Proteinases and signalling: pathophysiological and therapeutic implications via PARs and more

Abstract

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 1–4) via exposure of a tethered receptor‐triggering ligand. On their own, short synthetic PAR‐selective PAR‐activating peptides (PAR‐APs) mimicking the tethered ligand sequences can activate PARs 1, 2 and 4 and cause physiological responses both in vitro and in vivo. Using the PAR‐APs as sentinel 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 nervous system) and can promote cancer metastasis and invasion. In general, 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 or decreased nociception. Further, PARs have been implicated in a number of disease states, including cancer and inflammation of the cardiovascular, respiratory, musculoskeletal, gastrointestinal and nervous systems. In addition to activating PARs, proteinases can cause hormone‐like effects by other signalling mechanisms, like growth factor receptor activation, that may be as important as the activation of PARs. We, therefore, propose that the PARs themselves, their activating serine proteinases and their associated signalling pathways can be considered as attractive targets for therapeutic drug development. Thus, proteinases in general must now be considered as ‘hormone‐like’ messengers that can signal either via PARs or other mechanisms. British Journal of Pharmacology (2008) 153, S263–S282; doi:; published online 3 December 2007

Emerging roles of serine proteinases in tissue turnover in arthritis

“…For example, the tissue factor-factor VIIa complex and factor Xa activate PAR-2 (16), while thrombin activates PAR-1, PAR-3, and PAR-4 (for review, see ref. 17). Thus, some coagulation cascade serine proteinases have noncoagulant functions in the joint that can modulate various cellular processes such as cell proliferation and survival, gene transcription, and protein translation (18).…”

“…17). Synovial fibroblasts, chondrocytes, macrophages, neutrophils, mast cells, T cells, and dendritic cells all express PARs, which exhibit both antiinflammatory and proinflammatory properties, although recent data point toward a detrimental role especially in the context of immune-mediated effects in arthritis (157).…”

Granzyme A and thrombin differentially promote the release of interleukin-8 from alveolar epithelial A549 cells

“…We first analyzed the expression of functional PAR-1 in A549 cells we used. Besides proteases, a synthetic sixamino-acid peptide (TRAP-6) can stimulate PAR-1 (Ramachandran and Hollenberg 2008;Steinhoff et al 2005). A rise in [Ca 2? ]…”

“…Some of them are known to be involved in the regulation of innate immune inflammatory responses. For instance, thrombin (a blood coagulation protease) and trypsin (a pancreatic digestive protease) stimulate the production and release of cytokines and chemokines in diverse cell types (Ramachandran and Hollenberg 2008;Steinhoff et al 2005). To date, it has been recognized that the effects of thrombin and trypsin on Y. Yoshikawa Á H. Hirayasu Á S. Tsuzuki (&) Á T. Fushiki Laboratory of Nutrition Chemistry, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan e-mail: tkmone@kais.kyoto-u.ac.jp the production of inflammatory mediators are largely attributed to their ability to activate a unique class of G-protein-coupled receptors, named protease-activated receptors (PARs).…”

“…Each of PARs (PAR-1, PAR-2, PAR-3, and PAR-4) is cleaved by certain proteases at a specific site on the N-terminal extension protruding into the extracellular space. In each of the four PARs, the newly exposed N-terminus itself acts as a tethered ligand to activate the receptor through an intramolecular interaction (Ramachandran and Hollenberg 2008;Steinhoff et al 2005). Indeed, thrombin and trypsin cleave PAR-1/PAR-4 and PAR-2, respectively, thereby triggering intracellular signaling pathways involved in the production of inflammatory mediators (Ramachandran and Hollenberg 2008;Steinhoff et al 2005).…”