Physiology and Pharmacology Publications
Proteinases, their extracellular targets, and inflammatory signaling
Document Type
Article
Publication Date
10-1-2016
Journal
Pharmacological Reviews
Volume
68
Issue
4
First Page
1110
Last Page
1142
URL with Digital Object Identifier
10.1124/pr.115.010991
Abstract
© 2016 by The American Society for Pharmacology and Experimental Therapeutics. Given that over 2% of the human genome codes for proteolytic enzymes and their inhibitors, it is not surprising that proteinases serve many physiologicpathophysiological 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.