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P55086 (PAR2_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 114. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Proteinase-activated receptor 2

Short name=PAR-2
Alternative name(s):
Coagulation factor II receptor-like 1
G-protein coupled receptor 11
Thrombin receptor-like 1
Gene names
Name:F2rl1
Synonyms:Gpcr11, Gpr11, Par2
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length399 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Receptor 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. 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 By similarity. Ref.2 Ref.3 Ref.6 Ref.13 Ref.14

Subunit structure

Interacts with TLR4, COPS5 and TMED2 By similarity. Interacts with GNAQ, GNA11, GNA12, GNA13 and GNA14. Ref.14

Subcellular location

Cell membrane By similarity; Multi-pass membrane protein.

Post-translational modification

A 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 By similarity.

N-glycosylated and sialylated By similarity.

Multiple phosphorylated on serine and threonine residues in the cytoplasmic region upon receptor activation; required for receptor desensitization and recruitment of beta-arrestin.

Monoubiquitinated 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 By similarity.

Disruption phenotype

Delayed onset of inflammation. Reduced progression of osteoarthritis, infectious colitis, allergic dermatitis and experimental autoimmune encephalomyelitis. Upon induced allergic and toxic contact dermatitis ear swelling responses, plasma extravasation and leuocyte adherence are significantly attenuated. Upon ovalbumin (OA) sensitization and following challenge infiltration of eosinophils and increse of eotaxin content in bronchoalveolar lavage fluid are abrogated. Ref.3 Ref.4 Ref.5 Ref.8 Ref.9 Ref.10 Ref.12

Miscellaneous

Synthetic 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 By similarity.

Sequence similarities

Belongs to the G-protein coupled receptor 1 family.

Ontologies

Keywords
   Biological processImmunity
Inflammatory response
Innate immunity
   Cellular componentCell membrane
Membrane
   DomainSignal
Transmembrane
Transmembrane helix
   Molecular functionG-protein coupled receptor
Receptor
Transducer
   PTMDisulfide bond
Glycoprotein
Lipoprotein
Palmitate
Phosphoprotein
Ubl conjugation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processT cell activation involved in immune response

Inferred from direct assay Ref.13. Source: UniProtKB

blood coagulation

Inferred from electronic annotation. Source: InterPro

chemokine (C-C motif) ligand 2 secretion

Inferred from sequence or structural similarity. Source: UniProtKB

chemokine secretion

Inferred from direct assay PubMed 19494303. Source: UniProtKB

defense response to virus

Inferred from direct assay PubMed 19494303. Source: UniProtKB

establishment of endothelial barrier

Inferred from electronic annotation. Source: Ensembl

inflammatory response

Inferred from electronic annotation. Source: UniProtKB-KW

innate immune response

Inferred from electronic annotation. Source: UniProtKB-KW

interferon-gamma secretion

Inferred from direct assay PubMed 19494303. Source: UniProtKB

interleukin-1 beta secretion

Inferred from sequence or structural similarity. Source: UniProtKB

interleukin-10 secretion

Inferred from sequence or structural similarity. Source: UniProtKB

leukocyte migration

Inferred from sequence or structural similarity. Source: UniProtKB

leukocyte proliferation

Inferred from direct assay PubMed 19494303. Source: UniProtKB

mature dendritic cell differentiation

Inferred from direct assay Ref.13. Source: UniProtKB

negative regulation of JNK cascade

Inferred from electronic annotation. Source: Ensembl

negative regulation of chemokine secretion

Inferred from electronic annotation. Source: Ensembl

negative regulation of toll-like receptor 3 signaling pathway

Inferred from electronic annotation. Source: Ensembl

negative regulation of tumor necrosis factor-mediated signaling pathway

Inferred from electronic annotation. Source: Ensembl

neutrophil activation

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of ERK1 and ERK2 cascade

Inferred from direct assay Ref.14. Source: UniProtKB

positive regulation of I-kappaB kinase/NF-kappaB signaling

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of JNK cascade

Inferred from electronic annotation. Source: Ensembl

positive regulation of Rho protein signal transduction

Inferred from direct assay Ref.14. Source: UniProtKB

positive regulation of actin filament depolymerization

Inferred from electronic annotation. Source: Ensembl

positive regulation of cell migration

Inferred from direct assay Ref.14. Source: UniProtKB

positive regulation of chemotaxis

Inferred from direct assay Ref.6. Source: UniProtKB

positive regulation of cytokine secretion involved in immune response

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of cytosolic calcium ion concentration

