Blood, 15 February 2003, Vol. 101, No. 4, pp. 1210-1212
Urokinase mediates receptor cross-talk
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
2 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.
Klaus T. Preissner
Justus-Liebig-University
