PAR2_RAT
ID PAR2_RAT Reviewed; 397 AA.
AC Q63645; Q499T9;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 159.
DE RecName: Full=Proteinase-activated receptor 2;
DE Short=PAR-2;
DE AltName: Full=Coagulation factor II receptor-like 1;
DE AltName: Full=Thrombin receptor-like 1;
DE Flags: Precursor;
GN Name=F2rl1; Synonyms=Par2;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=Sprague-Dawley; TISSUE=Intestine, and Kidney;
RX PubMed=8762073; DOI=10.1111/j.1476-5381.1996.tb15433.x;
RA Saifeddine M., Al-Ani B., Cheng C.H., Wang L., Hollenberg M.D.;
RT "Rat proteinase-activated receptor-2 (PAR-2): cDNA sequence and activity of
RT receptor-derived peptides in gastric and vascular tissue.";
RL Br. J. Pharmacol. 118:521-530(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Prostate;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP FUNCTION.
RX PubMed=11884377; DOI=10.1161/hh0402.105372;
RA McLean P.G., Aston D., Sarkar D., Ahluwalia A.;
RT "Protease-activated receptor-2 activation causes EDHF-like coronary
RT vasodilation: selective preservation in ischemia/reperfusion injury:
RT involvement of lipoxygenase products, VR1 receptors, and C-fibers.";
RL Circ. Res. 90:465-472(2002).
RN [4]
RP INTERACTION WITH TMED2.
RX PubMed=17693410; DOI=10.1074/jbc.m703205200;
RA Luo W., Wang Y., Reiser G.;
RT "p24A, a type I transmembrane protein, controls ARF1-dependent
RT resensitization of protease-activated receptor-2 by influence on receptor
RT trafficking.";
RL J. Biol. Chem. 282:30246-30255(2007).
CC -!- FUNCTION: Receptor for trypsin and trypsin-like enzymes coupled to G
CC proteins. Its function is mediated through the activation of several
CC signaling pathways including phospholipase C (PLC), intracellular
CC calcium, mitogen-activated protein kinase (MAPK), I-kappaB kinase/NF-
CC kappaB and Rho. Can also be transactivated by cleaved F2R/PAR1.
CC Involved in modulation of inflammatory responses and regulation of
CC innate and adaptive immunity, and acts as a sensor for proteolytic
CC enzymes generated during infection. Generally is promoting
CC inflammation. Can signal synergistically with TLR4 and probably TLR2 in
CC inflammatory responses and modulates Tlr3 signaling. Has a protective
CC role in establishing the endothelial barrier; the activity involves
CC coagulation factor X. Regulates endothelial cell barrier integrity
CC during neutrophil extravasation, probably following proteolytic
CC cleavage by PRTN3 (By similarity). Proposed to have a bronchoprotective
CC role in airway epithelium, but also shown to compromise the airway
CC epithelial barrier by interrupting E-cadherin adhesion. Involved in the
CC regulation of vascular tone; activation results in hypotension
CC presumably mediated by vasodilation. Associates with a subset of G
CC proteins alpha subunits such as GNAQ, GNA11, GNA14, GNA12 and GNA13,
CC but probably not with G(o)-alpha, G(i) subunit alpha-1 and G(i) subunit
CC alpha-2. Believed to be a class B receptor which internalizes as a
CC complex with arrestin and traffic with it to endosomal vesicles,
CC presumably as desensitized receptor, for extended periods of time.
CC Mediates inhibition of TNF-alpha stimulated JNK phosphorylation via
CC coupling to G GNAQ and GNA11; the function involves dissociation of
CC RIPK1 and Tradd from TNFR1. Mediates phosphorylation of nuclear factor
CC NF-kappa-B RELA subunit at 'Ser-536'; the function involves Ikbkb and
CC is predominantly independent of G proteins. Involved in cellular
CC migration. Involved in cytoskeletal rearrangement and chemotaxis
CC through beta-arrestin-promoted scaffolds; the function is independent
CC of GNAQ and GNA11 and involves promotion of cofilin dephosphorylation
CC and actin filament severing. Induces redistribution of COPS5 from the
CC plasma membrane to the cytosol and activation of the JNK cascade is
CC mediated by Cops5. Involved in the recruitment of leukocytes to the
CC sites of inflammation and is the major PAR receptor capable of
CC modulating eosinophil function such as pro-inflammatory cytokine
CC secretion, superoxide production and degranulation. During inflammation
CC promotes dendritic cell maturation, trafficking to the lymph nodes and
CC subsequent T-cell activation. Involved in antimicrobial response of
CC innate immune cells; activation enhances phagocytosis of Gram-positive
CC and killing of Gram-negative bacteria. Acts synergistically with
CC interferon-gamma in enhancing antiviral responses (By similarity).
