Plasminogen activator inhibitor type 2: still an enigmatic serpin but a model for gene regulation

Plasminogen activator inhibitor type-2 (PAI-2; SERPINB2) is an atypical member of the Ov-serpin family of serine protease inhibitors. While it is an undisputed inhibitor of urokinase and tissue-type plasminogen activator in the extracellular space and on the cell surface, the weight of circumstantial evidence suggests that PAI-2 also fulfills an intracellular role which is independent of plasminogen activator inhibition and indeed may not even involve protease inhibition at all. More and more data continue to implicate a role for PAI-2 in many settings, the most recent associating it as a modulator of the innate immune response. Further to the debates concerning its physiological role, there are few genes, if any, that display the regulation profile of the PAI-2 gene: PAI-2 protein and mRNA levels can be induced in the order of, not hundred-, but thousand-folds in a process that is controlled at many levels including gene transcription and mRNA stability while an epigenetic component is also likely. The ability of some cells, including monocytes, fibroblasts, and neurons to have the capacity to increase PAI-2 synthesis to such high levels is intriguing enough. So why do these cells have the capacity to synthesize so much of this protein? While tantalizing clues continue to be revealed to the field, an understanding of how this gene is regulated so profoundly has provided insights into the broader mechanics of gene expression and regulation.