Urokinase-type plasminogen activator inhibits alpha 4 beta 1 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 alpha4beta1(+)/alpha5beta1(+) K562 cell adhesion on fibronectin by 30-40%, and completely suppressed integrin alpha4beta1-dependent T lymphocyte and alpha4beta1(+)/alpha5beta1(+) 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 alpha4beta1(-)/alpha5beta1(+) K562 cells to an RGD-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 alpha4beta1 nor with a suppression of alpha4beta1 ligand-binding function. Our results demonstrate that u-PA inhibits alpha4beta1- but not alpha5beta1-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.
Olivier
P
P
Centre Pluridisciplinaire d'Oncologie, School of Medicine, University of Lausanne, Lausanne, Switzerland.
Bieler
G
G
Müller
K M
KM
Hauzenberger
D
D
Rüegg
C
C
D002384:Catalysis; D002448:Cell Adhesion / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000737:chemistry; D005353:Fibronectins / Q000276:immunology / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D039041:Integrin alpha4beta1; D016023:Integrins / Q000037:antagonists & inhibitors* / Q000502:physiology*; D020014:K562 Cells; D010455:Peptides / Q000276:immunology / Q000378:metabolism; D017469:Receptors, Fibronectin / Q000378:metabolism; D016201:Receptors, Lymphocyte Homing / Q000037:antagonists & inhibitors* / Q000502:physiology*; D013601:T-Lymphocytes / Q000201:enzymology / Q000378:metabolism*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism / Q000502:physiology*
D017077:Culture Media, Conditioned; D005353:Fibronectins; D039041:Integrin alpha4beta1; D016023:Integrins; D010455:Peptides; D017469:Receptors, Fibronectin; D016201:Receptors, Lymphocyte Homing; D014568:Urokinase-Type Plasminogen Activator