Certain extracellular proteases, derived from the circulation and inflammatory cells, can specifically cleave and trigger protease-activated receptors (PARs), a small, but important, sub-group of the G-protein-coupled receptor super-family. Four PARs have been cloned and they all share the same basic mechanism of activation: proteases cleave at a specific site within the extracellular N-terminus to expose a new N-terminal tethered ligand domain, which binds to and thereby activates the cleaved receptor. Thrombin activates PAR1, PAR3 and PAR4, trypsin activates PAR2 and PAR4, and mast cell tryptase activates PAR2 in this manner. Activated PARs couple to signalling cascades that affect cell shape, secretion, integrin activation, metabolic responses, transcriptional responses and cell motility. PARs are 'single-use' receptors: proteolytic activation is irreversible and the cleaved receptors are degraded in lysosomes. Thus, PARs play important roles in 'emergency situations', such as trauma and inflammation. The availability of selective agonists and antagonists of protease inhibitors and of genetic models has generated evidence to suggests that proteases and their receptors play important roles in coagulation, inflammation, pain, healing and protection. Therefore, selective antagonists or agonists of these receptors may be useful therapeutic agents for the treatment of human diseases.
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October 2002
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Review Article|
October 01 2002
Protease-activated receptors: the role of cell-surface proteolysis in signalling
Graeme S Cottrell
;
Graeme S Cottrell
*Department of Surgery, University of California at San Francisco, 521 Parnassus Avenue, San Francisco, CA 94143-0660, U.S.A.
†Department of Physiology, University of California at San Francisco, 521 Parnassus Avenue, San Francisco, CA 94143-0660, U.S.A.
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Anne-Marie Coelho
;
Anne-Marie Coelho
*Department of Surgery, University of California at San Francisco, 521 Parnassus Avenue, San Francisco, CA 94143-0660, U.S.A.
†Department of Physiology, University of California at San Francisco, 521 Parnassus Avenue, San Francisco, CA 94143-0660, U.S.A.
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Nigel W Bunnett
Nigel W Bunnett
1
*Department of Surgery, University of California at San Francisco, 521 Parnassus Avenue, San Francisco, CA 94143-0660, U.S.A.
†Department of Physiology, University of California at San Francisco, 521 Parnassus Avenue, San Francisco, CA 94143-0660, U.S.A.
1To whom correspondence should be addressed (e-mail: nigelb@itsa.ucsf.edu).
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Essays Biochem (2002) 38: 169–183.
Citation
Nigel M. Hooper, Graeme S Cottrell, Anne-Marie Coelho, Nigel W Bunnett; Protease-activated receptors: the role of cell-surface proteolysis in signalling. Essays Biochem 1 October 2002; 38 169–183. doi: https://doi.org/10.1042/bse0380169
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