Proteinases as hormone-like signal messengers - Proteinase-activated receptors and the pathophysiology of inflammation, pain, cardiovascular disease and cancer

Proteinases like thrombin and trypsin, long known for their ability to activate the coagulation cascade or to act as hormone-processing enzymes, are now recognised as hormone-like regulators of cell function. These serine proteinases activate cell signalling by triggering a novel four-member family of G-protein-coupled receptors, termed Proteinase-Activated Receptors (PARS). This review article summarises historically the discovery of PARS as well as their unique mechanism of activation and outlines a number of different pathophysiological settings in which PARs can act to regulate cell and tissue function. PARS can be seen to play a role in pathophysiological processes ranging from inflammation and pain to cardiovascular disease and cancer. Apart from activating PARS to cause their physiological effects in tissues, proteinases can also mediate cell signalling via a number of other mechanisms, including the activation of growth factor receptors, like the one for insulin. Therefore, this article also describes the non-PAR mechanisms whereby proteinases can have hormone-like actions in cells and tissues.