CC {ECO:0000250|UniProtKB:P55085, ECO:0000269|PubMed:11884377}.
CC -!- SUBUNIT: Interacts with TLR4, COPS5 and TMED2. Interacts with GNAQ,
CC GNA11, GNA12, GNA13 and GNA14 (By similarity). {ECO:0000250}.
CC -!- INTERACTION:
CC Q63645; Q63524: Tmed2; NbExp=2; IntAct=EBI-4303358, EBI-918600;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250}; Multi-pass membrane
CC protein.
CC -!- PTM: A proteolytic cleavage generates a new N-terminus that functions
CC as a tethered ligand. Activating serine proteases include trypsin, mast
CC cell tryptase, coagulation factors VII and Xa, myeloblastin/PRTN3 and
CC membrane-type serine protease 1/ST14. Proposed subsequent cleavage by
CC serine proteases is leading to receptor deactivation and include
CC neutrophil elastase and cathepsin G. At least in part, implicated
CC proteases are also shown to activate the receptor; the glycosylation
CC status of the receptor is thought to contribute to the difference.
CC {ECO:0000250|UniProtKB:P55085}.
CC -!- PTM: N-glycosylated and sialylated. {ECO:0000250|UniProtKB:P55085}.
CC -!- PTM: Multiple phosphorylated on serine and threonine residues in the
CC cytoplasmic region upon receptor activation; required for receptor
CC desensitization and recruitment of beta-arrestin.
CC -!- PTM: Monoubiquitinated by Cbl at the plasma membrane and in early
CC endosomes; not required for receptor endocytosis but for translocation
CC to late endosomes or lysosomes. Deubiquitination involves Stambp and
CC Usp8; required for lysosomal trafficking and receptor degradation (By
CC similarity). {ECO:0000250}.
CC -!- MISCELLANEOUS: Synthetic PAR agonist peptides (APs) that mimic the
CC first six amino acids of the newly formed N-terminus activate the
CC native, uncleaved receptor nonenzymatically by binding directly to the
CC corresponding second extracellular loop to mediate signaling.
CC {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the G-protein coupled receptor 1 family.
CC {ECO:0000255|PROSITE-ProRule:PRU00521}.
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DR EMBL; U61373; AAC52703.1; -; mRNA.
DR EMBL; BC099765; AAH99765.1; -; mRNA.
DR RefSeq; NP_446349.1; NM_053897.2.
DR AlphaFoldDB; Q63645; -.
DR SMR; Q63645; -.
DR BioGRID; 250560; 2.
DR IntAct; Q63645; 2.
DR STRING; 10116.ENSRNOP00000058298; -.
DR BindingDB; Q63645; -.
DR ChEMBL; CHEMBL2429706; -.
DR GlyGen; Q63645; 2 sites.
DR PhosphoSitePlus; Q63645; -.
DR PaxDb; Q63645; -.
DR ABCD; Q63645; 9 sequenced antibodies.
DR Ensembl; ENSRNOT00000061580; ENSRNOP00000058298; ENSRNOG00000018003.
DR GeneID; 116677; -.
DR KEGG; rno:116677; -.
DR UCSC; RGD:620866; rat.
DR CTD; 2150; -.
DR RGD; 620866; F2rl1.
DR eggNOG; ENOG502QR8S; Eukaryota.
DR GeneTree; ENSGT01050000244840; -.
DR HOGENOM; CLU_009579_8_2_1; -.
DR InParanoid; Q63645; -.
DR OMA; SQSHVYA; -.
DR OrthoDB; 892946at2759; -.
DR Reactome; R-RNO-375276; Peptide ligand-binding receptors.
DR Reactome; R-RNO-416476; G alpha (q) signalling events.
DR PRO; PR:Q63645; -.
DR Proteomes; UP000002494; Chromosome 2.
DR Bgee; ENSRNOG00000018003; Expressed in jejunum and 17 other tissues.
DR Genevisible; Q63645; RN.
DR GO; GO:0005769; C:early endosome; ISO:RGD.
DR GO; GO:0005887; C:integral component of plasma membrane; ISO:RGD.
DR GO; GO:0005886; C:plasma membrane; ISO:RGD.
DR GO; GO:0031143; C:pseudopodium; ISS:UniProtKB.
DR GO; GO:0004930; F:G protein-coupled receptor activity; ISS:UniProtKB.
DR GO; GO:0001965; F:G-protein alpha-subunit binding; ISS:UniProtKB.
