Cell-cell and cell-matrix interactions are key events in inflammatory cell reactions or during tissue remodeling. For cellular migration or invasion to occur, both integrin adhesion receptors and proteolytic systems linked to the cell surface are required. Here, the urokinase (uPA) receptor plays a central role: It can concentrate its ligand uPA and concomitant plasmin formation within the pericellular space and can also regulate integrin function by direct physical interactions. Although (enzymatically inactive) uPA was known also to induce cellular responses of cells lacking the glycolipid-anchored uPA receptor, a conclusive mechanistic explanation for these activities was missing so far.

Pluskota and colleagues (page 1582) have now identified the major β2 integrin on neutrophils, Mac-1, as an additional receptor for uPA, and present conclusive evidence that the kringle and protease domains of the “new” ligand uPA are recognized by the I-domain of this integrin. Mac-1 thereby becomes an even more crowded multifunctional recognition platform, particularly on neutrophils or monocytes: besides binding of other proteases (factor X, elastase), complement C3bi, or kininogen, the ligands ICAM-1 (on endothelium) or JAM-3 and GPIb (both on platelets), as well as fibrinogen, mediate adhesion, migration, or cell-cell contacts via Mac-1.

Although Pluskota et al show a competiton of fibrinogen and ICAM-1 binding by uPA, it remains to be demonstrated whether sufficient (extravascular) uPA is available to modulate these activities of Mac-1. Since the authors propose that uPA can simultaneously bind to the uPA receptor and Mac-1 to form a trimolecular complex, Mac-1 could act either as a direct signaling receptor or as an “adaptor” for transmission of uPA receptor–dependent exodomain interactions. Whether such a trimolecular entity with a comparable activity is also formed with different integrins on other cell types remains to be shown. Finally, with the present knowledge, additional uPA-based substances may become available that allow one to specifically target one or the other function of Mac-1 in inflammation- or tumor-related pathologies.