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Regulation of cell signalling by uPAR

Key Points

  • The urokinase-type plasminogen activator receptor (uPAR) binds the serine protease urokinase-type plasminogen activator (uPA; also known as urokinase) and also activates intracellular signalling pathways. It can therefore coordinate extracellular matrix (ECM) proteolysis with activation of intracellular signalling pathways.

  • uPAR has been shown to bind the ECM component vitronectin and this can occur at the same time as uPA binding. Vitronectin binding is important for activation of some signalling pathways by uPAR.

  • uPAR expression is strongly activated during inflammation, immune responses, injury or stress, and conditions of tissue remodelling such as embryo implantation and wound healing. uPAR is also expressed in a large proportion of human cancers because many oncogenic signalling pathways and tumour microenvironmental conditions (such as hypoxia) activate transcription factors that act on the uPAR promoter.

  • Regulation of cell signalling and proteolysis by uPAR requires its association with the outer layer of the plasma membrane by a glycosyl phosphatidylinositol (GPI) anchor, but uPAR can also be secreted or shed from the cell surface and might act as a paracrine signalling molecule

  • uPAR signalling involves integrins, with different integrins activating distinct signalling pathways. Crosstalk might occur between separate uPAR–integrin signalling pathways and pathways might involve common events such as activation of Src family Tyr kinases.

  • uPAR signalling pathways involving β1 and β3 integrins are the most extensively characterized. uPAR–β1 integrin signalling promotes tumour cell proliferation and emergence from dormancy through activation of focal adhesion kinase (FAK; also known as PTK2) and the Ras–extracellular signal-regulated kinase (ERK) pathway, whereas uPAR–β3 integrin signalling activates the Rho-family small GTPase Rac to promote filamentous actin assembly, cell motility and invasion. However, much still needs to be learnt about the mechanisms of signalling.

  • Although integrins are required for uPAR-driven intracellular signalling, the mechanisms of uPAR–integrin interaction remain controversial. There is conflicting evidence for the direct binding of uPAR to integrins and there are several models for how these interactions might activate integrin signalling.

Abstract

Urokinase-type plasminogen activator receptor (uPAR) expression is elevated during inflammation and tissue remodelling and in many human cancers, in which it frequently indicates poor prognosis. uPAR regulates proteolysis by binding the extracellular protease urokinase-type plasminogen activator (uPA; also known as urokinase) and also activates many intracellular signalling pathways. Coordination of extracellular matrix (ECM) proteolysis and cell signalling by uPAR underlies its important function in cell migration, proliferation and survival and makes it an attractive therapeutic target in cancer and inflammatory diseases. uPAR lacks transmembrane and intracellular domains and so requires transmembrane co-receptors for signalling. Integrins are essential uPAR signalling co-receptors and a second uPAR ligand, the ECM protein vitronectin, is also crucial for this process.

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Figure 1: Function and regulation of uPAR in the plasminogen activation system.
Figure 2: Structure of uPAR.
Figure 3: uPAR–β1 integrin signalling.
Figure 4: uPAR–β3 integrin signalling.
Figure 5: Models of uPAR–integrin signalling.
Figure 6: Potential therapeutic targeting of uPAR.

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Glossary

Glycosyl phosphatidylinositol (GPI) anchor

A glycolipid group added post-translationally near the C terminus of proteins containing a GPI anchor signal sequence. GPI anchors locate proteins to the external leaflet of the plasma membrane after secretion. The anchor consists of a phosphoethanolamine linker, a glycan core containing mannose, glucosamine and myo-inositol, and a phospholipid tail.

Matrix metalloprotease

One of a family of secreted, transmembrane or GPI-anchored metal ion-dependent enzymes that digest ECM proteins and are produced in a latent (zymogen) form.

Growth factor domain

The N-terminal domain of uPA (amino acids 1–49), which exhibits homology with the EGF family and mediates the binding of uPA to uPAR.