DR GO; GO:0031681; F:G-protein beta-subunit binding; ISS:UniProtKB.
DR GO; GO:0015057; F:thrombin-activated receptor activity; IEA:InterPro.
DR GO; GO:0007596; P:blood coagulation; IEA:InterPro.
DR GO; GO:0045217; P:cell-cell junction maintenance; ISO:RGD.
DR GO; GO:0051607; P:defense response to virus; ISS:UniProtKB.
DR GO; GO:0061028; P:establishment of endothelial barrier; ISO:RGD.
DR GO; GO:0007186; P:G protein-coupled receptor signaling pathway; ISO:RGD.
DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0050900; P:leukocyte migration; ISS:UniProtKB.
DR GO; GO:0070661; P:leukocyte proliferation; ISS:UniProtKB.
DR GO; GO:0097029; P:mature conventional dendritic cell differentiation; ISS:UniProtKB.
DR GO; GO:0032682; P:negative regulation of chemokine production; ISO:RGD.
DR GO; GO:0046329; P:negative regulation of JNK cascade; ISO:RGD.
DR GO; GO:0034140; P:negative regulation of toll-like receptor 3 signaling pathway; ISO:RGD.
DR GO; GO:0010804; P:negative regulation of tumor necrosis factor-mediated signaling pathway; ISO:RGD.
DR GO; GO:0042119; P:neutrophil activation; ISS:UniProtKB.
DR GO; GO:0030836; P:positive regulation of actin filament depolymerization; ISO:RGD.
DR GO; GO:0030335; P:positive regulation of cell migration; ISS:UniProtKB.
DR GO; GO:0032722; P:positive regulation of chemokine production; ISS:UniProtKB.
DR GO; GO:0050921; P:positive regulation of chemotaxis; ISS:UniProtKB.
DR GO; GO:0002720; P:positive regulation of cytokine production involved in immune response; ISS:UniProtKB.
DR GO; GO:0007204; P:positive regulation of cytosolic calcium ion concentration; ISS:UniProtKB.
DR GO; GO:0051482; P:positive regulation of cytosolic calcium ion concentration involved in phospholipase C-activating G protein-coupled signaling pathway; IBA:GO_Central.
DR GO; GO:0043311; P:positive regulation of eosinophil degranulation; ISO:RGD.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; ISS:UniProtKB.
DR GO; GO:0003104; P:positive regulation of glomerular filtration; IDA:UniProtKB.
DR GO; GO:0043547; P:positive regulation of GTPase activity; ISO:RGD.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB signaling; ISS:UniProtKB.
DR GO; GO:0032729; P:positive regulation of interferon-gamma production; ISS:UniProtKB.
DR GO; GO:0032731; P:positive regulation of interleukin-1 beta production; ISS:UniProtKB.
DR GO; GO:0032733; P:positive regulation of interleukin-10 production; ISS:UniProtKB.
DR GO; GO:0032755; P:positive regulation of interleukin-6 production; ISS:UniProtKB.
DR GO; GO:0032757; P:positive regulation of interleukin-8 production; ISS:UniProtKB.
DR GO; GO:0046330; P:positive regulation of JNK cascade; ISO:RGD.
DR GO; GO:0002690; P:positive regulation of leukocyte chemotaxis; ISO:RGD.
DR GO; GO:0070963; P:positive regulation of neutrophil mediated killing of gram-negative bacterium; ISO:RGD.
DR GO; GO:0060100; P:positive regulation of phagocytosis, engulfment; ISO:RGD.
DR GO; GO:0014068; P:positive regulation of phosphatidylinositol 3-kinase signaling; ISS:UniProtKB.
DR GO; GO:0050927; P:positive regulation of positive chemotaxis; ISO:RGD.
DR GO; GO:0031274; P:positive regulation of pseudopodium assembly; ISS:UniProtKB.
DR GO; GO:1900135; P:positive regulation of renin secretion into blood stream; ISS:UniProtKB.
DR GO; GO:0035025; P:positive regulation of Rho protein signal transduction; ISS:UniProtKB.
DR GO; GO:0032930; P:positive regulation of superoxide anion generation; ISS:UniProtKB.
DR GO; GO:0034137; P:positive regulation of toll-like receptor 2 signaling pathway; ISO:RGD.
DR GO; GO:0034141; P:positive regulation of toll-like receptor 3 signaling pathway; ISO:RGD.
DR GO; GO:0034145; P:positive regulation of toll-like receptor 4 signaling pathway; ISO:RGD.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISO:RGD.
DR GO; GO:0009306; P:protein secretion; TAS:RGD.
DR GO; GO:0030193; P:regulation of blood coagulation; ISO:RGD.