Inferred from direct assay Ref.14. Source: UniProtKB

positive regulation of eosinophil degranulation

Inferred from electronic annotation. Source: Ensembl

positive regulation of glomerular filtration

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of interleukin-6 secretion

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of interleukin-8 secretion

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of leukocyte chemotaxis

Inferred from electronic annotation. Source: Ensembl

positive regulation of neutrophil mediated killing of gram-negative bacterium

Inferred from electronic annotation. Source: Ensembl

positive regulation of phagocytosis, engulfment

Inferred from electronic annotation. Source: Ensembl

positive regulation of phosphatidylinositol 3-kinase signaling

Inferred from direct assay Ref.14. Source: UniProtKB

positive regulation of positive chemotaxis

Inferred from electronic annotation. Source: Ensembl

positive regulation of pseudopodium assembly

Inferred from direct assay Ref.6. Source: UniProtKB

positive regulation of renin secretion into blood stream

Inferred from direct assay PubMed 21859963. Source: UniProtKB

positive regulation of superoxide anion generation

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of toll-like receptor 2 signaling pathway

Inferred from electronic annotation. Source: Ensembl

positive regulation of toll-like receptor 3 signaling pathway

Inferred from electronic annotation. Source: Ensembl

positive regulation of toll-like receptor 4 signaling pathway

Inferred from electronic annotation. Source: Ensembl

positive regulation of transcription from RNA polymerase II promoter

Inferred from electronic annotation. Source: Ensembl

positive regulation of vasodilation

Inferred from direct assay PubMed 21859963. Source: UniProtKB

regulation of I-kappaB kinase/NF-kappaB signaling

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of JNK cascade

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of blood coagulation

Inferred from electronic annotation. Source: Ensembl

   Cellular_componentintegral component of plasma membrane

Inferred from electronic annotation. Source: Ensembl

pseudopodium

Inferred from direct assay Ref.6. Source: UniProtKB

   Molecular_functionG-protein alpha-subunit binding

Inferred from direct assay Ref.14. Source: UniProtKB

G-protein beta-subunit binding

Inferred from direct assay Ref.14. Source: UniProtKB

G-protein coupled receptor activity

Inferred from mutant phenotype Ref.14. Source: UniProtKB

heterotrimeric G-protein binding

Traceable author statement Ref.14. Source: UniProtKB

thrombin receptor activity

Inferred from electronic annotation. Source: InterPro

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 2525 Potential
Propeptide26 – 3813Removed for receptor activation By similarity
PRO_0000012752
Chain39 – 399361Proteinase-activated receptor 2
PRO_0000012753

Regions

Topological domain39 – 7739Extracellular Potential
Transmembrane78 – 10326Helical; Name=1; Potential
Topological domain104 – 1129Cytoplasmic Potential
Transmembrane113 – 13220Helical; Name=2; Potential
Topological domain133 – 15119Extracellular Potential
Transmembrane152 – 17322Helical; Name=3; Potential
Topological domain174 – 19219Cytoplasmic Potential
Transmembrane193 – 21321Helical; Name=4; Potential
Topological domain214 – 24330Extracellular Potential
Transmembrane244 – 26219Helical; Name=5; Potential
Topological domain263 – 28725Cytoplasmic Potential
Transmembrane288 – 31023Helical; Name=6; Potential
Topological domain311 – 32515Extracellular Potential
Transmembrane326 – 34924Helical; Name=7; Potential
Topological domain350 – 39950Cytoplasmic Potential
Compositional bias385 – 39410Poly-Ser

Sites

Site38 – 392Cleavage; by trypsin By similarity

Amino acid modifications

Lipidation3631S-palmitoyl cysteine By similarity
Glycosylation331N-linked (GlcNAc...) Potential
Glycosylation2241N-linked (GlcNAc...) Potential
Disulfide bond150 ↔ 228 By similarity

Sequences

Sequence LengthMass (Da)Tools
P55086 [UniParc].