Somatomedin B (SMB) domain

The Cys-rich N-terminal domain of vitronectin (amino acids 1–44), which interacts with uPAR and PAI1. Many of the same residues of SMB interact with both uPAR and PAI1; these interactions are therefore mutually exclusive.

Fluorescence resonance energy transfer

(FRET). Energy transfer from a donor fluorophore to an acceptor fluorophore on excitation of the donor, leading to fluorescence of the acceptor only when the two fluorophores are in close proximity (typically less than 10 nm). FRET is used to detect and quantify protein–protein interactions in living cells by expressing proteins of interest as fusions with donor and acceptor fluorescent proteins.

Monocyte

A leukocyte of the myeloid lineage that phagocytoses pathogens and debris and releases cytokines, which modulate innate and adaptive immune responses. After migrating into tissues, monocytes can differentiate into macrophages (longer-lived phagocytic, antigen-presenting and cytokine-releasing cells) and myeloid dendritic cells (antigen-presenting cells that stimulate T and B cell responses).

Basophil

A type of granulocyte (a myeloid-derived leukocyte that is characterized by prominent cytoplasmic granules) that is involved in inflammatory and allergic responses. Basophils secrete anticoagulants, proteases and pro-inflammatory molecules such as histamine and cytokines.

Clathrin-dependent endocytosis

A pathway for the internalization of plasma membrane proteins. Receptor clustering in membrane domains containing a polymeric clathrin coat and a complex of adaptor proteins and GTPases leads to membrane invagination and scission to form a clathrin-coated vesicle containing the internalized receptors.

Chemotaxis

The directional cell migration that occurs in response to gradients of soluble extracellular signalling molecules (chemoattractants) that bind plasma membrane receptors to activate cell signalling.

Clathrin-independent endocytosis

A group of pathways for receptor internalization that do not involve clathrin. This diverse group of processes includes endocytosis of caveolae (membrane microdomains enriched in the transmembrane protein caveolin), pathways dependent on Rho and Arf family small GTPases, and mechanisms used to internalize large portions of membrane along with extracellular particles or fluid (phagocytosis and macropinocytosis, respectively).

Proteinuric disease

A disease that is characterized by the presence of excess serum proteins in the urine (proteinuria) owing to damage or dysfunction of the ultrafiltration system in the glomerulus of the kidney.

Xenograft assay

An assay involving the introduction of the cells or tissue of one species into a host organism of a different species. In cancer research, human tumour cells are often injected or implanted into immunocompromised mice to study tumour growth and metastasis.

Alanine scanning mutagenesis

The systematic mutation of individual amino acids in a protein to Ala, which has a highly unreactive methyl side chain and is thought to impose few conformational, electrostatic and steric effects on protein structure. The library of single amino acid mutants created by this technique is then used to analyse the role of each mutated amino acid in a particular function.

Neutrophil

A granulocyte that migrates rapidly to sites of inflammation in response to substances produced by pathogens, dying cells and other inflammatory cells (such as macrophages). Neutrophils phagocytose pathogens and debris and secrete antimicrobial proteins, proteases and cytokines.

Fibronectin fibrillogenesis

The process by which soluble fibronectin molecules bound to integrins undergo conformational changes leading to intermolecular interactions that assemble them into insoluble fibrils. This process is regulated through the control of integrin activation and cytoskeletal dynamics.

Chorioallantoic membrane (CAM) assay

An assay in which cultured mammalian cells are grafted onto the chicken chorioallantoic membrane (a highly vascularized thin membrane attached to the inner surface of the eggshell) to examine growth, blood vessel recruitment and dissemination.

Oncolytic virus

A virus that is naturally selected or genetically engineered to preferentially infect and kill tumour cells.

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Smith, H., Marshall, C. Regulation of cell signalling by uPAR. Nat Rev Mol Cell Biol 11, 23–36 (2010). https://doi.org/10.1038/nrm2821

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