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PMID:20826780

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Citation

Bae, JS, Yang, L and Rezaie, AR (2010) Factor X/Xa elicits protective signaling responses in endothelial cells directly via PAR-2 and indirectly via endothelial protein C receptor-dependent recruitment of PAR-1. J. Biol. Chem. 285:34803-12

Abstract

We recently demonstrated that the Gla domain-dependent interaction of protein C with endothelial protein C receptor (EPCR) leads to dissociation of the receptor from caveolin-1 and recruitment of PAR-1 to a protective signaling pathway. Thus, the activation of PAR-1 by either thrombin or PAR-1 agonist peptide elicited a barrier-protective response if endothelial cells were preincubated with protein C. In this study, we examined whether other vitamin K-dependent coagulation protease zymogens can modulate PAR-dependent signaling responses in endothelial cells. We discovered that the activation of both PAR-1 and PAR-2 in endothelial cells pretreated with factor FX (FX)-S195A, but not other procoagulant protease zymogens, also results in initiation of protective intracellular responses. Interestingly, similar to protein C, FX interaction with endothelial cells leads to dissociation of EPCR from caveolin-1 and recruitment of PAR-1 to a protective pathway. Further studies revealed that, FX activated by factor VIIa on tissue factor bearing endothelial cells also initiates protective signaling responses through the activation of PAR-2 independent of EPCR mobilization. All results could be recapitulated by the receptor agonist peptides to both PAR-1 and PAR-2. These results suggest that a cross-talk between EPCR and an unknown FX/FXa receptor, which does not require interaction with the Gla domain of FX, recruits PAR-1 to protective signaling pathways in endothelial cells.

Links

PubMed PMC2966096 Online version:10.1074/jbc.M110.163642

Keywords

Amino Acid Substitution; Antigens, CD/genetics; Antigens, CD/metabolism; Caveolin 1/genetics; Caveolin 1/metabolism; Cell Line; Endothelial Cells/cytology; Endothelial Cells/metabolism; Enzyme Activation/drug effects; Enzyme Activation/physiology; Enzyme Precursors/genetics; Enzyme Precursors/metabolism; Enzyme Precursors/pharmacology; Factor VIIa/genetics; Factor VIIa/metabolism; Factor Xa/genetics; Factor Xa/metabolism; Factor Xa/pharmacology; Humans; Mutation, Missense; Protein C/genetics; Protein C/metabolism; Protein C/pharmacology; Protein Structure, Tertiary; Receptor, PAR-1/genetics; Receptor, PAR-1/metabolism; Receptor, PAR-2/genetics; Receptor, PAR-2/metabolism; Receptors, Cell Surface/agonists; Receptors, Cell Surface/genetics; Receptors, Cell Surface/metabolism; Signal Transduction/drug effects; Signal Transduction/physiology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:PAR1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q03135

F

Seeded From UniProt

complete

HUMAN:PAR1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9UNN8

F

Seeded From UniProt

complete

HUMAN:PAR2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q14868

F

Seeded From UniProt

complete

HUMAN:CAV1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P25116

F

Seeded From UniProt

complete

HUMAN:Q14868

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P55085

F

Seeded From UniProt

complete

HUMAN:EPCR

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P25116

F

Seeded From UniProt

complete

HUMAN:PAR2

involved_in

GO:0035025: positive regulation of Rho protein signal transduction

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PAR2

involved_in

GO:0061028: establishment of endothelial barrier

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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