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Protein

Proteinase-activated receptor 2

Gene

F2rl1

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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).By similarity

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sitei38 – 392Cleavage; by trypsinBy similarity

GO - Molecular functioni

  • G-protein alpha-subunit binding Source: UniProtKB
  • G-protein beta-subunit binding Source: UniProtKB
  • G-protein coupled receptor activity Source: UniProtKB
  • heterotrimeric G-protein binding Source: UniProtKB
  • thrombin receptor activity Source: InterPro

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

G-protein coupled receptor, Receptor, Transducer

Keywords - Biological processi

Immunity, Inflammatory response, Innate immunity

Enzyme and pathway databases

ReactomeiREACT_319210. Peptide ligand-binding receptors.
REACT_347934. G alpha (q) signalling events.

Names & Taxonomyi

Protein namesi
Recommended 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 namesi
Name:F2rl1
Synonyms:Gpcr11, Gpr11, Par2
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
ProteomesiUP000000589 Componenti: Chromosome 13

Organism-specific databases

MGIiMGI:101910. F2rl1.

Subcellular locationi

Topology

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini39 – 7739ExtracellularSequence AnalysisAdd
BLAST
Transmembranei78 – 10326Helical; Name=1Sequence AnalysisAdd
BLAST
Topological domaini104 – 1129CytoplasmicSequence Analysis
Transmembranei113 – 13220Helical; Name=2Sequence AnalysisAdd
BLAST
Topological domaini133 – 15119ExtracellularSequence AnalysisAdd
BLAST
Transmembranei152 – 17322Helical; Name=3Sequence AnalysisAdd
BLAST
Topological domaini174 – 19219CytoplasmicSequence AnalysisAdd
BLAST
Transmembranei193 – 21321Helical; Name=4Sequence AnalysisAdd
BLAST
Topological domaini214 – 24330ExtracellularSequence AnalysisAdd
BLAST
Transmembranei244 – 26219Helical; Name=5Sequence AnalysisAdd
BLAST
Topological domaini263 – 28725CytoplasmicSequence AnalysisAdd
BLAST
Transmembranei288 – 31023Helical; Name=6Sequence AnalysisAdd
BLAST
Topological domaini311 – 32515ExtracellularSequence AnalysisAdd
BLAST
Transmembranei326 – 34924Helical; Name=7Sequence AnalysisAdd
BLAST
Topological domaini350 – 39950CytoplasmicSequence AnalysisAdd
BLAST

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Membrane

Pathology & Biotechi

Disruption phenotypei

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.7 Publications

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Signal peptidei1 – 2525Sequence AnalysisAdd
BLAST
Propeptidei26 – 3813Removed for receptor activationBy similarityPRO_0000012752Add
BLAST
Chaini39 – 399361Proteinase-activated receptor 2PRO_0000012753Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Glycosylationi33 – 331N-linked (GlcNAc...)Sequence Analysis
Disulfide bondi150 ↔ 228PROSITE-ProRule annotation
Glycosylationi224 – 2241N-linked (GlcNAc...)Sequence Analysis
Lipidationi363 – 3631S-palmitoyl cysteineBy similarity

Post-translational modificationi

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).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).By similarity

Keywords - PTMi

Disulfide bond, Glycoprotein, Lipoprotein, Palmitate, Phosphoprotein, Ubl conjugation

Proteomic databases

PRIDEiP55086.

PTM databases

PhosphoSiteiP55086.

Expressioni

Gene expression databases

BgeeiP55086.
CleanExiMM_F2RL1.
ExpressionAtlasiP55086. baseline and differential.
GenevisibleiP55086. MM.

Interactioni

Subunit structurei

Interacts with TLR4, COPS5 and TMED2 (By similarity). Interacts with GNAQ, GNA11, GNA12, GNA13 and GNA14.By similarity1 Publication

Protein-protein interaction databases

STRINGi10090.ENSMUSP00000022185.

Structurei

3D structure databases

ProteinModelPortaliP55086.
SMRiP55086. Positions 67-354.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi385 – 39410Poly-Ser

Sequence similaritiesi

Belongs to the G-protein coupled receptor 1 family.PROSITE-ProRule annotation

Keywords - Domaini

Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiNOG145128.
GeneTreeiENSGT00760000119001.
HOGENOMiHOG000116291.
HOVERGENiHBG105658.
InParanoidiP55086.
KOiK04234.
OMAiLAMYLIC.
OrthoDBiEOG7DNNVR.
PhylomeDBiP55086.
TreeFamiTF330775.

