify LGL clones silently underlying other hematological conditions, and routine characterization of Vβ skewing might identify recurrent TCR rearrangements that might trigger aberrant immune responses during hematological or autoimmune conditions
Soluble and cleaved forms of the urokinase-receptor: degradation products or active molecules?
No full textThe urokinase-mediated plasminogen activation (PA) system is involved in many physiological and pathological events that include cell migration and tissue remodelling, such as embryogenesis, ovulation, inflammation, wound healing, angiogenesis and tumor invasion and metastasis. The urokinase receptor (uPAR) is a key molecule of this system and can bind extracellular and cell membrane molecules such as urokinase (uPA), vitronectin (VN), integrins and chemotaxis receptors. These multiple interactions can be modulated by the shedding or the cleavage of the cell membrane receptor. Indeed, cleaved forms of uPAR, lacking the N-terminal D1 domain, have been detected on the surface of cells and in tissues, while soluble forms have been found in biological fluids. Cleaved and soluble forms could represent the intermediary products of the uPAR metabolism or active molecules with precise and distinct functional roles.
Here, we review the data concerning the in vitro and in vivo identification of these uPAR forms, their origin and functions, and the role that uPAR shedding and cleavage could play in biological processes
The cleavage of the urokinase receptor regulates its multiple functions.
No full textThe urokinase-type plasminogen activator (uPA) is able to cleave its cell surface receptor (uPAR) anchored to the cell membrane through a glycophosphatidylinositol tail. The cleavage leads to the formation of cell surface truncated forms, devoid of the N-terminal domain 1 (D1) and unmasks or disrupts, depending on the cleavage site, a sequence in the D1-D2 linker region (residues 88-92), which in the soluble form is a potent chemoattractant for monocyte-like cells. To investigate the possible role(s) of the cleaved forms of cell surface glycophosphatidylinositol-anchored uPAR, uPAR-negative human embrional kidney 293 cells were transfected with the cDNA of intact uPAR (uPAR-293) or with cDNAs corresponding to the truncated forms of uPAR exposing (D2D3-293) or lacking (D2D3wc-293) the peptide 88-92 (P88-92). Cell adhesion assays and co-immunoprecipitation experiments indicated that the removal of D1, independently of the presence of P88-92, abolished the lateral interaction of uPAR with integrins and its capability to regulate integrin adhesive functions. The expression of intact uPAR induced also a moderate increase in 293 cell proliferation, which was accompanied by the activation of ERK. Also this effect was abolished by D1 removal, independently of the presence of P88-92. The expression of intact and truncated uPARs regulated cell directional migration toward uPA, the specific uPAR ligand, and toward fMLP, a bacterial chemotactic peptide. In fact, the uPA-dependent cell migration required the expression of intact uPAR, including D1, whereas the fMLP-dependent cell migration required the expression of a P88-92 containing uPAR and was independent of the presence of D1. Together these observations indicate that uPA-mediated uPAR cleavage and D1 removal, occurring on the cell surface of several cell types, can play a fundamental role in the regulation of multiple uPAR functions
The urokinase receptor: A multifunctional receptor in cancer cell biology. therapeutic implications
No full textProteolysis is a key event in several biological processes; proteolysis must be tightly controlled because its improper activation leads to dramatic consequences. Deregulation of proteolytic activity characterizes many pathological conditions, including cancer. The plasminogen activation (PA) system plays a key role in cancer; it includes the serine-protease urokinase-type plasminogen activator (uPA). uPA binds to a specific cellular receptor (uPAR), which concentrates proteolytic activity at the cell surface, thus supporting cell migration. However, a large body of evidence clearly showed uPAR involvement in the biology of cancer cell independently of the proteolytic activity of its ligand. In this review we will first describe this multifunctional molecule and then we will discuss how uPAR can sustain most of cancer hallmarks, which represent the biological capabilities acquired during the multistep cancer development. Finally, we will illustrate the main data available in the literature on uPAR as a cancer biomarker and a molecular target in anti-cancer therapy
Plasminogen System in the Pathophysiology of Sepsis: Upcoming Biomarkers
No full textSevere hemostatic disturbances and impaired fibrinolysis occur in sepsis. In the most serious cases, the dysregulation of fibrinolysis contributes to septic shock, disseminated intravascular coagulation (DIC), and death. Therefore, an analysis of circulating concentrations of pro- and anti-fibrinolytic mediators could be a winning strategy in both the diagnosis and the treatment of sepsis. However, the optimal cutoff value, the timing of the measurements, and their combination with coagulation indicators should be further investigated. The purpose of this review is to summarize all relevant publications regarding the role of the main components of the plasminogen activation system (PAS) in the pathophysiology of sepsis. In addition, the clinical value of PAS-associated biomarkers in the diagnosis and the outcomes of patients with septic syndrome will be explored. In particular, experimental and clinical trials performed in emergency departments highlight the validity of soluble urokinase plasminogen activator receptor (suPAR) as a predictive and prognostic biomarker in patients with sepsis. The measurements of PAI-I may also be useful, as its increase is an early manifestation of sepsis and may precede the development of thrombocytopenia. The upcoming years will undoubtedly see progress in the use of PAS-associated laboratory parameters
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