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Review ArticleReview Article

Proteinases, Their Extracellular Targets, and Inflammatory Signaling

Rithwik Ramachandran, Christophe Altier, Katerina Oikonomopoulou and Morley D. Hollenberg
Paul A. Insel, ASSOCIATE EDITOR
Pharmacological Reviews October 2016, 68 (4) 1110-1142; DOI: https://doi.org/10.1124/pr.115.010991
Rithwik 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.)
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Christophe 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.)
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Katerina 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.)
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Morley D. Hollenberg
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.)
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Paul A. Insel
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.)
Roles: ASSOCIATE EDITOR
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Abstract

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.

Footnotes

  • Work in the authors’ laboratories that underpins the information in this review is funded by operating grants from the Canadian Institutes for Health Research (M.D.H., C.A.), Prostate Cancer Canada (M.D.H., C.A., R.R.), the Natural Sciences and Engineering Research Council of Canada (C.A.), and The Calgary Motorcycle TELUS Ride for Dad and the Prostate Cancer Fight Foundation (M.D.H.).

  • dx.doi.org/10.1124/pr.115.010991.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Pharmacological Reviews: 68 (4)
Pharmacological Reviews
Vol. 68, Issue 4
1 Oct 2016
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Review ArticleReview Article

Proteinase-Mediated Signaling and Inflammation

Rithwik Ramachandran, Christophe Altier, Katerina Oikonomopoulou and Morley D. Hollenberg
Pharmacological Reviews October 1, 2016, 68 (4) 1110-1142; DOI: https://doi.org/10.1124/pr.115.010991

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Review ArticleReview Article

Proteinase-Mediated Signaling and Inflammation

Rithwik Ramachandran, Christophe Altier, Katerina Oikonomopoulou and Morley D. Hollenberg
Pharmacological Reviews October 1, 2016, 68 (4) 1110-1142; DOI: https://doi.org/10.1124/pr.115.010991
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  • Article
    • Abstract
    • I. Introduction
    • II. Classification and Overview of Mechanisms Regulating Proteolytic Enzymes
    • III. Proteinase-Mediated Signaling: Molecular Targets that Trigger the Response
    • IV. Adhesion G Protein-Coupled Receptors: A Proteinase-Activated Receptor-like Tethered Ligand Signaling Mechanism Driven by Receptors with Intrinsic Proteinase Activity
    • V. Proteolytic Regulation of Ion Channels
    • VI. Therapeutic Targeting of the Proteolytic Signaling System
    • VII. Future Perspectives
    • Acknowledgments
    • Authorship Contributions
    • Footnotes
    • Abbreviations
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