Last modified October 1, 1996. Version 1.
Checksum: A93749425ED0B194

FASTA39944,752
        10         20         30         40         50         60 
MRSLSLAWLL GGITLLAASV SCSRTENLAP GRNNSKGRSL IGRLETQPPI TGKGVPVEPG 

        70         80         90        100        110        120 
FSIDEFSASI LTGKLTTVFL PVVYIIVFVI GLPSNGMALW IFLFRTKKKH PAVIYMANLA 

       130        140        150        160        170        180 
LADLLSVIWF PLKISYHLHG NNWVYGEALC KVLIGFFYGN MYCSILFMTC LSVQRYWVIV 

       190        200        210        220        230        240 
NPMGHPRKKA NIAVGVSLAI WLLIFLVTIP LYVMKQTIYI PALNITTCHD VLPEEVLVGD 

       250        260        270        280        290        300 
MFNYFLSLAI GVFLFPALLT ASAYVLMIKT LRSSAMDEHS EKKRQRAIRL IITVLAMYFI 

       310        320        330        340        350        360 
CFAPSNLLLV VHYFLIKTQR QSHVYALYLV ALCLSTLNSC IDPFVYYFVS KDFRDHARNA 

       370        380        390 
LLCRSVRTVN RMQISLSSNK FSRKSGSYSS SSTSVKTSY 

« Hide

References

[1]"The mouse proteinase-activated receptor-2 cDNA and gene. Molecular cloning and functional expression."
Nystedt S., Larsson A.-K., Aaberg H., Sundelin J.
J. Biol. Chem. 270:5950-5955(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]"Cardiovascular responses mediated by protease-activated receptor-2 (PAR-2) and thrombin receptor (PAR-1) are distinguished in mice deficient in PAR-2 or PAR-1."
Damiano B.P., Cheung W.M., Santulli R.J., Fung-Leung W.P., Ngo K., Ye R.D., Darrow A.L., Derian C.K., de Garavilla L., Andrade-Gordon P.
J. Pharmacol. Exp. Ther. 288:671-678(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN CARDIOVASCULAR RESPONSES.
[3]"Delayed onset of inflammation in protease-activated receptor-2-deficient mice."
Lindner J.R., Kahn M.L., Coughlin S.R., Sambrano G.R., Schauble E., Bernstein D., Foy D., Hafezi-Moghadam A., Ley K.
J. Immunol. 165:6504-6510(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN INFLAMMATORY RESPONSE, DISRUPTION PHENOTYPE.
[4]"Effect of protease-activated receptor-2 deficiency on allergic dermatitis in the mouse ear."
Kawagoe J., Takizawa T., Matsumoto J., Tamiya M., Meek S.E., Smith A.J., Hunter G.D., Plevin R., Saito N., Kanke T., Fujii M., Wada Y.
Jpn. J. Pharmacol. 88:77-84(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: DISRUPTION PHENOTYPE.
[5]"Proinflammatory role of proteinase-activated receptor-2 in humans and mice during cutaneous inflammation in vivo."
Seeliger S., Derian C.K., Vergnolle N., Bunnett N.W., Nawroth R., Schmelz M., Von Der Weid P.Y., Buddenkotte J., Sunderkotter C., Metze D., Andrade-Gordon P., Harms E., Vestweber D., Luger T.A., Steinhoff M.
FASEB J. 17:1871-1885(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: DISRUPTION PHENOTYPE.
[6]"A beta-arrestin-dependent scaffold is associated with prolonged MAPK activation in pseudopodia during protease-activated receptor-2-induced chemotaxis."
Ge L., Ly Y., Hollenberg M., DeFea K.
J. Biol. Chem. 278:34418-34426(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN CYTOSKELETAL REARRANGEMENT AND CHEMOTAXIS.
[7]"Protease-activated receptor-2 activation induces acute lung inflammation by neuropeptide-dependent mechanisms."
Su X., Camerer E., Hamilton J.R., Coughlin S.R., Matthay M.A.
J. Immunol. 175:2598-2605(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: POSSIBLE INVOLVEMENT IN LUNG INFLAMMATION.
[8]"Abrogation of bronchial eosinophilic inflammation and attenuated eotaxin content in protease-activated receptor 2-deficient mice."
Takizawa T., Tamiya M., Hara T., Matsumoto J., Saito N., Kanke T., Kawagoe J., Hattori Y.
J. Pharmacol. Sci. 98:99-102(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: DISRUPTION PHENOTYPE.
[9]"A major role for proteolytic activity and proteinase-activated receptor-2 in the pathogenesis of infectious colitis."
Hansen K.K., Sherman P.M., Cellars L., Andrade-Gordon P., Pan Z., Baruch A., Wallace J.L., Hollenberg M.D., Vergnolle N.
Proc. Natl. Acad. Sci. U.S.A. 102:8363-8368(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: INVOLVEMENT IN INFECTIOUS COLITIS, ACTIVATION BY GRANZYME A, DISRUPTION PHENOTYPE.
[10]"Proteinase-activated receptor 2 modulates neuroinflammation in experimental autoimmune encephalomyelitis and multiple sclerosis."
Noorbakhsh F., Tsutsui S., Vergnolle N., Boven L.A., Shariat N., Vodjgani M., Warren K.G., Andrade-Gordon P., Hollenberg M.D., Power C.
J. Exp. Med. 203:425-435(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: DISRUPTION PHENOTYPE.
[11]"'Role reversal' for the receptor PAR1 in sepsis-induced vascular damage."
Kaneider N.C., Leger A.J., Agarwal A., Nguyen N., Perides G., Derian C., Covic L., Kuliopulos A.
Nat. Immunol. 8:1303-1312(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: TRANSACTIVATION BY F2R.
[12]"Protease-activated receptor 2: a novel pathogenic pathway in a murine model of osteoarthritis."
Ferrell W.R., Kelso E.B., Lockhart J.C., Plevin R., McInnes I.B.
Ann. Rheum. Dis. 69:2051-2054(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: DISRUPTION PHENOTYPE.
[13]"Protease-activated receptor 2 signalling promotes dendritic cell antigen transport and T-cell activation in vivo."
Ramelli G., Fuertes S., Narayan S., Busso N., Acha-Orbea H., So A.
Immunology 129:20-27(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[14]"PAR1 and PAR2 couple to overlapping and distinct sets of G proteins and linked signaling pathways to differentially regulate cell physiology."
McCoy K.L., Traynelis S.F., Hepler J.R.
Mol. Pharmacol. 77:1005-1015(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH GNAQ; GNA11; GNA12; GNA13 AND GNA14.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
Z48043 mRNA. Translation: CAA88097.1.
CCDSCCDS26700.1.
PIRI48705.
RefSeqNP_032000.3. NM_007974.4.
UniGeneMm.1614.

