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Multifaceted Role of the Urokinase-Type Plasminogen Activator (uPA) and Its Receptor (uPAR): Diagnostic, Prognostic, and Therapeutic Applications - PubMed

  • ️Mon Jan 01 2018

Review

Multifaceted Role of the Urokinase-Type Plasminogen Activator (uPA) and Its Receptor (uPAR): Diagnostic, Prognostic, and Therapeutic Applications

Niaz Mahmood et al. Front Oncol. 2018.

Abstract

The plasminogen activator (PA) system is an extracellular proteolytic enzyme system associated with various physiological and pathophysiological processes. A large body of evidence support that among the various components of the PA system, urokinase-type plasminogen activator (uPA), its receptor (uPAR), and plasminogen activator inhibitor-1 and -2 (PAI-1 and PAI-2) play a major role in tumor progression and metastasis. The binding of uPA with uPAR is instrumental for the activation of plasminogen to plasmin, which in turn initiates a series of proteolytic cascade to degrade the components of the extracellular matrix, and thereby, cause tumor cell migration from the primary site of origin to a distant secondary organ. The components of the PA system show altered expression patterns in several common malignancies, which have identified them as ideal diagnostic, prognostic, and therapeutic targets to reduce cancer-associated morbidity and mortality. This review summarizes the various components of the PA system and focuses on the role of uPA-uPAR in different biological processes especially in the context of malignancy. We also discuss the current state of knowledge of uPA-uPAR-targeted diagnostic and therapeutic strategies for various malignancies.

Keywords: ATN-658; PAI-2; cancer imaging; metastasis; plasminogen activator inhibitor-1; plasminogen activator system; uPA; urokinase-type plasminogen activator receptor.

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Figures

Figure 1
Figure 1

Different components of the plasminogen activator (PA) system and role in fibrinolysis. Schematic representation of the ability of type plasminogen activator (tPA) and uPA to independently activate “plasminogen” to form the active proteolytic enzyme “plasmin” which can mediate fibrinolysis to keep the blood free from clotting. In addition to their fibrinolytic effects, tPA and uPA are implicated in many other physiological and pathophysiological processes. Both tPA and uPA can be inhibited by plasminogen activator inhibitors (PAI) such as plasminogen activator inhibitor-1 and PAI-2, while plasmin can be inhibited by α2-antiplasmin (α2-AP) and α2-macroglobulin (α2-MG). The different components belonging to the PA system are enclosed within the square region.

Figure 2
Figure 2

Structure of pro-uPA and uPA. The pro-uPA containing a growth factor domain (GFD), a kringle domain (KD), and a catalytic serine protease domain is secreted as a single-chain precursor that undergoes proteolytic cleavage between the Lys158 and Ile159 peptide bond to generate the two-chain form of uPA. By action of a second proteolytic cleavage, the two-chain form of uPA can be further cut between Lys135 and Lys136 resulting in the formation of an inactive amino-terminal fragment (ATF) as well as a catalytically active low-molecular weight form of uPA (LMW uPA).

Figure 3
Figure 3

Schematic diagram of the uPA–urokinase-type plasminogen activator receptor (uPAR)-mediated pathways. The glysocylphosphatidylinositol (GPI)-anchored receptor uPAR consisting of three domains (D1, D2, and D3) has the ability to bind the zymogen pro-uPA as well as the active uPA through the growth factor domain. The catalytically active form of uPA then converts inactive plasminogen into plasmin, which in turn can cleave and activate GFs, matrix metalloproteases (MMPs), as well as the extracellular matrix (ECM). The activated MMPs can directly cause the degradation of ECM and thereby release various growth factors. Plasminogen activator inhibitor-1 can inhibit the catalytic activity of both uPA and plasmin. Apart from uPA, uPAR also binds to integrins and other cell surface receptors to activate different intracellular signaling pathways [example: Jak–STAT, PI3K, focal adhesion kinase (FAK), and Rac] and regulates cellular processes such as cell proliferation, survival, migration, invasion, angiogenesis, and metastasis.

Figure 4
Figure 4

The major physiological roles of the uPA–urokinase-type plasminogen activator receptor (uPAR) system. In normal physiologic conditions, apart from fibrinolysis, the uPA–uPAR system takes part in different biological processes such as the generation of matured myeloid cells, spermatogenesis, chemotaxis, cell migration, wound healing, as well as mediating different types of immune response.

Figure 5
Figure 5

Selected use of the uPA–urokinase-type plasminogen activator receptor (uPAR) system in cancer diagnosis. (A) uPA and plasminogen activator inhibitor-1 (PAI-1) enzyme-linked immunosorbent assay can assess the risk of breast cancer recurrence and based on the results obtained from the assay clinicians decide if chemotherapy is needed after surgery. This method is already used by many oncologists. (B) Assessment of promoter methylation status of the gene encoding uPA can be used to predict the aggressiveness of the primary tumor. It has been shown that the CpG sites on the uPA promoter are hypomethylated in high-grade tumors compared with the control and less aggressive tumors. This method can be used to determine the invasiveness of cancer. (C) Conjugation of a labeled dye with antibodies (ATN-658 for uPAR) or peptide targeting uPA–uPAR interaction (AE105) can distinguish between the tumorigenic and non-tumorigenic area, and this method showed great diagnostic potential in several known cancers.

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