Production of Second Messengers Following Chemotactic and Mitogenic Urokinase-Receptor Interaction in Human Fibroblasts and Mouse Fibroblasts Transfected with Human Urokinase Receptor

Functions of the Fibrinolytic System in Human Ito Cells and Its Control by Basic Fibroblast and Platelet–Derived Growth Factor

“…25 possible that at low u-PA concentrations, only a few cohorts of u-PARs have the possibility of being stimulated as a result of receptor internalization and u-PA degradation. 27,41 At high u-PA concentrations, the subsequent occupancy of many cohorts of u-PARs, as a result of many cycles of receptor internalization and re-exposure, can stimulate a sustained production of second messengers (namely diacylglycerol 40 ), required to trigger mitosis, as previously reported for PDGF. 44 Studies in other cell systems have shown that u-PA localization on cell membranes enables u-PAR-bearing cells to activate plasmin, membrane-type MMP (MT-MMP), progelatinase A, and perhaps other MMPs 18,45-49 directly on the cell surface, thus providing the cells with a directional proteolytic machinery.…”

“…Similar results were obtained in u-PA-dependent mobilization of all the cell types challenged with u-PA under chemotactic conditions. 25,27,[40][41][42] We have previously suggested 41 that clustering of u-PAR at the leading edge of the cell membrane is required to sense the gradient, as in many other ligand-receptor systems. 43 In the presence of high u-PA concentrations, the gradient formation in the lower compartment of the chamber may be too fast, thus increasing the possibility of an overall stimulation of u-PARs that cannot undergo the clustering required to orient the leading edge of the cell in the direction of the gradient.…”

“…However, some data suggest that signaling and activation of a chemotactic and proliferative program may take place upon interaction of u-PAR with a truncated form of u-PA, lacking the catalytic site, or in the presence of inhibitors of plasmin generation. 19,27,42,51,52 Furthermore, it has been shown that u-PAR, which is spatially located in focal contacts and at the leading edge of migrating cells, 53,54 may directly interact via its extracellular domain with activated integrins promoting adhesion and migration toward specific matrix proteins even in the absence of u-PA. 55 Thus, the potential biological interactions of the u-PA/u-PAR system appear more complex than expected and require further studies.…”

“…Cross-linking assays with 125 I-ATF were performed as previously described on aliquots of cell lysates 27 (Fig. 1).…”

Generation and characterization of urokinase receptor-deficient mice.

“…The mature protein consists of three homologous cysteine-rich domains, the first of which comprises the u-PA binding domain (10). The receptor binds both single-chain and two-chain u-PA without inactivation, thus concentrating plasmin generation at the cell surface (2); it may be involved in internalization of u-PA/inhibitor complexes (5,11,12) and in signal transduction (13)(14)(15).…”