3D structure databases

ProteinModelPortalP55086.
SMRP55086. Positions 67-354.
ModBaseSearch...
MobiDBSearch...

Protein family/group databases

GPCRDBSearch...

PTM databases

PhosphoSiteP55086.

Proteomic databases

PRIDEP55086.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000022185; ENSMUSP00000022185; ENSMUSG00000021678.
GeneID14063.
KEGGmmu:14063.
UCSCuc011zda.2. mouse.

Organism-specific databases

CTD2150.
MGIMGI:101910. F2rl1.

Phylogenomic databases

eggNOGNOG145128.
HOGENOMHOG000116291.
HOVERGENHBG105658.
InParanoidP55086.
KOK04234.
OMALAMYLIC.
OrthoDBEOG7DNNVR.
PhylomeDBP55086.
TreeFamTF330775.

Gene expression databases

ArrayExpressP55086.
BgeeP55086.
CleanExMM_F2RL1.
GenevestigatorP55086.

Family and domain databases

Gene3D1.20.1070.10. 1 hit.
InterProIPR000276. GPCR_Rhodpsn.
IPR017452. GPCR_Rhodpsn_7TM.
IPR002281. Pro_rcpt_2.
IPR003912. Protea_act_rcpt.
[Graphical view]
PfamPF00001. 7tm_1. 1 hit.
[Graphical view]
PRINTSPR00237. GPCRRHODOPSN.
PR01428. PROTEASEAR.
PR01152. PROTEASEAR2.
PROSITEPS50262. G_PROTEIN_RECEP_F1_2. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSF2RL1. mouse.
NextBio285036.
PROP55086.
SOURCESearch...

Entry information

Entry namePAR2_MOUSE
AccessionPrimary (citable) accession number: P55086
Entry history
Integrated into UniProtKB/Swiss-Prot: October 1, 1996
Last sequence update: October 1, 1996
Last modified: July 9, 2014
This is version 114 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot

7-transmembrane G-linked receptors

List of 7-transmembrane G-linked receptor entries