PT - JOURNAL ARTICLE AU - Rithwik Ramachandran AU - Christophe Altier AU - Katerina Oikonomopoulou AU - Morley D. Hollenberg ED - Insel, Paul A. TI - Proteinases, Their Extracellular Targets, and Inflammatory Signaling AID - 10.1124/pr.115.010991 DP - 2016 Oct 01 TA - Pharmacological Reviews PG - 1110--1142 VI - 68 IP - 4 4099 - http://pharmrev.aspetjournals.org/content/68/4/1110.short 4100 - http://pharmrev.aspetjournals.org/content/68/4/1110.full SO - Pharmacol Rev2016 Oct 01; 68 AB - Given that over 2% of the human genome codes for proteolytic enzymes and their inhibitors, it is not surprising that proteinases serve many physiologic-pathophysiological roles. In this context, we provide an overview of proteolytic mechanisms regulating inflammation, with a focus on cell signaling stimulated by the generation of inflammatory peptides; activation of the proteinase-activated receptor (PAR) family of G protein-coupled receptors (GPCR), with a mechanism in common with adhesion-triggered GPCRs (ADGRs); and by proteolytic ion channel regulation. These mechanisms are considered in the much wider context that proteolytic mechanisms serve, including the processing of growth factors and their receptors, the regulation of matrix-integrin signaling, and the generation and release of membrane-tethered receptor ligands. These signaling mechanisms are relevant for inflammatory, neurodegenerative, and cardiovascular diseases as well as for cancer. We propose that the inflammation-triggering proteinases and their proteolytically generated substrates represent attractive therapeutic targets and we discuss appropriate targeting strategies.