Proteinases, Their Extracellular Targets, and Inflammatory Signaling.
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.
Inflammation Research Network-Snyder Institute for Chronic Disease, Department of Physiology & Pharmacology (R.R., C.A., M.D.H.) and Department of Medicine (M.D.H.),University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada; Department of Pathology and Laboratory Medicine, Toronto Western Hospital, Toronto, Ontario, Canada (K.O.); and Department of Physiology and Pharmacology, Western University, London, Ontario, Canada (R.R.).
Rithwik
R
Ramachandran
Inflammation Research Network-Snyder Institute for Chronic Disease, Department of Physiology & Pharmacology (R.R., C.A., M.D.H.) and Department of Medicine (M.D.H.),University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada; Department of Pathology and Laboratory Medicine, Toronto Western Hospital, Toronto, Ontario, Canada (K.O.); and Department of Physiology and Pharmacology, Western University, London, Ontario, Canada (R.R.).
Christophe
C
Altier
Inflammation Research Network-Snyder Institute for Chronic Disease, Department of Physiology & Pharmacology (R.R., C.A., M.D.H.) and Department of Medicine (M.D.H.),University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada; Department of Pathology and Laboratory Medicine, Toronto Western Hospital, Toronto, Ontario, Canada (K.O.); and Department of Physiology and Pharmacology, Western University, London, Ontario, Canada (R.R.).
Katerina
K
Oikonomopoulou
Inflammation Research Network-Snyder Institute for Chronic Disease, Department of Physiology & Pharmacology (R.R., C.A., M.D.H.) and Department of Medicine (M.D.H.),University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada; Department of Pathology and Laboratory Medicine, Toronto Western Hospital, Toronto, Ontario, Canada (K.O.); and Department of Physiology and Pharmacology, Western University, London, Ontario, Canada (R.R.) mhollenb@ucalgary.ca.
Morley D
MD
Hollenberg