Plasminogen receptors and their role in the pathogenesis of inflammatory, autoimmune and malignant disease


  • A. GODIER,

    1. Department of Anaesthesia and Critical Care, Groupe Hospitalier Cochin Hôtel-Dieu, Université Paris Descartes
    2. INSERM UMR S765, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
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  • B. J. HUNT

    1. Thrombosis & Haemostasis, Kings College
    2. Director of the Haemostasis Research Unit, Departments of Thrombosis & Haemophilia, Lupus and Pathology, Guy’s & St Thomas’ NHS Foundation Trust, London, UK
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Beverley J. Hunt, Thrombosis & Haemophilia Centre, St Thomas’ Hospital, London, SE1 7EH, UK.
Tel.: +44 2071882736; fax: +44 2071882117.


Summary.  Plasminogen is the proenzyme of plasmin, the key protease of the fibrinolytic system, but its role is not limited to fibrinolysis regulation. Plasminogen binds not only to fibrin, but also to different receptors on cell surfaces, including the heterotetrameric complex Annexin A2-S100A10, enolase-1, histone H2B and the plasminogen receptor Plg-RKT. These receptors localize plasmin generation to the cell surface and provide a broad spectrum of reactions including proteolytic activity, cell migration and recruitment as well as signaling pathway activation. These plasminogen-binding proteins are involved in both physiologic and pathologic processes such as inflammation, thrombosis and cancer. Thus, plasminogen is at the center of a complex tightly controlled and regulated system where plasminogen-binding proteins have a crucial role, suggesting new therapeutic and diagnostic strategies. This review will discuss currently available information on plasminogen receptors, particularly their mechanisms of action and their roles in inflammatory, autoimmune and malignant disease.


Plasminogen is the pro-enzyme of plasmin, the key enzyme of the fibrinolytic system. Its major role in fibrinolysis regulation is well known and has been integrated in therapeutic strategies through either inhibition or activation of this zymogen. Indeed, the antifibrinolytic agent tranexamic acid (TXA) is one of the first treatments given to trauma patients since the CRASH-2 (Clinical Randomization of an Antifibrinolytic in Significant Haemorrhage 2) trial of TXA in bleeding trauma patients demonstrated a significant reduction in death as a result of bleeding and all-cause mortality [1]. TXA has also been shown to reduce bleeding in elective surgery [2]. In contrast, fibrinolytic therapy has become the greatest step forward in the early management of acute ST segment elevation myocardial infarction [3] and recombinant tissue plasminogen activator (tPA) is licensed for the acute phase of an ischemic stroke [4].

However, the role of plasminogen is not limited to fibrinolysis activation. Plasminogen binds not only to fibrin, to generate soluble fibrin degradation products [5,6], but also to different cell surface molecules collectively called plasminogen receptors. These receptors localize plasminogen on cell surfaces and provide a broad spectrum of reactions including proteolytic activity, cell migration and signaling pathway activation, which are involved in both physiologic and pathologic processes such as inflammation, thrombosis and cancer [7]. Plasminogen is at the center of a complex tightly controlled and regulated system where plasminogen-binding proteins have a crucial role. The importance of plasminogen receptors in the pathophysiology of inflammatory and malignant conditions is being increasingly recognized. This article brings together a review of the main plasminogen receptors, heterotetrameric complex Annexin A2-S100A10, enolase-1, histone H2B and Plg-RKT, and what is known of their role in disease.