DR GO; GO:2000341; P:regulation of chemokine (C-X-C motif) ligand 2 production; ISS:UniProtKB.
DR GO; GO:0043122; P:regulation of I-kappaB kinase/NF-kappaB signaling; ISS:UniProtKB.
DR GO; GO:0046328; P:regulation of JNK cascade; ISS:UniProtKB.
DR GO; GO:0002286; P:T cell activation involved in immune response; ISS:UniProtKB.
DR GO; GO:0042311; P:vasodilation; IDA:GO_Central.
DR InterPro; IPR000276; GPCR_Rhodpsn.
DR InterPro; IPR017452; GPCR_Rhodpsn_7TM.
DR InterPro; IPR002281; Pro_rcpt_2.
DR InterPro; IPR003912; Protea_act_rcpt.
DR Pfam; PF00001; 7tm_1; 1.
DR PRINTS; PR00237; GPCRRHODOPSN.
DR PRINTS; PR01428; PROTEASEAR.
DR PRINTS; PR01152; PROTEASEAR2.
DR PROSITE; PS50262; G_PROTEIN_RECEP_F1_2; 1.
PE 1: Evidence at protein level;
KW Cell membrane; Disulfide bond; G-protein coupled receptor; Glycoprotein;
KW Immunity; Inflammatory response; Innate immunity; Lipoprotein; Membrane;
KW Palmitate; Phosphoprotein; Receptor; Reference proteome; Signal;
KW Transducer; Transmembrane; Transmembrane helix; Ubl conjugation.
FT SIGNAL 1..25
FT /evidence="ECO:0000255"
FT PROPEP 26..36
FT /note="Removed for receptor activation"
FT /evidence="ECO:0000250"
FT /id="PRO_0000012754"
FT CHAIN 37..397
FT /note="Proteinase-activated receptor 2"
FT /id="PRO_0000012755"
FT TOPO_DOM 37..71
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:P55085"
FT TRANSMEM 72..101
FT /note="Helical; Name=1"
FT /evidence="ECO:0000250|UniProtKB:P55085"
FT TOPO_DOM 102..108
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P55085"
FT TRANSMEM 109..137
FT /note="Helical; Name=2"
FT /evidence="ECO:0000250|UniProtKB:P55085"
FT TOPO_DOM 138..149
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:P55085"
FT TRANSMEM 150..177
FT /note="Helical; Name=3"
FT /evidence="ECO:0000250|UniProtKB:P55085"
FT TOPO_DOM 178..183
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P55085"
FT TRANSMEM 184..211
FT /note="Helical; Name=4"
FT /evidence="ECO:0000250|UniProtKB:P55085"
FT TOPO_DOM 212..235
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:P55085"
FT TRANSMEM 236..269
FT /note="Helical; Name=5"
FT /evidence="ECO:0000250|UniProtKB:P55085"
FT TOPO_DOM 270..277
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P55085"
FT TRANSMEM 278..317
FT /note="Helical; Name=6"
FT /evidence="ECO:0000250|UniProtKB:P55085"
FT TOPO_DOM 318..323
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:P55085"
FT TRANSMEM 324..347
FT /note="Helical; Name=7"
FT /evidence="ECO:0000250|UniProtKB:P55085"
FT TOPO_DOM 348..397
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P55085"
FT SITE 36..37
FT /note="Cleavage; by trypsin"
FT /evidence="ECO:0000250"
FT LIPID 361
FT /note="S-palmitoyl cysteine"
FT /evidence="ECO:0000250"
FT CARBOHYD 23
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 222
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 148..226
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00521"
SQ SEQUENCE 397 AA; 44441 MW; 27DE0C3ACABC798D CRC64;
MRSLSLAWLL GGITLLAASA SCNRTVNAPG PNSKGRSLIG RLDTPPPITG KGAPVEPGFS
VDEFSASVLT GKLTTVFLPV IYIIVFVIGL PSNGMALWVF FFRTKKKHPA VIYMANLALA
DLLSVIWFPL KISYHLHGND WTYGDALCKV LIGFFYGNMY CSILFMTCLS VQRYWVIVNP
MGHSRKRANI AVGVSLAIWL LIFLVTIPLY VMRQTIYIPA LNITTCHDVL PEEVLVGDMF
SYFLSLAIGV FLFPALLTAS AYVLMIKTLR SSAMDEHSEK KRRRAIRLII TVLSMYFICF
APSNVLLVVH YFLIKSQRQS HVYALYLVAL CLSTLNSCID PFVYYFVSKD FRDQARNALL
CRSVRTVKRM QISLTSNKFS RKSSSYSSSS TSVKTSY
