Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Structure and Functions of the Urokinase Receptor

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_536


Historical Background

The receptor (uPAR) for the urokinase-type plasminogen activator (uPA) was firstly identified in 1985 on the surface of monocyte-like cells but only in 1990 uPAR protein was purified and cDNA cloned and sequenced. The first role proposed for uPAR was the focusing of the uPA proteolytic activity on the cell membrane, thus allowing cell migration through the extracellular matrix (ECM), without affecting the general architecture of the tissue. Since then, a large body of evidence clearly showed various roles for uPAR, independent of uPA enzymatic activity. In fact, uPAR is able to transduce proliferation, differentiation, adhesion, and migration signals into the cells, despite the absence of a transmembrane region and a cytosolic tail. However, the ability of uPAR to focus uPA activity on the cell membrane attributed to this specific receptor a key role in the plasminogen activation system.

Plasminogen is a plasma zymogen; the cleavage at the Arg561-Val562 bond converts the single polypeptide chain plasminogen into plasmin, that consists of two polypeptide chains held together by a disulfide bond. Plasminogen can associate to fibrin via lysine-binding sites located in the noncatalytic region. In fact, the primary in vivo function of plasminogen/plasmin is to regulate fibrinolysis, i.e., the process wherein the fibrin clot, end product of the coagulation process, is degraded. However, plasminogen/plasmin ability to bind low-affinity cellular receptors and to degrade extracellular matrix (ECM) proteins indicated a crucial role for plasmin in other processes involving protein degradation, in particular in cell migration, an important event occurring in various physiologic and pathologic processes, such as embryogenesis, wound healing, angiogenesis, and tumor cell dissemination (Castellino and Ploplis 2005).

Plasminogen can be activated by different proteases, but its specific physiologic activators are the tissue-type (tPA) and the urokinase-type (uPA) plasminogen activators. Both serine-proteases are secreted as single chains and are activated by a single cleavage, that yields two chains held together by a disulfide bond.

tPA is mainly involved in fibrinolysis since it binds fibrin with high affinity. The assembly of fibrinolytic components, plasminogen and tPA, at the surface of fibrin results in efficient fibrin degradation (Rijken and Lijnen 2009). uPA, which lacks fibrin-binding sites but is able to bind cellular receptors, is instead mainly involved in processes including cell migration and tissue invasion, such as inflammation, angiogenesis, and tumor invasion (Irigoyen et al. 1999).

The plasminogen activation system represents a very efficient proteolytic machinery, thus its activity must be strictly regulated. The primary plasmin inhibitor is the alfa2-antiplasmin; the most efficient inhibitor of plasminogen activators (PAs) is the type-1 inhibitor (PAI-1) (Balsara and Ploplis 2008). The other specific PA inhibitor is the type-2 inhibitor (PAI-2); its lower inhibitory efficiency, as compared to PAI-1, and the intracellular detection of PAI-2 nonglycosylated forms suggested a regulatory role for PAI-2 in the activity of enzymes other than uPA (Medcalf and Stasinopoulos 2005).

Plasminogen, tPA, and uPA can bind cellular receptors. Binding to cellular receptors represents another crucial regulatory step, since focusing enzymes and substrates on the cell surface strongly enhances the proteolytic cascade. Plasminogen binds in a lysine- and/or carbohydrate-dependent manner to the cell surface, with low affinity but high capacity. Cell-bound plasmin is protected from its natural inhibitors, since both receptors and inhibitors utilize plasminogen/plasmin C-terminal lysines. Different cellular binding sites for tPA have been described.

uPA binds a specific high-affinity cell-anchored receptor, the urokinase-type plasminogen activator receptor (uPAR), which, in the last decades, has been largely characterized in its expression, structure, and function.

uPAR Expression

The human uPAR gene is located on the long arm of chromosome 19 (19q13) and contains seven exons and six introns extending over 23 kb of genomic DNA. This region lacks TATA and CAAT boxes and contains GC-rich sequences and consensus elements for SP1, AP1, AP2, NF-k B, and the Kruppel-like transcription factor, which have been reported to drive uPAR transcription.

