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MGP001006

UniProt Annotations

Entry Information
Gene Namecoagulation factor II (thrombin) receptor-like 1
Protein EntryPAR2_HUMAN
UniProt IDP55085
SpeciesHuman
Comments
Comment typeDescription
FunctionReceptor for trypsin and trypsin-like enzymes coupled to G proteins. Its function is mediated through the activation of several signaling pathways including phospholipase C (PLC), intracellular calcium, mitogen-activated protein kinase (MAPK), I- kappaB kinase/NF-kappaB and Rho. Can also be transactivated by cleaved F2R/PAR1. Involved in modulation of inflammatory responses and regulation of innate and adaptive immunity, and acts as a sensor for proteolytic enzymes generated during infection. Generally is promoting inflammation. Can signal synergistically with TLR4 and probably TLR2 in inflammatory responses and modulates TLR3 signaling. Has a protective role in establishing the endothelial barrier; the activity involves coagulation factor X. Proposed to have a bronchoprotective role in airway epithelium, but also shown to compromise the airway epithelial barrier by interrupting E-cadherin adhesion. Involved in the regulation of vascular tone; activation results in hypotension presumably mediated by vasodilation. Associates with a subset of G proteins alpha subunits such as G alpha-q, G alpha-11, G alpha-14, G alpha- 12 and G alpha-13, but probably not with G(o) alpha, G(i) subunit alpha-1 and G(i) subunit alpha-2. However, according to PubMed:21627585 can signal through G(i) subunit alpha. Believed to be a class B receptor which internalizes as a complex with arrestin and traffic with it to endosomal vesicles, presumably as desensitized receptor, for extended periods of time. Mediates inhibition of TNF-alpha stimulated JNK phosphorylation via coupling to G alpha-q/11; the function involves dissociation of RIPK1 and TRADD from TNFR1. Mediates phosphorylation of nuclear factor NF-kappa-B RELA subunit at 'Ser-536'; the function involves IKBKB and is predominantly independent of G proteins. Involved in cellular migration. Involved in cytoskeletal rearrangement and chemotaxis through beta-arrestin-promoted scaffolds; the function is independent of G alpha-q/11 and involves promotion of cofilin dephosphoryltaion and actin filament severing. Induces redistribution of COPS5 from the plasma membrane to the cytosol and activation of the JNK cascade is mediated by COPS5. Involved in the recruitment of leukocytes to the sites of inflammation and is the major PAR receptor capable of modulating eosinophil function such as proinflammatory cytokine secretion, superoxide production and degranulation. During inflammation promotes dendritic cell maturation, trafficking to the lymph nodes and subsequent T-cell activation. Involved in antimicrobial response of innate immnune cells; activation enhances phagocytosis of Gram- positive and killing of Gram-negative bacteria. Acts synergistically with interferon-gamma in enhancing antiviral responses. Implicated in a number of acute and chronic inflammatory diseases such as of the joints, lungs, brain, gastrointestinal tract, periodontium, skin, and vascular systems, and in autoimmune disorders. {ECO:0000269|PubMed:10086357, ECO:0000269|PubMed:10725339, ECO:0000269|PubMed:11413129, ECO:0000269|PubMed:11441110, ECO:0000269|PubMed:11447194, ECO:0000269|PubMed:11714832, ECO:0000269|PubMed:12832443, ECO:0000269|PubMed:15155775, ECO:0000269|PubMed:16359518, ECO:0000269|PubMed:16410250, ECO:0000269|PubMed:16478888, ECO:0000269|PubMed:16714334, ECO:0000269|PubMed:17404307, ECO:0000269|PubMed:17500066, ECO:0000269|PubMed:18424071, ECO:0000269|PubMed:18453611, ECO:0000269|PubMed:18474671, ECO:0000269|PubMed:18622013, ECO:0000269|PubMed:19494303, ECO:0000269|PubMed:19781631, ECO:0000269|PubMed:19864598, ECO:0000269|PubMed:19865078, ECO:0000269|PubMed:20826780, ECO:0000269|PubMed:21501162}.
InteractionP22681:CBL; NbExp=3; IntAct=EBI-4303189, EBI-518228; Q92905:COPS5; NbExp=8; IntAct=EBI-4303189, EBI-594661; Q14868:EPR-1; NbExp=4; IntAct=EBI-4303189, EBI-4309771; Q15363:TMED2; NbExp=6; IntAct=EBI-4303189, EBI-998485;
MiscellaneousSynthetic PAR agonist peptides (APs) that mimic the first six amino acids of the newly formed N-terminus activate the native, uncleaved receptor nonenzymatically by binding directly to the corresponding second extracellular loop to mediate signaling.
PtmA proteolytic cleavage generates a new N-terminus that functions as a tethered ligand. Activating serine proteases include trypsin, mast cell tryptase, coagulation factors VII and Xa, myeloblastin/PRTN3 and membrane-type serine protease 1/ST14. Proposed subsequent cleaveage by serine proteases is leading to receptor deactivation and include neutrophil elastase and cathepsin G. At least in part, implicated proteases are also shown to activate the receptor; the glycosylation status of the receptor is thought to contribute to the difference. In addition to conventional trypsin-like proteases is proposed to be activated by other proteases and glycosidases derived from bacteria, fungi and insects: serine protease allergens such as dust mite Der p3 and Der p9 and mold Pen c13, Porphyromonas gingivalis arginine- specific (trypsin-like) cysteine proteinases called gingipains, Streptomyces griseus exogenous chitinase, and an Alternaria alternata aspartate protease. Cleavage by the Alternaria alternata aspartate protease generates non-conventional processed forms. {ECO:0000269|PubMed:12171601}.
PtmMonoubiquitinated by CBL at the plasma membrane and in early endosomes; not required for receptor endocytosis but for translocation to late endosomes or lysosomes. Deubiquitination involves STAMBP and USP8; required for lysosomal trafficking and receptor degradation.
PtmMultiple phosphorylated on serine and threonine residues in the cytoplasmic region upon receptor activation; required for receptor desensitization and recruitment of beta-arrestin. {ECO:0000269|PubMed:19815543}.
PtmN-glycosylated and sialylated. {ECO:0000269|PubMed:12171601}.
SimilarityBelongs to the G-protein coupled receptor 1 family. {ECO:0000255|PROSITE-ProRule:PRU00521}.
Subcellular LocationCell membrane; Multi-pass membrane protein.
SubunitInteracts with TLR4, COPS5 and TMED2. Interacts with GNAQ, GNA11, GNA12, GNA13 and GNA14 (By similarity). {ECO:0000250}.
Tissue SpecificityWidely expressed in tissues with especially high levels in pancreas, liver, kidney, small intestine, and colon. Moderate expression is detected in many organs, but none in brain or skeletal muscle.
Web ResourceName=SeattleSNPs; URL="http://pga.gs.washington.edu/data/f2rl1/";
Web ResourceName=Wikipedia; Note=Protease-activated receptor entry; URL="http://en.wikipedia.org/wiki/Protease-activated_receptor";
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