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

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 in 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, rat 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, Sp 1 - and AP2binding 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; however, only in the reproductive organs in rats and mice. 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 ovary. In addition to the roles of PCI in coagulation, fibrinolysis and fertilization, human PCI is also suggested to regulate wound healing and renal tumor 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.