uPAR expression can be regulated also at a posttranscriptional level. In fact, several sequence elements regulating uPAR mRNA decay have been identified throughout the transcript. These sequences are present both in the coding and in the 3′ untranslated region (UTR) of the uPAR transcript and are able to bind proteins that promote stability or degradation of uPAR mRNA. Interestingly, uPA regulates the expression of its receptor both at transcriptional and posttranscriptional levels (Nagamine et al. 2005).

uPAR is expressed constitutively in many cell lines; however, its expression in culture is inducible by several factors as phorbol esters or various growth factors. In vivo, uPAR is moderately expressed in various tissues including lungs, kidneys, spleen, vessels, uterus, bladder, thymus, heart, liver, and testis. uPAR expression can be strongly up-regulated in organs undergoing extensive tissue remodeling, as in gestational tissues during embryo implantation and placental development or in keratinocytes during epidermal wound healing. Stress, injury, and inflammation also induce uPAR expression. In blood, the expression of uPAR is strongly increased upon activation of neutrophils, monocytes, and T cells (Smith and Marshall 2010). Up-regulation of uPAR expression has been also reported in peripheral CD33+ myeloid and CD14+ monocytic cells, following granulocyte-colony-stimulating factor (G-CSF)-induced mobilization of CD34+ hematopoietic stem cells (Ragno and Blasi 2008).

A wide variety of human and mouse cancers overexpress uPAR. uPAR-deficient mice show phenotypes consistent with these observations and not always coincident with phenotypes of uPA-deficient mice, strongly suggesting additional proteolysis-independent in vivo role of uPAR.

uPAR Structure

uPAR is synthesized as a single polypeptide chain of 313 amino acid residues, with a 21-residues signal peptide. Posttranslational cleavage and removal of the last 30 C-terminal residues allow the attachment of a glycosyl-phosphatidyl-inositol (GPI) tail to Gly 283 that anchors the receptor to the cell surface. Mature uPAR consists of three homologous domains of approximately 90 amino acids (D1, D2 and D3, from the N-terminus), belonging to the Ly-6/uPAR/alfa-neurotoxin protein domain family. By virtue of its GPI-tail, uPAR partitions preferentially to lipid rafts, cholesterol-rich microdomains of cell membrane, which represent anchoring platforms for specific cell-signaling mediators.

The crystal structure of a uPAR soluble form bound to an antagonist peptide has been solved, thus confirming that uPAR consists of three domains with a typical three-finger fold, each domain containing three adjacent loops rich in beta-pleated sheets and a small C-terminal loop. The three domains of uPAR form an almost globular receptor with a breach between D1 and D3, thus generating a central cavity where the ligand peptide is located. The top of the cavity is quite large and progressively narrows toward the bottom. The peptide establishes multiple contacts with the walls of the cavity; D1 plays a predominant role in this ligand interaction by providing half of the binding interface. uPAR exhibits a large outer surface that harbors the interdomain linker regions and the five possible N-linked glycosylation sites. This model suggests that uPA is embedded in the central cavity and that the large outer receptor surface is available to bind additional ligands (Kjaergaard et al. 2008).

The three domains of the GPI-anchored uPAR are joined by linker sequences. The D1-D2 linker region is particularly exposed to proteolysis and can be cleaved by several enzymes, including plasmin and uPA itself. The cleavage can occur at different sites in the D1-D2 linker region and may disrupt or not a specific sequence (SRSRY), corresponding to amino acids 88–92, involved in cell migration. In both cases, the cleavage generates truncated forms of GPI-uPAR, lacking D1 (D2-D3 uPAR), which have been detected on the surface of different cell lines and in normal and cancer tissues.

Both full-length and cleaved uPAR can be shed, thus generating soluble uPAR forms (suPAR and D2-D3 suPAR, respectively) identified in biological fluids, both in vitro and in vivo. The shedding can be due to the activity of glycosyl-phosphatidyl-inositol specific phospholipase C or D, or to a juxtamembrane proteolytic cleavage of uPAR. D2-D3 suPAR can also be generated by proteolytic cleavage of full-length suPAR mediated by metalloproteases, cathepsin G or elastase (Montuori et al. 2005).

uPAR Interactors

uPAR Extracellular Ligands

uPAR was firstly identified as the cellular receptor for the urokinase-type plasminogen activator (uPA). uPA is secreted as a 54 kDa single-chain pro-enzyme that can be converted, likely following binding to uPAR, into the two-chain active form by a single cleavage at Lys158-Ile159. The N-terminal A chain or its amino terminal fragment (ATF, residues 1–135) binds uPAR with high affinity and specificity. The C-terminal B chain contains the serine-protease domain and is unable to bind the receptor (Carriero et al. 2009).

uPA binds the N-terminal uPAR domain 1 (D1), even though the full-length uPAR is required for an efficient uPA binding. uPA binding to GPI-anchored uPAR allows the cell to focus uPA proteolytic activity, which activates cell-bound or free plasminogen into plasmin. Plasmin promotes ECM degradation directly, by degrading ECM components, including fibrinogen, fibronectin, and vitronectin, and indirectly, by activating several metalloproteases.