Plasmin is a serine protease formed by the proteolytic action of the two main plasminogen activators, tissue plasminogen activator (tPA) or urokinase (uPA) on its circulating zymogen plasminogen, and is inhibited mainly by α2-antiplasmin, but also by α2-macroglobulin. The circulating form of plasminogen, amino-terminal glutamic acid (Glu) plasminogen, is a single-chain multidomain glycoprotein of 90 kDa composed of 791 amino acids, divided into seven different structural domains: a N-terminal pre-activation peptide (amino-terminal glutamic acid (Glu) plasminogen N-terminal peptide), 5 kringle domains and the C-terminal trypsin-like serine protease domain carrying the catalytic triad His603, Asp646 and Ser741 [8]. The kringle domains regulate plasminogen/plasmin binding. They are five homologous triple loop structures, containing between 78 and 80 amino acids each, stabilized by intrachain disulfide bridges. Four out of these five domains (K1, K2, K4 and K5) contain lysine-binding sites (LBS) that allow plasminogen binding to proteins with carboxyl-terminal lysines or conformational mimetics of these residues. These four LBS share a common structure, whereas K3 contains a mutation in the LBS sequence [9]; thus K3-LBS is non-functional and does not bind lysine. Biochemical analysis demonstrated that, relative to K2 or K5, K1 and K4 have significantly higher affinities for lysine [10]. In fact, recent descriptions of the plasminogen X-ray crystal structure revealed that K1-LBS is the only LBS available for ligand binding in the compact form of circulating plasminogen, whereas all other LBS are blocked as they are engaged in intra-molecular interactions, responsible for a closed activation-resistant conformation [11,12]. This suggests that K1-LBS mediates initial recruitment to fibrin or the cell surface and second other kringles LBS interactions trigger conformational changes, leading plasminogen to switch from the compact closed state to an open extended form [12]. Plasmin hydrolyzes the Lys77-Lys78 peptide bond of native Glu-plasminogen yielding a small N-terminal peptide and the 714-amino-acid variant Lys-plasminogen, which can be activated to plasmin more readily than the Glu-form [11]. Then, plasminogen is converted into plasmin by cleavage of the activation site, composed of a single Arg561-Val562 peptide bond. This cleavage results in a two-chain plasmin molecule, composed of a N-terminal heavy-chain and a disulfide-linked C-terminal light chain. The light chain contains the proteolytically active site, which identifies the molecule as a serine protease, exhibits substrate specificity not limited to fibrin. Therefore, activation of the plasminogen system is highly regulated. The circulating form of plasminogen, Glu-plasminogen, exhibits a very compact, closed, spiral structure, in which the activation site is buried, thus it is a poor substrate for plasminogen activators [12]. Its conversion to the open form stimulates plasmin generation and is enhanced when plasminogen is fibrin or cell-associated compared with being in the solution phase [13]. This mechanism colocalizes plasminogen, plasmin and its activators, and concentrates the proteolytic activity on specific places. Thus, plasminogen forms a ternary complex with tissue plasminogen activator (t-PA) and fibrin on the sites of thrombus formation, whereas it interacts with its activators on plasminogen receptors on cell surfaces.

These receptors are present on most cell types, except erythrocytes, in high density. For example, their global density is around 1–200.105/endothelial cell; 5.105/lymphocyte; 4.5.105/monocyte or 35 000 sites/platelet [14]. They represent a very heterogeneous group. Most of them expose a carboxy-terminal lysine, such as the ones most described, heterotetrameric complex Annexin A2-S100A10, enolase-1, histone H2B, Plg-RKT, but also TIP49a [15] or the high mobility group box-1 protein (HMGB-1), also called amphoterin [16]. Other molecules without C terminal lysine have been identified and include cytokeratin 8 [17] and integrins, dominated by the β2 integrin subfamily. A list of candidate plasminogen receptors had previously included GpIIb-IIIa [18], actin [19] and even non-protein molecules such as gangliosides [20]. This review will focus only on the four most described receptors with exposed c-terminal lysines, the heterotetrameric complex Annexin A2-S100A10, enolase-1, histone H2B and Plg-RKT.

These receptors localize plasminogen on the cell surface although the bulk of the molecules are primarily found in the intracellular compartment. Mechanisms regulating their cell surface expression usually occur during a cellular response to stimuli. Then, their stimulatory effect on plasminogen relative to the effect of fibrin is dependent on the environment (presence or absence of fibrin), the plasminogen activator as well as the glycosylation pattern of plasminogen [12]. Indeed, the activation of type I plasminogen is enhanced more than that of type II plasminogen in the presence of fibrin [21], whereas type II has 10-fold more affinity for cells in comparison to type I [22].

