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Collagenolytic matrix metalloproteinases antagonize proteinase-activated receptor-2 activation, providing insights into extracellular matrix turnover

Lookup NU author(s): Dr Adrian Falconer, Dr Chun Chan, Dr Joseph Gray, Emeritus Professor Drew Rowan, Dr David Wilkinson



This is the final published version of an article that has been published in its final definitive form by American Society for Biochemistry and Molecular Biology Inc., 2019.

For re-use rights please refer to the publisher's terms and conditions.


© 2019 Falconer et al.The collagenase subfamily of matrix metalloproteinases (MMPs) have important roles in the remodeling of collagenous matrices. The proteinase-activated receptor (PAR) family has a unique mechanism of activation requiring proteolysis of an extracellular domain forming a neo-N terminus that acts as a tethered ligand, a process that has been associated with the development of arthritis. Canonical PAR2 activation typically occurs via a serine proteinase at Arg36-Ser37, but other proteinases can cleave PARs downstream of the tethered ligand and “disarm” the receptor. To identify additional cleavage sites within PAR2, we synthesized a 42-amino-acid peptide corresponding to the extracellular region. We observed that all three soluble MMP collagenases, MMP-1, MMP-8, and MMP-13, cleave PAR2 and discovered a novel cleavage site (Ser37-Leu38). Metalloproteinases from resorbing bovine nasal cartilage and recombinant human collagenases could cleave a quenched fluorescent peptide mimicking the canonical PAR2 activation region, and kinetic constants were determined. In PAR2-over-expressing SW1353 chondrocytes, we demonstrated that the activator peptide SLIGKV-NH2 induces rapid calcium flux, inflammatory gene expression (including MMP1 and MMP13), and the phosphorylation of extracellular signal-regulated kinase (ERK) and p38 kinase. The corresponding MMP cleavage-derived peptide (LIGKVD-NH2) exhibited no canonical activation; however, we observed phosphorylation of ERK, providing evidence of biased agonism. Importantly, we demonstrated that preincubation with active MMP-1 reduced downstream PAR2 activation by a canonical activator, matriptase, but not SLIGKV-NH2. These results support a role for collagenases as proteinases capable of disarming PAR2, revealing a mechanism that suppresses PAR2-mediated inflammatory responses.

Publication metadata

Author(s): Falconer AMD, Chan CM, Gray J, Nagashima I, Holland RA, Shimizu H, Pickford AR, Rowan AD, Wilkinson DJ

Publication type: Article

Publication status: Published

Journal: Journal of Biological Chemistry

Year: 2019

Volume: 294

Issue: 26

Pages: 10266-10277

Online publication date: 19/05/2019

Acceptance date: 02/04/2016

Date deposited: 30/07/2020

ISSN (print): 0021-9258

ISSN (electronic): 1083-351X

Publisher: American Society for Biochemistry and Molecular Biology Inc.


DOI: 10.1074/jbc.RA119.006974

PubMed id: 31110047


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