Activation of endothelial cell protease activated receptor 1 by the protein C pathway.
The coagulant and inflammatory exacerbation in sepsis is counterbalanced by the protective protein C (PC) pathway. Activated PC (APC) was shown to use the endothelial cell PC receptor (EPCR) as a coreceptor for cleavage of protease activated receptor 1 (PAR1) on endothelial cells. Gene profiling demonstrated that PAR1 signaling could account for all APC-induced protective genes, including the immunomodulatory monocyte chemoattractant protein-1 (MCP-1), which was selectively induced by activation of PAR1, but not PAR2. Thus, the prototypical thrombin receptor is the target for EPCR-dependent APC signaling, suggesting a role for this receptor cascade in protection from sepsis.
Riewald
Matthias
M
Department of Immunology, C204, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Petrovan
Ramona J
RJ
Donner
Aaron
A
Mueller
Barbara M
BM
Ruf
Wolfram
W
D000818:Animals; D001779:Blood Coagulation Factors; D002460:Cell Line; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D004789:Enzyme Activation; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D011486:Protein C / Q000378:metabolism*; D044463:Receptor, PAR-1; D044464:Receptor, PAR-2; D011956:Receptors, Cell Surface / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D018179:Receptors, Thrombin / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction; D013917:Thrombin / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics
D001779:Blood Coagulation Factors; D018932:Chemokine CCL2; D004268:DNA-Binding Proteins; C539821:NR4A1 protein, human; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011486:Protein C; D044463:Receptor, PAR-1; D044464:Receptor, PAR-2; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D018179:Receptors, Thrombin; D014157:Transcription Factors; C091963:activated protein C receptor; D020928:Mitogen-Activated Protein Kinases; D013917:Thrombin