Heterotetrameric complex Annexin A2-S100A10

This plasminogen receptor is a complex composed of a dimer of the protein S100A10 linked to two molecules of annexin A2:

  • 1 S100A10 (p11) is a member of the S100 family of proteins containing two EF-hand calcium-binding motifs. However, S100A10 is not regulated by Ca2+ and its EF-hand motif is maintained in the open form by a network of hydrogen bonds. One of the main characteristics of this 11-kDa acid protein is the presence of a C-terminal lysine residue that forms a binding site for plasminogen activators, plasminogen and plasmin. The majority of intracellular S100A10 is found associated with annexin A2 and the excess of S100A10 is unstable, it is ubiquitinated and targeted for proteasomal degradation.
  • 2 Annexin A2 (p36) is a 36-kDa calcium-regulated phospholipid-binding protein primarily localized in the cytoplasm and plasma membrane with a small population in the nucleus. Originally, it was thought to be a plasminogen receptor; however, it is now recognized that it does not possess a carboxyl-terminal lysine and does not bind to or activate plasminogen [23].

To become a plasminogen receptor, S100A10 and annexin A2 need to interact together (Fig. 1). In the cytoplasm, annexin A2 exists in a soluble, monomeric form. When sufficient A2 is expressed, it binds to S100A10, generating a stable heterotetrameric complex. After phosphorylation of annexin 2 at Tyr23 through a Src-like tyrosine kinase dependent mechanism [24] and conformational changes, the heterotetramer is translocated to the cell surface. This annexin A2 S100A10 heterotetramer is composed of two molecules of annexin A2 linked together by a dimer of S100A10. The S100A10 dimer is positioned in the center, with an annexin A2 molecule on each side.

Figure 1.

 The role of A2-S100A10 during monocyte macrophage recruitment. Inflammatory stimulation induces generation of a heterotetramer, secondly translocated to the cell surface. Plasminogen is activated. Plasmin cleavage of the annexin A2 subunit generates an amino terminal peptide, which serves as a ligand for transmembrane receptors activating intracellular signaling cascades. Plg, plasminogen; Pln, plasmin; LYS, lysine residues.

Modulation of annexin A2 expression on the cell surface appears to be different from other plasminogen receptors. Other receptors are mainly modulated by changes in proteins trafficking, whereas upregulation of A2 cell surface expression is associated with an increase in both total cellular expression and mRNA levels, suggesting new protein synthesis [25].

The respective roles of S100A10 and annexin 2 in binding and activation have been difficult to separate. In having a C-terminal lysine, S100A10 imparts plasminogen-binding activity to the annexin 2 heterotetramer [26]. With its N-terminus containing the binding site for S100A10, Annexin A2 directly localizes S100A10 to the cell surface of cells [23], anchors it to the plasma membrane and stabilize S100A10 protein levels, protecting it from proteasome-dependent degradation. This assembly augments the catalytic efficiency of plasminogen activation by 1- to 2-log orders of magnitude and thus has a central role in promoting fibrinolysis. The binding of plasmin to the heterotetamer, on the C-terminal lysine of the S100A10 subunit, protects plasmin from inactivation by α2-antiplasmin and localizes the proteolytic activity of plasmin to the cell surface. Plasminogen binding to the annexin A2 S100A10 heterotetramer plays a role in inflammation, thrombosis and autoimmune disease and cancer, and these roles are discussed below.

The annexin A2 S100A10 heterotetramer and inflammation

In response to inflammatory stimuli, the heterotetramer, located on peripheral monocytes and macrophage surfaces, binds plasminogen and induces plasmin generation resulting in extracellular matrix protein degradation and activation of other proteinases with pericellular matrix-degrading activity, resulting in recruitment and migration of macrophages.

Moreover, Annexin A2-S100A10 heterotetramer also initiates intracellular signaling. Plasmin cleavage of the annexin A2 subunit generates an amino-terminal peptide, which serves as a ligand for transmembrane receptors, activating intracellular signaling cascades and leading to a full-scale pro-inflammatory response. This amino-terminal part of annexin A2 can cause phosphorylation of several MAP kinases, as well as translocation of p65 NF-κB to the nucleus and expression of tumur necrosis factor-alpha, interleukin (IL)-1 and IL-6 as well as several members of the chemokine family in human monocytes-derived macrophages [27].

