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. Urokinase-type plasminogen activator receptor (uPAR) regulates extracellular matrix (ECM) proteolysis by binding the extracellular protease uPA and also activates many intra