In spite of its name, uPAR acts also as a receptor for other extracellular molecules, such as vitronectin (VN), an ECM component, and the cleaved form of high molecular mass kininogen (HKa). The functional epitope on uPAR that is responsible for its interaction with the full-length, extended form of vitronectin is formed by three residues in domain I (Trp(32), Arg(58), and Ile(63)) and two residues located in the flexible linker peptide connecting uPAR domains I and II (Arg(91) and Tyr(92)). uPA positively regulates VN binding to uPAR, likely by inducing formation of uPAR dimers that exhibit a higher affinity for VN as compared to the monomers. HKa, unlike uPA, inhibits uPAR-mediated cell adhesion to VN, likely because it binds and blocks the VN-binding site in uPAR. Furthermore, the type-1 plasminogen activator inhibitor (PAI-1) competes with uPAR in the binding to VN because they bind overlapping regions on VN located in the N-terminal somatomedin B (SMB) domain, close to the integrin-binding site. uPAR expression confers to the cell the ability to adhere to VN, thus it is a non-integrinic VN receptor (Madsen and Sidenius 2008).

uPA and VN can be bound only by full-length uPAR, both in the cell-anchored and in the soluble form, even if, in the latter case, with less efficiency; the cleaved forms of uPAR are unable to bind both uPA and VN (Montuori et al. 2005).

Cell Surface uPAR Interactors

Cell surface uPAR interactors encompass a long list of proteins. The structural basis of these interactions is still poorly understood; however, much evidence demonstrates that the physical/functional interaction of uPAR with these proteins is essential for its non-proteolytic functions. uPAR functionally interacts with receptor tyrosine kinases, as the epidermal growth factor receptor (EGFR) and the platelet-derived growth factor receptor (PDGFR)-beta, various integrins, caveolin, the receptors for bacterial formylated peptides (fMLP receptors, fMLP-Rs), the collagen receptor uPARAP/Endo180, and receptors of the low-density lipoprotein receptor family including the LDL receptor-related protein (LRP) and LRP1B. In addition, uPAR has been shown to associate with the cation-independent Mannose 6-phosphate/insulin-like growth factor-II receptor that has been implicated in the targeting of uPAR to lysosomes. As a consequence of some of these interactions, uPAR activates intracellular signaling molecules involved in cell proliferation, survival, differentiation, adhesion, and migration. In fact, uPAR lacks a transmembrane region and a cytosolic tail, thus it could not transduce signals inside the cell unless it associates to signaling partners; the best candidates to this role seem to be integrins and fMLP receptors (Blasi and Sidenius 2010).

uPAR and Integrins

uPAR co-capping with the β2 integrin Mac-1 was firstly demonstrated in resting neutrophils; subsequently, the presence of uPAR and β2 integrins was identified in large receptor complexes that included signaling molecules. Fluorescence resonance energy transfer analysis (FRET), immunolocalization, and co-immunoprecipitation have identified uPAR in complex with several integrin families, such as β1, β2, β3, and β5. uPAR-binding sites have been identified on α- and β1-integrin chains. α3β1 integrin associates with uPAR via a surface loop within the α3 β-propeller, outside the ligand-binding region; cell treatment with a 17 mer α3β1 integrin peptide (peptide α 325) or Ala mutations within the uPAR-interacting loop of α3 (H245A) chain abolishes uPAR co-immunoprecipitation with α3β1 integrin and impairs uPA-uPAR-dependent signals. A uPAR-binding site has also been identified in a β1-chain loop (residues 224–232) of α5β1 integrin; this loop is very close to the β-propeller of α5 chain in the energy-minimized model of the integrin structure. The synthetic peptide corresponding to the uPAR-binding site of β1 or a β1 chain Ser227Ala point mutation abrogates functional uPAR effects on α5β1 integrin.