Li et al. [28] demonstrated that this N-terminal peptide is capable of activating type I cytokine receptors to induce the tyrosine kinase JAK1 and STAT3 phosphorylation. This signaling pathway activation results in an increase in monocyte expression and the release of monocyte/macrophage chemoattractant protein (MCP)-1. Swisher et al. [27] also demonstrated that this heterotetramer directly activates human monocyte-derived macrophages by inducing MAPK and NF-κB signaling, resulting in inflammatory cytokine and chemokine production and an increase in bacterial phagocytic efficiency. The modulation of macrophage function by this heterotetramer is mediated through Toll-like receptor 4 [29].

Thus, with the release of inflammatory functional cytokines, the heterotetramer induces chemotaxis and pro-inflammatory cells recruitment. As Annexin A2-S100A10 heterotetramer mediates the plasmin-induced signaling in monocytes, blockage of its function may be potentially useful in inflammatory diseases.

In S100A10-deficient mice, macrophage migration across an inflammatory peritoneal membrane is decreased [30]. This loss in invasion is a result of both a decreased generation of plasmin and a decreased activation of macrophage matrix metalloproteinase (MMP-9) by S100A10-deficient macrophages [30]. These results established that the Annexin A2-S100A10 heterotetramer is a major mediator of the plasminogen-dependent inflammatory response. Variations in the cell surface expression of the heterotetramer Annexin A2-S100A10 dramatically affect tumor cell-mediated pericellular proteolysis, tumor cell invasiveness and metastasis.

Annexin A2-S100A10 heterotetramer and autoimmune disease

While upregulation of Annexin A2-S100A10 heterotetramer causes increased fibrinolysis, down regulation may contribute to thrombotic disease. In mice globally deficient in annexin A2 [31], as well as in S100A10-null mouse [32], tissues display ubiquitously increased deposition of fibrin in the microvasculature and reduced clearance of injury-induced arterial thrombi.

The clinical relevance of this heterotetramer down-regulation is illustrated in autoimmune conditions in which annexin A2 is a target antigen for autoantibodies. Cesarman-Maus et al. [33] described anti-annexin A2-specific antibodies in patients with antiphospholipid syndrome, an autoimmune disorder characterized by recurrent arterial or venous thrombosis, or fetal loss, in the presence of antiphospholipid antibodies (aPL). Analysis of serum samples from 434 individuals showed that anti-Annexin A2 antibodies were more prevalent in patients with antiphospholipid syndrome than in healthy individuals, patients with non-autoimmune thrombosis or patients with lupus without thrombosis [33]. Annexin A2 is an important binding site for beta2-glycoprotein I (β2GPI), the main antigen for aPL, on the surface of endothelial cells. aPL activate endothelial cells in vitro in a β2GPI-dependent manner, after binding β2GPI to endothelial cell annexin A2 [34]. Whether endothelial cell activation is a primary event in the pathophysiological cascade leading to thrombus development in patients with antiphospholipid syndrome is uncertain. In vitro anti-annexin A2 antibodies by inducing endothelial cell activation, enhancing the expression of endothelial cell tissue factor and inhibiting cell surface plasmin generation [33], possibly contribute to the prothrombotic diathesis in patients with antiphospholipid antibodies.

The presence of annexin A2 antibodies was sought [35] in a cohort of 40 patients with previous cerebral sinus thromboses. These antibodies were more prevalent than in healthy individuals and this suggest there may be a subset of individuals with immune-mediated cerebral thrombosis.

The annexin A2-S100A10 heterotetramer and cancer

The heterotetramer has an important role in cancer development, mainly affecting the invasive property of tumor cells. Several cancer cells synthesize S100, annexin A2 or t-PA, including breast cancer, lung carcinoma, pancreatic cancer, fibrosarcoma, brain tumors, acute glioma, gastric cancer, colorectal carcinoma, hepatocellular carcinoma, promyelocytic leukemia and multiple myeloma [36–38]. Hence with these tumours there is increased plasmin production, enhancing the ability of cancer cells to degrade extracellular matrix (ECM) and to infiltrate into surrounding tissues. For example, in a model of human carcinoma cells, cell transfection with the S100A10 gene increased cell surface S100A10 expression and plasmin generation, hence enhanced ECM degradation and cell invasion and migration [37].

