Urokinase-Type Plasminogen Activator Receptor (uPAR) in Inflammation and Disease: A Unique Inflammatory Pathway Activator

Abstract

The urokinase-type plasminogen activator receptor (uPAR) is a unique protease binding receptor, now recognized as a key regulator of inflammation. Initially, uPA/uPAR was considered thrombolytic (clot-dissolving); however, recent studies have demonstrated its predominant immunomodulatory functions in inflammation and cancer. The uPA/uPAR complex has a multifaceted central role in both normal physiological and also pathological responses. uPAR is expressed as a glycophosphatidylinositol (GPI)-linked receptor interacting with vitronectin, integrins, G protein-coupled receptors, and growth factor receptors within a large lipid raft. Through protein-to-protein interactions, cell surface uPAR modulates intracellular signaling, altering cellular adhesion and migration. The uPA/uPAR also modifies extracellular activity, activating plasminogen to form plasmin, which breaks down fibrin, dissolving clots and activating matrix metalloproteinases that lyse connective tissue, allowing immune and cancer cell invasion and releasing growth factors. uPAR is now recognized as a biomarker for inflammatory diseases and cancer; uPAR and soluble uPAR fragments (suPAR) are increased in viral sepsis (COVID-19), inflammatory bowel disease, and metastasis. Here, we provide a comprehensive overview of the structure, function, and current studies examining uPAR and suPAR as diagnostic markers and therapeutic targets. Understanding uPAR is central to developing diagnostic markers and the ongoing development of antibody, small-molecule, nanogel, and virus-derived immune-modulating treatments that target uPAR.

Keywords: Serp-1; cancer; inflammation; inflammatory bowel disease; sepsis; serpin; uPAR; urokinase-type plasminogen receptor; virus.

Figure 1

Schematic of the enzymatic processing of uPA. uPA is secreted as a 411-amino-acid-long inactive protein containing growth factor, kringle, and serine protease domains. Activation of uPA occurs through a proteolytic cleavage between K158 and I159 followed by linkage of the two peptides by a disulfide bond. A second round of proteolytic cleavage between K135 and K136 results in a catalytically inactive amino terminal fragment and a catalytically active soluble low-molecular-weight serine protease. uPA—urokinase-type plasminogen activator; uPAR—uPA receptor.

Figure 2

Schematic of the uPA receptor (uPAR). uPAR has three domains: D1, D2, and D3. D1 binds uPA and D3 is linked by GPI to the outer cell membrane. GPI—glycophosphatidyl inositol; uPA—urokinase-type plasminogen activator.

Figure 3

The urokinase-type plasminogen activator receptor (uPAR) modifies intracellular and extracellular pathways. uPAR is a GPI-linked membrane protein that modifies intracellular downstream pathway responses via protein-to-protein interactions in a large lipid raft of associated membrane proteins. uPAR modifies intracellular activation through interactions with integrins and GPCRs, as illustrated here. Mammalian serpin PAI-1 binding to the uPA/uPAR complex inhibits uPA/uPAR activity and can also be internalized, further modifying and altering intracellular activity pathways. uPA/uPAR also modifies extracellular activity via activation of plasminogen to form plasmin, with subsequent activation of MMPs and growth factors that alter cellular invasion into the extracellular matrix surrounding adjacent cells. The virus-derived serpin Serp-1 also binds and inhibits uPA and the uPAR as well as plasmin. MMP—matrix metalloproteinases; GPCR—G protein-coupled receptor; PAI—plasminogen activator inhibitor; C—complement; Vn—vitronectin; GPI—glycophosphatidyl inostitol; ECM—extracellular matrix; Serp-1—virus-derived serpin.