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Plasminogen activator inhibitor type 2: a regulator of monocyte proliferation and differentiation
Journal Article Research Support, Non-U.S. Gov't --- Old month value: Apr 15
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.
Amino Acid Substitution Binding Sites/genetics/physiology Cell Adhesion/drug effects Cell Differentiation/drug effects Cell Division/drug effects Humans Monocytes/*cytology/drug effects Mutation Plasminogen Activator Inhibitor 2/genetics/pharmacology/*physiology Protein Binding/physiology Serine Proteinase Inhibitors/genetics/pharmacology/*physiology Signal Transduction/drug effects Transfection Tumor Cells, Cultured Urinary Plasminogen Activator/drug effects/metabolism/physiology
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