In contrast, the loss of S100A10 cell expression reduced plasmin production, ECM degradation and cellular invasiveness. In a mice model, the loss of S100A10 cell expression resulted in a reduced development of lung metastasis.

In a breast cancer cell model set up by Sharma et al. [36] invasive cells secreted annexin A2 and t-PA, producing plasmin, which correlated with neovascularization of the tumor. Silencing of the annexin A2 gene inhibited tPA-dependent plasmin generation and reduced cell motility [36]. Administration of anti-annexin A2 antibodies attenuated neoangiogenic activity and partly inhibited tumor growth [39], suggesting that annexin II may be an attractive target for therapeutic strategies aimed to inhibit neoangiogenesis in human breast cancer.

In patients with acute promyelocytic leukaemia (APML), Annexin A2 is overexpressed on t(15;17) positive cells and microparticles [40,41]. APML is a subtype of acute myeloid leukemia usually associated with a coagulopathy, often with features of hyperfibrinolysis, and associated with a high risk of death owing to excessive bleeding. It has been hypothesized that the increased expression of annexin 2 on cerebral endothelial cells [42] may contribute to the high rate of an intracerebral hemorrhage in APML. This increases the t-PA-dependent plasmin generation, leading to abnormal bleeding. This increase in plasmin production can be blocked by an anti-annexin A2 antibody [40] ex vivo, but also by antifibrinolytic agents such as tranexamic acid and aminocaproic acid [40,43]. APML is usually treated with All-trans retinoic acid (ATRA) [41], which induces terminal differentiation of leukemic promyelocytes and almost complete resolution of the associated coagulopathy within 2 weeks of treatment. The exact mechanisms have not been clearly defined, but in vitro treatment of APML blast cells with ATRA reduced annexin A2 expression [44]. These results suggest that overexpression of Annexin2 plays a vital role in the coagulopathy of APML and that the use of ATRA downregulates Annexin A2 expression and thus reduces the risk of severe hemorrhagic events.


Enolase-1 (also called α-enolase) is one of the many plasminogen-binding molecules. It is a metalloenzyme (45 kDa) with C-terminal lysines localized on almost all adult tissues [45]. It is primarily an intracellular glycolytic enzyme, involved in the synthesis of pyruvate. It is also expressed on the surface of hematopoietic cells such as monocytes, T cells and B cells, neuronal cells and endothelial cells, where it acts as a plasminogen receptor [45]. The plasminogen-enolase-1 interaction is mediated by binding of Plg kringle domains to lysine residues, identified in two different sites of the C-terminal domain of enolase-1 [46]. Thus, lysine analogs, such as tranexamic acid inhibit plasminogen binding to enolase-1 [47]. Interaction of plasminogen with enolase-1 enhances its activation to plasmin by t-PA or uPA, hence the proteolytic activity of cell-bound plasmin protects plasmin from inhibition by the α2-plasmin inhibitor.

Plasmin-enolase-1 interactions are involved in promoting cell migration in pathophysiological processes, such as the inflammatory response, cell invasion and cancer metastasis. Research data suggests cell-surface expression of enolase-1 mediates an important mechanism of inflammatory cell recruitment [47]. Inflammatory stimulation of monocytic cells with lipopolysaccharide induces rapid translocation of enolase-1 from cytosolic pools to the cell surface, in as little as 6 h (Fig. 2). This increases plasmin generation, enhances monocyte migration and promotes matrix degradation. These effects are abrogated by antibodies directed against the plasminogen binding site of enolase-1. Enolase-1 has also a central role as a plasminogen receptor in monocyte recruitment in inflammatory lung disease. Indeed, blood and alveolar monocytes from patients with pneumonia showed intense expression of enolase-1, whereas monocytes from healthy individuals did not [47].

Figure 2.

 The role of enolase-1 during monocyte macrophage recruitment. Inflammatory stimulation induces translocation of enolase-1 from the cytosolic pool. Plasmin generation induces proteolysis of extracellular matrix (ECM), migration and inflammation. Plg, plasminogen; Pln, plasmin; LYS, lysine residues.

