RT Journal Article
SR Electronic
T1 Proteinases, Their Extracellular Targets, and Inflammatory Signaling
JF Pharmacological Reviews
JO Pharmacol Rev
FD American Society for Pharmacology and Experimental Therapeutics
SP 1110
OP 1142
DO 10.1124/pr.115.010991
VO 68
IS 4
A1 Rithwik Ramachandran
A1 Christophe Altier
A1 Katerina Oikonomopoulou
A1 Morley D. Hollenberg
A2 Paul A. Insel
YR 2016
UL http://pharmrev.aspetjournals.org/content/68/4/1110.abstract
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.