Abstract
Plasminogen activator inhibitor-1 (PAI-1) is the main physiological inhibitor of plasminogen activators (PAs) and is therefore an important inhibitor of the plasminogen/plasmin system. Being the fast-acting inhibitor of tissue-type PA (tPA), PAI-1 primarily attenuates fibrinolysis. Through inhibition of urokinase-type PA (uPA) and interaction with biological ligands such as vitronectin and cell-surface receptors, the function of PAI-1 extends to pericellular proteolysis, tissue remodeling and other processes including cell migration. This review aims at providing a general overview of the properties of PAI-1 and the role it plays in many biological processes and touches upon the possible use of PAI-1 inhibitors as therapeutics.
Highlights
Plasminogen activator inhibitor-1 (PAI-1) belongs to the family of serine protease inhibitors and is an important regulator of the plasminogen/plasmin system (Figure 1) [1]
These effects are mediated by binding of the somatomedin B (SMB) domain or the neighboring Arg-Gly-Asp (RGD) motif [38,39] of vitronectin to cell surfaceassociated proteins including integrins and transmembrane receptors such as the urokinase-type PA (uPA) receptor, which initiates intracellular signaling events
Internalization of the complex through endocytosis results in the degradation of the PAI-1/uPA complex and recycling of free uPA receptor (uPAR) to the cell surface. Since both the uPAR and low-density lipoprotein receptor (LDLR) receptors are important for intracellular signaling as well, binding of PAI-1 or the PAI-1/uPA complex can either indirectly affect signaling activity by regulating receptor levels on the cell surface, or directly by inducing receptor activity through a direct binding interaction
Summary
Plasminogen activator inhibitor-1 (PAI-1) belongs to the family of serine protease inhibitors (serpins) and is an important regulator of the plasminogen/plasmin system (Figure 1) [1]. Several PAI-1 inhibitors have been developed to further study the role of PAI-1 in disease models and to explore their potential applications in a therapeutic setting. This narrative review aims at providing a general overview of the properties of PAI-1 and the role it plays in many biological processes and touches upon the possible use of PAI-1 inhibitors as therapeutics
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