Proteinases, proteinase-activated receptors (PARs) and the pathophysiology of cancer and diseases of the cardiovascular, musculoskeletal, nervous and gastrointestinal systems.

摘要

Proteinases like thrombin, trypsin and tissue kallikreins are now known to regulate cell signaling by cleaving and activating a novel family of G-protein-coupled proteinase-activated receptors (PARs 1 to 4) via exposure of a 'tethered' receptor-triggering ligand. On their own, short synthetic peptides based on the 'tethered ligand' sequences of the PARs (PAR-APs) can, in the absence of receptor proteolysis, selectively activate PARs 1, 2 and 4 and cause physiological responses both in vitro and in vivo. Using the PAR-APs as probes in vivo, it has been found that PAR activation can affect the vascular, renal, respiratory, gastrointestinal, musculoskeletal and nervous systems (both central and peripheral) and can promote cancer metastasis and invasion. The responses triggered by PARs 1, 2 and 4 are in keeping with an innate immune inflammatory response, ranging from vasodilatation to intestinal inflammation, increased cytokine production and increased nociception. Thus, PARs have been implicated in a number of disease states including cancer and inflammation of the cardiovascular, respiratory, musculoskeletal, gastrointestinal and nervous systems. Furthermore, PAR-regulating proteinases have been implicated in pathogen-induced inflammation. The identities of the proteinases that regulate PARs in these pathological settings in vivo have yet to be explored in depth. In addition to activating or dis-arming PARs, proteinases can also cause hormone-like effects by signaling mechanisms that do not involve the PARs and that may be as important as the activation of PARs. Thus, the working hypotheses of this article are: (1) that proteinases in general must now be considered as 'hormone-like' messengers that can signal either via PARs or other mechanisms and (2) that the PARs themselves, their activating serine proteinases and their associated signaling pathways can be considered as attractive targets for therapeutic drug development.