Enolase-1 plays a role in tumorigenesis. Its expression is increased in many tumors and it has been identified on the surface of lung, breast and pancreatic cancers [48]. Plasminogen activation leads to proteolysis, contributing to cell invasion, proliferation and metastasis. Enolase-1 also induces a specific immune response in tumors (for review see [7,48]) with the production of autoantibodies. For example, in pancreatic ductal adenocarcinoma, enolase-1 is up-regulated and elicits a specific production of autoantibodies against isoforms phosphorylated on serine [49]. These antibodies may have a diagnostic value as their presence correlated with a significantly better clinical outcome in advanced patients treated with standard chemotherapy [49].

Histone H2B

Histone H2B (H2B) is a small highly conserved protein of 17 kDa with a C-terminal lysine, primary found within the eukaryotic cell nucleus. Together with two molecules each of histones H2A, H3 and H4, H2B forms the nucleosome core particle, a basic organizational unit of chromosomal DNA that wrap and compact DNA into chromatin, and it plays a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability.

However, H2B is also a membrane protein. Its cell-surface expression has been seen mainly on human blood monocytes/macrophages but also on activated lymphocytes, on cultured neutrophils, on lung carcinoma cells or on cells undergoing apoptosis. Cell surface expression of H2B can be modulated by cells activation [50,51] and H2B expression is enhanced in activated monocytoid cells [50]. On the cell surface, H2B is a plasminogen-binding protein and an increased expression of this receptor is correlated with up-regulation of the plasminogen binding capacity of cells [50].

Mechanisms promoting upregulation of H2B are incompletely understood but seem to be mainly associated with calcium-dependent changes in protein trafficking (Fig. 3) [25]. Indeed, in a model of monocytoid cells, monocyte to macrophage differentiation induces an increase in both plasminogen binding and cell surface expression of plasminogen receptors, including H2B [25]. Thus, H2B upregulation is an increase in receptor numbers and not a modulation of their plasminogen affinity. It is also independent of new protein synthesis, as neither total cellular protein expression nor mRNA levels are increased [25]. After membrane translocation, H2B tethers to the cell surface via an anionic interaction with phosphatidylserine, which plays the role of an anchor to the cell surface [52]. This interaction contributes to plasmin generation.

Figure 3.

 The role of H2B during monocyte macrophage recruitment. Inflammation stimulation induces calcium mobilization through L-type Ca2+ channels leading to H2B translocation on the cell surface where phosphatidylserine acts as an anchor. Then, plasminogen binding induces cell recruitment. Plg, plasminogen; Pln, plasmin; LTCCL, L-type Ca2+ channels.

H2B membrane translocation is calcium regulated and is dependent on the expression of Cav1.2, a pore subunit of L-type Ca2+ channels. Monocyte to macrophage differentiation increases the pore subunit expression as well as calcium mobilization. L-type calcium channel blockers such as verapamil or amlodipine block the increased expression of all plasminogen receptors, including histone H2B, as well as phosphatidylserine exposure [25,26,52]. Treatment with lysine analogs also reduces the level of binding of plasminogen to H2B [50], and carboxypeptidase B has the same effect.

Like other plasminogen receptors, H2B is involved in the inflammatory response. H2B expression is increased in activated macrophages compared with monocytes [51]. This enhanced expression contributes significantly to plasminogen binding, plasmin generation and macrophage migration to sites of inflammation. The H2B contribution to inflammatory cells recruitment was demonstrated in vivo. In a mice model of thioglycollate peritonitis, injection of anti-H2B Fab significantly reduced macrophage recruitment [51]. L-type calcium channel blockers also exert this anti-inflammatory effect. Indeed in the same model of peritonitis, amlopidine and verapamil reduce cell surface expression of several plasminogen receptors including H2B and impair macrophage recruitment, even at doses without affecting the blood pressure [25].

