Plasminogen activator inhibitor type 2: a regulator of monocyte proliferation and differentiation.
We have explored the role of plasminogen activator inhibitor type 2 (PAI-2) in THP-1 monocyte-like cells. These cells possess a mutation in the PAI-2 gene and do not produce an active PAI-2 protein. Transfection of THP-1 cells with plasmids expressing active PAI-2 reduced the cells' inherent adhesive properties and decreased the rate of cell proliferation. THP-1 cells expressing active PAI-2 also displayed an altered phenotype in response to phorbol ester-induced differentiation that was concomitant with a reduction in CD14 expression. THP-1 cells transfected with a variant PAI-2 containing a mutation in the reactive center (PAI-2(Ala380)) displayed no noticeable change in any of these parameters, suggesting the involvement of a PAI-2-sensitive serine protease(s). The antiproliferative effect of PAI-2 was attenuated by treating the PAI-2-expressing THP-1 cells with recombinant urokinase (u-PA), suggesting that PAI-2 was disruptive of a u-PA/u-PA receptor signaling pathway initiated on the cell surface. Consistent with this, treatment of wild-type THP-1 cells with recombinant PAI-2 also caused a reduction in cellular proliferation. These results implicate endogenous PAI-2 as a modulator of monocyte adhesion, proliferation, and differentiation.
Yu
Hong
H
Monash University Department of Medicine, Box Hill Hospital, Victoria, Australia.
Maurer
Fabienne
F
Medcalf
Robert L
RL
D019943:Amino Acid Substitution; D001665:Binding Sites / Q000235:genetics / Q000502:physiology; D002448:Cell Adhesion / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D006801:Humans; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects; D009154:Mutation; D017396:Plasminogen Activator Inhibitor 2 / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D011485:Protein Binding / Q000502:physiology; D015842:Serine Proteinase Inhibitors / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000187:drug effects / Q000378:metabolism / Q000502:physiology
D017396:Plasminogen Activator Inhibitor 2; D015842:Serine Proteinase Inhibitors; D014568:Urokinase-Type Plasminogen Activator