Urokinase-type plasminogen activator inhibits α4β1 integrin-mediated T lymphocyte adhesion to fibronectin independently of its catalytic activity

The urokinase-type plasminogen activator (u-PA)/plasmin system plays an important role in promoting cell migration and invasion, an effect which is largely ascribed to the proteolytic activity of these enzymes. We investigated whether u-PA modulates integrin-dependent T lymphocyte migration and adhesion on fibronectin independently of its plasminogen activator function. Here we report that u-PA reduced the spontaneous and phorbol 12-myristate 13-acetate-induced migration of peripheral blood T lymphocytes on fibronectin by 20-50 %, decreased the T lymphocyte and alpha 4 beta 1(+)/alpha 5 beta 1(+) K562 cell adhesion on fibronectin by 30-40 %, and completely suppressed integrin alpha 4 beta 1-dependent T lymphocyte and alpha 4 beta 1(+)/alpha 5 beta 1(+) K562 cell adhesion to the LDV-containing 40-kDa fibronectin fragment. The u-PA receptor was not essential for this effect. In contrast, adhesion of alpha 4 beta 1(-)/alpha 5 beta 1(+) K562 cells to an ROD-containing fibronectin fragment was unaffected. A recombinant protein comprising the N-terminal fragment of u-PA, but lacking its proteolytic domain, had the same inhibitory effect. Decreased adhesion was neither associated with a diminished cell surface expression of alpha 4 beta 1 nor with a suppression of alpha 4 beta 1 ligand-binding function. Our results demonstrate that u-PA inhibits alpha 4 beta 1- but not alpha 5 beta 1-mediated lymphocyte/leukocyte adhesion to fibronectin independently of its proteolytic activity. This finding provides additional evidence that matrix proteinases may participate in cell adhesion and migration control independently of their matrix-degrading activity.