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

FASEB J. 2020 Jan;34(1):1079-1090. doi: 10.1096/fj.201801986RR. Epub 2019 Nov 28.


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.

Keywords: FSAP; HABP2; PARs; apoptosis; mutations; vascular.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Cell Line, Tumor
  • HEK293 Cells
  • Humans
  • MAP Kinase Signaling System
  • Mutagenesis, Site-Directed
  • Peptides / chemistry
  • Phosphorylation
  • Protein Isoforms
  • Receptor, PAR-1 / metabolism*
  • Receptor, PAR-2 / metabolism*
  • Serine Endopeptidases / metabolism*
  • Signal Transduction
  • Thrombosis


  • Peptides
  • Protein Isoforms
  • Receptor, PAR-1
  • Receptor, PAR-2
  • HABP2 protein, human
  • Serine Endopeptidases