Subsequently, also putative integrin-binding sites on uPAR have been identified in the uPAR domains 2 and 3. The peptide covering the interaction site in D2 abolishes uPAR co-immunoprecipitation with αvβ3 and α5β1 integrins, activates αvβ3 integrin-dependent signaling pathways, and stimulates cell migration, whereas peptide D2A-Ala, generated by mutating two glutamic acids into two alanines, lacks chemotactic activity, and, in addition, inhibits VN-, FN-, and CG-dependent cell migration. The peptide covering D3 interaction site binds purified α5β1 integrin; substituting a single amino acid in this peptide or in full-length soluble uPAR impairs binding of the purified integrin. uPAR binding to integrins requires the full-length receptor, as in the case of uPAR binding to uPA and VN (Tang and Wei 2008).

Interestingly, uPA may bind simultaneously both uPAR and integrins. In fact, uPA interacts with uPAR through its growth factor-like domain (GFD) in the amino terminal fragment (ATF), whereas it recognizes Mac-1 and β1 integrins through the kringle domain and the αvβ5 integrin through the “connecting peptide” (residues 132–158). Mac-1 also is able to bind at the same time uPA and uPAR, through its I and non-I domains, respectively (Carriero et al. 2009; Tang and Wei 2008).

uPAR–integrin interactions seem to exert opposite effects, depending on the cell type examined. In fact, the first evidence of uPAR interaction with β1 integrins was reported in uPAR-transfected HEK-293 cells, in which uPAR and integrins form stable complexes that inhibit cell adhesion to fibronectin (FN) and, in parallel, increase RGD-independent uPAR-mediated cell adhesion to VN. By contrast, uPAR activates α5β1 integrin in human epidermoid carcinoma HEp-3 cells.

uPAR and fMLP Receptors

fMLP (fMet-Leu-Phe) is a formylated peptide of bacterial origin that stimulates chemotaxis by activating seven transmembrane domain receptors coupled to G-proteins. Three fMLP receptors (fMLP-R) have been identified and cloned: the high-affinity N-formyl-peptide receptor (FPR) and its homologues FPR-like 1 (FPRL1) and FPR-like2 (FPRL2). FPR is a high-affinity receptor for fMLP. FPRL1 has a much lower affinity for fMLP, whereas it is efficiently activated by several different molecules, such as lipoxin A4, serum amyloid A, the prion peptide PrP106-126, HIV-1 envelope peptides, the Helicobacter Pylori Hp(2–20) peptide, and various synthetic peptides. FPRL2 shows a high homology with the other two fMLP receptors but does not bind fMLP and shares some ligands with FPRL1, as Hp(2–20) and synthetic peptides. fMLP-Rs were firstly identified in leukocytes, and subsequently in several different cell types, including epithelial cells (Le et al. 2002).

Full-length GPI-anchored uPAR functionally interacts with fMLP-Rs through a specific SRSRY sequence (residues 88–92) in the D1-D2 linker region; in fact, uPAR expression is required for fMLP-dependent migration in monocytes and HEK-293 epithelial cells and, conversely, fMLP-R expression is required in cell migration induced by uPA or its amino terminal fragment (ATF).

Interaction of uPAR with fMLP-Rs was originally demonstrated by showing that the soluble cleaved form of uPAR (D2-D3 suPAR), or its derived peptides containing the SRSRY sequence (residues 88–92), bind and activate FPRL1 in monocyte-like cells, thus inducing their migration. Interestingly, D2-D3 suPAR does not induce calcium mobilization, unlike fMLP and other FPRL1 ligands. Subsequently, D2-D3 suPAR capability to induce cell migration through activation of all members of the fMLP-R family has been shown in various cell types. Unlike full-length GPI-anchored uPAR, full-length soluble uPAR does not bind fMLP receptors, even though it is able to interact with integrins and VN (Ragno 2006).

uPAR as Signal Transducer

A large body of evidence clearly shows that uPAR is able to activate intracellular signaling leading to cellular responses such as cell adhesion, migration, differentiation, proliferation, and survival. uPAR-dependent signaling can be activated by uPA (independently of its proteolytic activity), VN, and by uPAR overexpression itself. Many signaling partners have been proposed for uPAR, which lacks a transmembrane region and a cytosolic tail; however, the most important transmembrane receptors associated with uPAR signaling seem to belong to the integrin and fMLP-R families.

