Protein C inhibitor (PAI-3): structure and multi-function

Abstract Protein C inhibitor (PCI) is a member of the serine protease inhibitor (serpin) family, which was initially found to be an inhibitor of activated protein C (APC) and later a potent inhibitor of the thrombin-thrombomodulin complex, suggesting that PCI plays a pivotal role in the regulation of the anticoagulant protein C pathway in human plasma. PCI is also known as a plasminogen activator inhibitor-3 (PAI-3), since this serpin was found in urine forming a complex with urokinase type-plasminogen activator (uPA). Human PCI also inhibits several other serine proteases involved in blood coagulation and fibrinolysis. Precursor proteins of PCI deduced from human, rhesus monkey, bovine, rabbit, rats and mouse cDNAs have sequence homology from 62 to 93%. Human PCI gene is located in a region involving genes of related serpins in chromosome 14q32.1. As regulatory mechanism of PCI gene expression, Sp1- and AP2-binding sites in the 5′-flanking region are the promoter and the enhancer, respectively. PCI mRNA is expressed in many organs, such as liver, kidney, spleen, pancreas, and reproductive organs (including testis, prostate, seminal vesicles and ovary in humans) and also in the liver and reproductive organs in bovines and rabbits; though in rats and mice only in the reproductive organs. PCI appears to play a role in the regulation of fertilization, presumably by inhibiting prostate specific antigen and acrosin in the male reproductive organs or by inhibiting protease(s) in the ovaries. In addition to the roles of PCI in coagulation, fibrinolysis and fertilization, human PCI is also suggested to regulate wound healing and renal tumour metastasis by inhibiting hepatocyte growth factor activator and uPA, respectively. Thus, PCI is a unique multi-functional serpin member playing several roles depending on species and organ tissues.