Urokinase-type plasminogen activator (uPA) binding to uPAR induces migration, adhesion, and proliferation through multiple interactions with G proteins-coupled receptor FPRL1, integrins, or the epidermal growth factor (EGF) receptor (EGFR). At least two forms of uPAR are present on the cell surface: full-length and cleaved uPAR, each specifically interacting with one or more transmembrane proteins. The connection between these interactions and the effects on the signaling pathways activation is not clear. We have exploited an uPAR mutant (hcr, human cleavage resistant) to dissect the pathways involved in uPA-induced cell migration. This mutant is not cleaved by proteases, is glycosylphosphatidylinositol anchored, and binds uPA with a normal K d . Both wild-type (wt) and hcr-uPAR are able to mediate uPA-induced migration, are constitutively associated with the EGFR, and associate with ␣31 integrin upon uPA binding. However, they engage different pathways in response to uPA. wt-uPAR requires both integrins and FPRL1 to mediate uPA-induced migration, and association of wt-uPAR to ␣31 results in uPAR cleavage and extracellular signal-regulated kinase (ERK) activation. On the contrary, hcr-uPAR does not activate ERK and does not engage FPRL1 or any other G protein-coupled receptor, but it activates an alternative pathway initiated by the formation of a triple complex (uPAR-␣31-EGFR) and resulting in the autotyrosine phosphorylation of EGFR. INTRODUCTIONThe serine protease urokinase-type plasminogen activator (uPA) and its high-affinity cell surface receptor (uPAR) play an important role in a number of physiological as well as pathological extracellular degradation processes, where cell migration is required, such as inflammatory responses and tumor invasion (Blasi and Carmeliet, 2002). uPAR was first identified as a major player in the regulation of pericellular proteolysis by modulating and concentrating the uPA activity at the required sites of the cell surface . However, new evidence revealed that uPA binding to uPAR also induces proteolysis-dependent and -independent intracellular signaling affecting cell adhesion, migration, and proliferation in a variety of cells (Chapman, 1997;Ossowski and Aguirre-Ghiso, 2000;Preissner et al., 2000;Blasi and Carmeliet, 2002;Kjøller, 2002).uPAR is a heavily glycosylated glycosylphosphatidylinositol (GPI)-anchored protein formed by three cysteine-rich LY6-like extracellular domains (LU domains D1, D2, and D3) connected by short linker regions (Ploug and Ellis, 1994). The three consecutive three-finger domains of uPAR are organized in an almost circular manner and generate a deep internal cavity for the interaction with uPA. The receptor-binding domain of uPA is engaged in this central cavity, leaving the whole external surface available for other interactions (Llinas et al., 2005). Identified interactors include signaling molecules such as various integrins, the G protein-coupled receptor FPRL1, the epidermal growth factor (EGF) receptor (EGFR), the mannose-6-phosphate recep...
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