Even if a direct and physical uPAR interaction with integrins has been questioned, many studies show that uPAR signaling requires integrin cooperation. uPAR-β1 and uPAR-αv integrin interactions have been often associated with the activation of FAK/src signaling, leading to increased activities of Rac1 and/or ERK1/2.

The first uPAR–integrin interaction to be described involved the β2 integrin Mac-1, which is expressed primarily in leukocytes, where it regulates migration, differentiation, and phagocytosis. uPAR association with Mac-1 improves Mac-1 binding to fibrinogen; up-regulation and/or engagement of Mac-1 enhance uPAR-dependent adhesion to VN in monocytes. Signaling promoted by the uPAR-Mac-1 interaction seems to involve Src family kinases. A crucial role for uPAR in regulating β2 integrin activity has also been suggested in vivo; in fact, the β2 integrin-dependent recruitment of leukocytes to inflamed peritoneum and of neutrophils to the lung in response to P. aeruginosa pneumonia infection is significantly reduced in uPAR-deficient mice (Smith and Marshall 2010).

In normal microvascular endothelial cells (MVECs), full-size uPAR is connected with the actin cytoskeleton via the alphaM- and alphaX-subunits of β2 integrins. In systemic sclerosis (SSc), MVECs angiogenesis is blocked by uPAR cleavage; in fact, uPAR cleavage induces uPAR uncoupling from β2 integrins, impairing the activation of Rac and Cdc42 and the integrin-delivered signals to the actin cytoskeleton (Margheri et al. 2006).

One of the first reports on uPAR involvement in cell-signaling described a uPAR-dependent mechanism in which, in tumorigenic cells, high uPAR levels activated α5β1 integrin, thus promoting its binding to fibronectin and the assembly of integrin-bound fibronectin into insoluble structures during fibronectin fibrillogenesis. α5β1-dependent signaling induced a strong and persistent ERK1/2 activation, which promoted cell proliferation. By contrast, cells expressing low uPAR levels showed p38 MAPK activation, which inhibited ERK1/2 activation. In vivo, tumor cells with low ERKs/p38 activity ratio rapidly arrested in G0–G1 and remained viable but dormant for a prolonged period of time (Aguirre-Ghiso et al. 2003). Subsequently, several reports have shown that signaling events downstream of uPAR-β1 integrin interactions promote FAK phosphorylation and ERK1/2 activation. Src also co-immunoprecipitates with uPAR-β1 integrin complexes and is activated by uPAR signaling through both α5β1 and α3β1 integrins (fibronectin and laminin receptors, respectively). ERK1/2 and Src activation induced by uPAR-β1 integrin mediates cell adhesion, migration, invasion of ECM, proliferation, epithelial-mesenchymal transition (EMT), and, in addition, increase in the expression of uPA and metalloproteases, suggesting that uPAR signaling through β1 integrins can contribute to invasion also by increasing pericellular proteolysis (Smith and Marshall 2010).

αv- integrins have also been strongly implicated in uPAR signaling. Both uPAR and av integrins bind vitronectin, uPAR recognizing the SMB domain and av integrins the Arg-Gly-Asp sequence of vitronectin. The uPAR-av integrin interaction has an important role in signaling for cell migration. The functional effects of uPAR-αv integrin association were studied in fibrosarcoma and breast carcinoma cell lines, both of which exhibit uPA-dependent physical association between uPAR and αvβ5. uPA promoted cellular migration via a uPAR/αvβ5-dependent signaling cascade in which Ras, ERKs, and myosin light chain kinase (MLCK) serve as essential downstream effectors. In uPAR-transfected cells, uPAR signaling through αv-β3 integrin may activate Src, leading to phosphorylation of  p130Cas and subsequent binding of CRK; the p130Cas–CRK complex recruits DOCK1 for Rac activation. Further, uPAR is required to activate avβ3 integrin in podocytes, promoting cell motility and activation of the small GTPases Cdc42 and Rac1. Blocking αvβ3 integrin reduces podocyte motility in vitro and lowers proteinuria in mice; thus uPAR seems to play a physiologic role in the regulation of kidney permeability. Also, in some cells, uPAR signaling promotes the cell surface expression of αvβ3 integrin (Smith and Marshall 2010).

