Thrombin/Protease-Activated Receptor Signaling Pathway

Preferred Label : Thrombin/Protease-Activated Receptor Signaling Pathway;

NCIt synonyms : Thrombin Protease-Activated Receptor Signaling Pathway;

NCIt related terms : Thrombin signaling and protease-activated receptors;

Alternative definition : BIOCARTA: Thrombin is an extracellular protease that is involved in the clotting of blood and inflammation through its action on platelets and endothelial cells in the vasculature and that plays a role in thrombosis and myocardial infarction. The protease activated receptors PAR1 and PAR4 are cellular targets of thrombin signaling and members of the G-protein coupled receptor gene family. Both of these receptors are cleaved in their N-terminus by thrombin, unmasking a portion of the receptor sequence that acts itself as a tethered peptide ligand that activates the receptor. The tethered ligand that activates PAR1 is SFLLRN and the tethered ligand that activates PAR4 is GYPGQV. Other members of the family include PAR2 which is activated by trypsin rather than thrombin and PAR3 which seems to play a role in the activation of other PARs but does not itself transduce a signal directly. Addition of peptide agonist exogenously in solution can also activate PAR1, PAR2 and PAR4. PAR1 activation may be involved in the dilation of arteries during inflammation through the action of thrombin on endothelial cells and in platelet activation by thrombin during clotting. PAR1 and PAR2 activation cause bronchodilation in airway and may protect against asthma. PAR 4 activation by thrombin activates platelets during clotting and mice lacking PAR4 have impaired clotting and platelets that do not respond to thrombin signaling. The action of thrombin on PAR1 and PAR4 on platelets and endothelial cells may also contribute to vascular permeability and inflammation. Activated PARs appear to couple primarily through Gq-mediated stimulation of inositol phosphate metabolism and intracellular calcium levels to activate platelets. PAR1 and PAR4 also appear to couple to multiple G-proteins and transduce signals through more than one G-protein mediated pathway in some circumstances. Signaling by PAR1 and PAR4 through Galpha12 pathways couples to Rho signaling and changes in cytoskeletal structure and cell shape. Gi activation does not appear necessary for platelet activation by PAR1 or PAR4, and platelet activation by these receptors requires an ADP signal perhaps acting through the platelet-associated purinergic receptor P2Y12. Gi-coupled signaling may play a role in mitogenic PAR signaling in some settings through Map kinase activation. Activation of Rho by PAR1 can induce cellular transformation through a Galpha12 mediated mechanism and sustained rho-dependent phosphorylation of the myosin light chain by PAR1 contributes to cytoskeletal changes and activation of platelets. Since the activation of PARs by protease cleavage is irreversible the primary mechanism for down-regulation of the PAR signaling cascade appears to be internalization and degradation of PAR receptors. (This definition may be outdated - see the DesignNote.);

NCIt note : The BIOCARTA Definition (ALT_DEFINITION) for this pathway concept was provided by BioCarta. This property was not created by, nor is it maintained by the NCI Thesaurus staff. Additionally, BioCarta is no longer updating its pathway data; thus, the BIOCARTA Definition might be outdated or inaccurate. Please see the Terms and Conditions for Use at http://www.biocarta.com/.;

Biocarta ID : h_Par1Pathway;

Details

Origin ID

C39278;

UMLS CUI

C1515419;

Semantic type(s)
- Conceptual Entity [UMLS semantic type]
has_gene_product_element
- Guanine Nucleotide-Binding Protein G(i) Subunit Alpha-1 [NCIt concept]
- Guanine Nucleotide-Binding Protein G(q) Subunit Alpha [NCIt concept]
- Guanine Nucleotide-Binding Protein Subunit Alpha-12 [NCIt concept]
- Mitogen-Activated Protein Kinase Kinase Kinase 7 [NCIt concept]
- Phosphatidylinositol 3-Kinase Regulatory Subunit Alpha [NCIt concept]
- Phosphatidylinositol 4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha Isoform [NCIt concept]
- Phosphatidylinositol 4,5-Bisphosphate 3-Kinase Catalytic Subunit Gamma Isoform [NCIt concept]
- Protease-Activated Receptor 1 [NCIt concept]
- Protein Kinase C Alpha Type [NCIt concept]
- Protein-Tyrosine Kinase 2-Beta [NCIt concept]
- Proteinase-Activated Receptor 4 [NCIt concept]
- Prothrombin [NCIt concept]
- Rho Guanine Nucleotide Exchange Factor 1 [NCIt concept]
- Rho-Associated Protein Kinase 1 [NCIt concept]
- Transforming Protein RhoA [NCIt concept]
pathway_has_gene_element
- ARHGEF1 wt Allele [NCIt concept]
- F2 wt Allele [NCIt concept]
- F2R wt Allele [NCIt concept]
- F2RL3 wt Allele [NCIt concept]
- GNA12 wt Allele [NCIt concept]
- GNAI1 wt Allele [NCIt concept]
- GNAQ wt Allele [NCIt concept]
- MAP3K7 wt Allele [NCIt concept]
- PIK3CA wt Allele [NCIt concept]
- PIK3CG wt Allele [NCIt concept]
- PIK3R1 wt Allele [NCIt concept]
- PRKCA wt Allele [NCIt concept]
- PTK2B wt Allele [NCIt concept]
- RHOA wt Allele [NCIt concept]
- ROCK1 wt Allele [NCIt concept]

Keyword's position in hierarchy(ies) :

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