Protease activated receptors (PAR)‐1 and ‐2 mediate cellular effects of factor VII activating protease (FSAP) - Université Paris Cité Accéder directement au contenu
Article Dans Une Revue FASEB Journal Année : 2020

Protease activated receptors (PAR)‐1 and ‐2 mediate cellular effects of factor VII activating protease (FSAP)

Kristina Byskov
  • Fonction : Auteur
Sylvain M Le Gall
  • Fonction : Auteur
Bernd Thiede
  • Fonction : Auteur
Eric Camerer
Sandip M Kanse
  • Fonction : Auteur

Résumé

Factor VII activating protease (FSAP) is a circulating serine protease implicated in thrombosis, atherosclerosis, stroke, and cancer. Using an overexpression strategy, we have systematically investigated the role of protease activated receptors (PAR)-1, -2, -3, and -4 on FSAP-mediated signaling in HEK293T and A549 cells. Cleavage of PAR-reporter constructs and MAPK phosphorylation was used to monitor receptor activation. FSAP cleaved PAR-2 and to a lesser degree PAR-1, but not PAR-3 or PAR-4 in both cell types. Robust MAPK activation in response to FSAP was observed after PAR-2, but not PAR-1 overexpression in HEK293T. Recombinant serine protease domain of wild type FSAP, but not the Marburg I isoform of FSAP, could reproduce the effects of plasma purified FSAP. Canonical cleavage of both PARs was suggested by mass spectrometric analysis of synthetic peptide substrates from the N-terminus of PARs and site directed mutagenesis studies. Surprisingly, knockdown of endogenous PAR-1, but not PAR-2, prevented the apoptosis-inhibitory effect of FSAP, suggesting that PAR1 is nevertheless a direct or indirect target in some cell types. This molecular characterization of PAR-1 and -2 as cellular receptors of FSAP will help to define the actions of FSAP in the context of cancer and vascular biology.

Dates et versions

hal-03906222 , version 1 (19-12-2022)

Identifiants

Citer

Kristina Byskov, Sylvain M Le Gall, Bernd Thiede, Eric Camerer, Sandip M Kanse. Protease activated receptors (PAR)‐1 and ‐2 mediate cellular effects of factor VII activating protease (FSAP). FASEB Journal, 2020, 34 (1), pp.1079-1090. ⟨10.1096/fj.201801986RR⟩. ⟨hal-03906222⟩

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