AP1 Transcription Factor in the Regulation of the Urokinase Plasminogen Activation System

Urokinase plasminogen activation system regulates the activation of plasminogen to produce the ubiquitous extracellular protease plasmin. It is involved in different physiological and pathophysiological processes, which involve tissue reorganization, wound healing, cell migration and invasion, etc. The system comprises urokinase plasminogen activator, an extracellular protease, its inhibitor plasminogen activator inhibitor PAI1 and urokinase receptor, uPAR. The system is regulated at the level of transcription and posttranscriptionally, and the net urokinase activity depends on the balance between urokinase and PAI1. Promoters of urokinase, PAI1 and uPAR are regulated through different signaling pathways, mostly MAP kinases and TGFβ signaling. Urokinase promoter is complex and mostly depends on strong enhancers containing AP1/ETS binding sites for different combinations of AP1 dimers, whose members are phosphorylated through ERK, JNK and p38 kinases. The PAI1 promoter is mainly regulated through TGFβ signaling, which can use both Smad and AP1-dependent transcription. The uPAR promoter also depends on AP1 signaling, in addition to other transcription factors activated through other pathways. Although activated through common pathways, each of the promoters has specific regulation as a consequence of a signaling network, which enables fine-tuning of the system and urokinase activity according to the physiological needs.