Different forms of uPAR are present on the cell surface: full-length uPAR and cleaved uPAR forms (D2-D3 uPAR), lacking the D1 domain and exposing or not a specific SRSRY sequence (residues 88–92), which is able to functionally interact with fMLP-Rs. uPAR and D2-D3 uPAR appear to mediate different signaling pathways. A report on fibroblast-to-myofibroblast differentiation showed that fibroblasts express increased amounts of full-length cell surface uPAR as compared to myofibroblasts, which have increased expression of D2-D3 uPAR. uPAR cleavage seems to be required to induce fibroblast transition to myofibroblast, since inhibition of uPAR cleavage prevents myofibroblast differentiation (Ragno 2006).

uPAR can be shed from the cell surface. However, the soluble receptor is able to activate cell-signaling pathways in uPAR negative cells and can still activate β2 and β1 integrins, thus inducing leukocyte adhesion to endothelium or ERK1/2 activation in Hep3 carcinoma cells (Montuori et al. 2005).

The soluble form of D2-D3 uPAR (D2-D3 suPAR), or its derived peptides containing the SRSRY sequence, bind and activate fMLP-Rs, stimulating cell migration. Thus, D2-D3 suPAR can be considered as a ligand for fMLP receptors and is also able to activate cell-signaling pathways. Indeed, the SRSRY peptide increases uPAR-avβ5 association and stimulates PKC activity and ERK phosphorylation (Gargiulo et al. 2005).

uPAR can also cross-talk with growth factor receptors, such as EGFR and PDGFR-beta. Indeed, uPA binding to uPAR can initiate a cell-signaling pathway that is mediated by EGFR, and, conversely, uPAR-dependent cell-signaling may prime cells to proliferate in response to EGF.

uPAR cross-talk with the platelet-derived growth factor receptor (PDGFR)-beta has been reported in human vascular smooth muscle cells (VSMC), in which uPA induces uPAR association with PDGFR-beta, thus stimulating its phosphorylation. uPAR-PDGFR-beta association is required for uPA-induced migratory and proliferative downstream signals. However, unlike the association to EGFR, uPA strongly inhibits PDGF-induced migration (Ragno 2006).

Recently, the cross-talk between uPAR and CXCR4, the receptor for the stromal-derived factor 1 chemokine, has been reported; uPAR expression regulates CXCR4 activity on specific extracellular matrix components by a mechanism involving fMLP-Rs and av integrins (Montuori et al. 2010).


The urokinase receptor (uPAR) was firstly identified in 1985 on the surface of monocyte-like cells. It is moderately expressed in various tissues and its expression can be strongly up-regulated in organs undergoing extensive tissue remodeling. Stress, injury, and inflammation induce uPAR expression; a wide variety of human and mouse cancers also overexpress uPAR.

uPAR is a GPI-anchored protein that binds with high affinity the serine-protease urokinase-type plasminogen activator (uPA), thus regulating cell membrane–associated proteolytic activity and, hence, increasing cell ability to move and migrate through barriers.

uPAR mobility along the cell membrane, due to its GPI-tail, and its structure, recently solved, strongly suggest that uPAR is a molecule prone to interact with other cell surface molecules. In fact, over the years, a large body of evidence clearly showed that uPAR is capable of multiple interactions and, likely by virtue of these interactions, it is able to activate intracellular signaling, leading to cellular responses such as cell adhesion, migration, differentiation, proliferation, and survival. The majority of reports is focused on its likely interaction with integrins, which has been questioned in the last years, even though a crucial role of integrins in uPAR signaling activities is generally accepted. Other possible uPAR signaling partners could be the receptors for the fMLP formylated peptide (fMLP-Rs). In this case also, there are no reports on a direct interaction of cell membrane uPAR with fMLP-R; however, a direct binding between the cleaved form of soluble uPAR has been demonstrated in the past on monocyte-like cells. Thus, at present, the mechanism enabling uPAR to signal is still unclear and represents a very intriguing area of research; elucidation of these mechanisms could shed light on the real meaning and importance of uPAR in the various biologic and pathologic processes in which it is overexpressed and involved.


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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Chemistry and BiologyUniversity of SalernoFisciano, SalernoItaly