Autoantibodies to histone H2B are observed in several systemic autoimmune diseases. They are particularly frequent in systemic lupus erythematosus [53] but are also encountered in systemic sclerosis [54], scleroderma [55] and human immunodeficiency virus-infected individuals. Monestier et al. [53] observed that monoclonal IgG antibodies to H2B react with the amino terminus of H2B, characterized by the presence of lysine residues, that are important for interaction with plasminogen. Thus, they may alter H2B’s function as a plasminogen receptor and prevent binding. Herren et al. [50] hypothesized that these autoantibodies, by preventing plasminogen binding, may reduce plasmin generation, and hence decrease the fibrinolytic potential. This may help to explain the increased risk of thromboembolic events in systemic lupus erythematosus and other immunological diseases. Autoantibodies directed against H2B on CD4+ T lymphocytes are also seen in HIV-infected patients [56], with higher levels in patients with lymphadenopathy or symptomatic disease. Their role is still unclear as they may be involved in the destruction of the T lymphocyte population but may also contribute to the increased susceptibility of HIV patients to infectious diseases. This may be through reducing the potential of these cells to use plasminogen to support inflammatory cell migration [50] or the destruction of the T lymphocyte population [56].


Plg-RKT, a plasminogen receptor with a C-terminal lysine, was first described in 2010 [57]. The Plg-RKT structure is unique: this single 147-amino-acid protein with a molecular mass of 17 261 Da is the only integral membrane plasminogen receptor to date that exposes a C-terminal lysine on the cell surface to bind plasminogen. It is broadly expressed in human tissues. In peripheral blood cells, Plg-RKT is present in the membranes of normal human peripheral blood monocytes, but also in lymphocytes and granulocytes. However it is not detected in red blood cells.

Plg-RKT is detected in small aggregates dispersed over the cell surface, where it is colocalized with the urokinase receptor, uPAR. Hence, Plg-RKT allows plasminogen and uPA to be in very close proximity on the cell surface in order to promote plasminogen activation (Fig. 4). t-PA shares binding sites with plasminogen as it also binds specifically to the C-terminal peptide of Plg-RKT. Therefore, t-PA is bound on a Plg-RKT very close to other Plg-RKT binding plasminogen. This simultaneous binding of both ligands results in plasminogen activation. These mechanisms of colocalization of plasminogen, its receptor and its two major plasminogen activators illustrate that Plg-RKT regulates plasminogen activation on the cell surface. Plasminogen binding to Plg-RKT on the cell surface is inhibited by lysine analogs [57].

Figure 4.

 The role of Plg-RKT during monocyte macrophage recruitment. This integral membrane plasminogen receptor colocalizes plasminogen and its activators. Plasmin generation induces proteolysis and macrophage recruitment. Plg, plasminogen; Pln, plasmin; LYS, lysine residues.

Plg-RKT is believed to play a major role in plasminogen-dependent regulation of the inflammatory response (Fig. 4). This receptor is highly expressed on the human monocyte cell surface, where it regulates plasminogen activation [58]. It is involved in human monocytes chemotaxis and chemokinesis; Matrigel invasion by monocytes is inhibited by both the lysine analog and antibodies against Plg-RKT [58]. Plg-RKT also plays a major role in cell recruitment. Its involvement in plasminogen-dependent macrophage recruitment was demonstrated in a mouse model of thioglycollate-induced peritonitis [58]. Treatment with antibodies against Plg-RKT impaired macrophage and lymphocyte recruitment, where Plg-RKT is less strongly expressed. The role of Plg-RKT in macrophage migration depends on activation of matrix metalloproteases (MMP) and antibodies anti-Plg-RKT directly block activation of pro–MMP-9 and pro–MMP-2 synthesized by monocytoid cells [58].

In summary, Plg-RKT seems to be highly involved in plasminogen-dependent monocyte/macrophage recruitment, migration and invasion in the inflammatory response.

In conclusion, several distinct proteins have the potential to function as plasminogen receptors on cell surfaces. They represent a heterogenic population, critical for local regulation of proteolysis. Ongoing research suggests they play an important role in the pathogenesis of inflammatory, autoimmune and malignant disease. As we learn more about their function, the future challenge will be to determine how to modulate plasminogen-receptor expression as a therapeutic option.


This paper was supported by a grant from the Société française d’Anesthésie Réanimation.

Disclosure of Conflicts of Interest

The authors state that they have no conflict of interest.