Modulation of Cellular Function by the Urokinase Receptor Signalling: A Mechanistic View

Abstract

Urokinase-type plasminogen activator receptor (uPAR or CD87) is a glycosyl-phosphatidyl-inositol anchored (GPI) membrane protein. The uPAR primary ligand is the serine protease urokinase (uPA), converting plasminogen into plasmin, a broad spectrum protease, active on most extracellular matrix components. Besides uPA, the uPAR binds specifically also to the matrix protein vitronectin and, therefore, is regarded also as an adhesion receptor. Complex formation of the uPAR with diverse transmembrane proteins, including integrins, formyl peptide receptors, G protein-coupled receptors and epidermal growth factor receptor results in intracellular signalling. Thus, the uPAR is a multifunctional receptor coordinating surface-associated pericellular proteolysis and signal transduction, thereby affecting physiological and pathological mechanisms. The uPAR-initiated signalling leads to remarkable cellular effects, that include increased cell migration, adhesion, survival, proliferation and invasion. Although this is beyond the scope of this review, the uPA/uPAR system is of great interest to cancer research, as it is associated to aggressive cancers and poor patient survival. Increasing evidence links the uPA/uPAR axis to epithelial to mesenchymal transition, a highly dynamic process, by which epithelial cells can convert into a mesenchymal phenotype. Furthermore, many reports indicate that the uPAR is involved in the maintenance of the stem-like phenotype and in the differentiation process of different cell types. Moreover, the levels of anchor-less, soluble form of uPAR, respond to a variety of inflammatory stimuli, including tumorigenesis and viral infections. Finally, the role of uPAR in virus infection has received increasing attention, in view of the Covid-19 pandemics and new information is becoming available. In this review, we provide a mechanistic perspective, via the detailed examination of consolidated and recent studies on the cellular responses to the multiple uPAR activities.

Vitronectin-based hydrogels recapitulate neuroblastoma growth conditions

“…Our cell adhesion studies demonstrated that SK-N-BE (2) adhere and form focal adhesions when seeded on laminin, native VN, and PEGylated VN ( Figures 2B,D,E ). These results confirm that PEGylation does not reduce VN biological activity, but more importantly, they demonstrate that neuroblastic cells interact with VN to a similar extent than other studied glycoproteins such as laminin, supporting the role of VN in cell migration ( Alfano, Franco and Stoppelli, 2022 ). However, our results do not provide information about focal adhesion signaling activation, so further experiments such as phosphor-FAK focal adhesion protein assessment could deeper evaluate how cells interact with both PEGylated and native VN.…”

MIF promotes cell invasion by the LRP1-uPAR interaction in pancreatic cancer cells

“…uPAR has been shown to be upregulated in cancer cells, to play a critical role in driving plasminogen-dependent matrix degradation and to affect a variety of physiological and pathological processes, including cell migration, invasion, adhesion, survival and proliferation ( 73 ). In this report, we found a decreased protein abundance but not mRNA of uPAR in MIF-knockdown PDAC cells, suggesting that MIF may not affect PLAUR transcription.…”

The uPA/uPAR System Orchestrates the Inflammatory Response, Vascular Homeostasis, and Immune System in Fibrosis Progression

“…uPAR is a glycosyl-phosphatidyl-inositol anchored (GPI) membrane protein that consists of three domains: D1 (residues 1–92), D2 (residues 93–191) and D3 (residues 192–283) [ 50 ]. uPAR is cleaved between the D1 and D2 domains (linker region) and the GPI-anchor domain by several proteases, such as uPA, plasmin, MMPs, and GPI-specific phospholipase D, and then forms soluble uPAR (suPAR; full length D1-D3, D2D3, and D1) ( Figure 3 ) [ 51 ].…”

“…uPAR is cleaved between the D1 and D2 domains (linker region) and the GPI-anchor domain by several proteases, such as uPA, plasmin, MMPs, and GPI-specific phospholipase D, and then forms soluble uPAR (suPAR; full length D1-D3, D2D3, and D1) ( Figure 3 ) [ 51 ]. uPAR can interact with various transmembrane receptors, including integrins, epidermal growth factor receptor (EGFR), platelet-derived growth factor receptors (PDGFR), vascular endothelial growth factor receptor 2 (VEGFR2), and insulin-like growth factor 1 receptor (IGF1R), as well as regulate signal transduction [ 32 , 50 ]. In addition, uPAR can interact with low-density lipoprotein receptor (LRP), and this uPAR/LRP interaction is associated with uPAR recycling [ 52 ].…”