Family and domain databases

InterProiIPR000276. GPCR_Rhodpsn.
IPR017452. GPCR_Rhodpsn_7TM.
IPR002281. Pro_rcpt_2.
IPR003912. Protea_act_rcpt.
[Graphical view]
PfamiPF00001. 7tm_1. 1 hit.
[Graphical view]
PRINTSiPR00237. GPCRRHODOPSN.
PR01428. PROTEASEAR.
PR01152. PROTEASEAR2.
PROSITEiPS50262. G_PROTEIN_RECEP_F1_2. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

P55086-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MRSLSLAWLL GGITLLAASV SCSRTENLAP GRNNSKGRSL IGRLETQPPI
60 70 80 90 100
TGKGVPVEPG FSIDEFSASI LTGKLTTVFL PVVYIIVFVI GLPSNGMALW
110 120 130 140 150
IFLFRTKKKH PAVIYMANLA LADLLSVIWF PLKISYHLHG NNWVYGEALC
160 170 180 190 200
KVLIGFFYGN MYCSILFMTC LSVQRYWVIV NPMGHPRKKA NIAVGVSLAI
210 220 230 240 250
WLLIFLVTIP LYVMKQTIYI PALNITTCHD VLPEEVLVGD MFNYFLSLAI
260 270 280 290 300
GVFLFPALLT ASAYVLMIKT LRSSAMDEHS EKKRQRAIRL IITVLAMYFI
310 320 330 340 350
CFAPSNLLLV VHYFLIKTQR QSHVYALYLV ALCLSTLNSC IDPFVYYFVS
360 370 380 390
KDFRDHARNA LLCRSVRTVN RMQISLSSNK FSRKSGSYSS SSTSVKTSY
Length:399
Mass (Da):44,752
Last modified:October 1, 1996 - v1
Checksum:iA93749425ED0B194
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
Z48043 mRNA. Translation: CAA88097.1.
CCDSiCCDS26700.1.
PIRiI48705.
RefSeqiNP_032000.3. NM_007974.4.
UniGeneiMm.1614.

Genome annotation databases

EnsembliENSMUST00000022185; ENSMUSP00000022185; ENSMUSG00000021678.
GeneIDi14063.
KEGGimmu:14063.
UCSCiuc011zda.2. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
Z48043 mRNA. Translation: CAA88097.1.
CCDSiCCDS26700.1.
PIRiI48705.
RefSeqiNP_032000.3. NM_007974.4.
UniGeneiMm.1614.

3D structure databases

ProteinModelPortaliP55086.
SMRiP55086. Positions 67-354.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

STRINGi10090.ENSMUSP00000022185.

Protein family/group databases

GPCRDBiSearch...

PTM databases

PhosphoSiteiP55086.

Proteomic databases

PRIDEiP55086.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000022185; ENSMUSP00000022185; ENSMUSG00000021678.
GeneIDi14063.
KEGGimmu:14063.
UCSCiuc011zda.2. mouse.

Organism-specific databases

CTDi2150.
MGIiMGI:101910. F2rl1.

Phylogenomic databases

eggNOGiNOG145128.
GeneTreeiENSGT00760000119001.
HOGENOMiHOG000116291.
HOVERGENiHBG105658.
InParanoidiP55086.
KOiK04234.
OMAiLAMYLIC.
OrthoDBiEOG7DNNVR.
PhylomeDBiP55086.
TreeFamiTF330775.

Enzyme and pathway databases

ReactomeiREACT_319210. Peptide ligand-binding receptors.
REACT_347934. G alpha (q) signalling events.

Miscellaneous databases

ChiTaRSiF2rl1. mouse.
NextBioi285036.
PROiP55086.
SOURCEiSearch...

Gene expression databases

BgeeiP55086.
CleanExiMM_F2RL1.
ExpressionAtlasiP55086. baseline and differential.
GenevisibleiP55086. MM.

Family and domain databases

InterProiIPR000276. GPCR_Rhodpsn.
IPR017452. GPCR_Rhodpsn_7TM.
IPR002281. Pro_rcpt_2.
IPR003912. Protea_act_rcpt.
[Graphical view]
PfamiPF00001. 7tm_1. 1 hit.
[Graphical view]
PRINTSiPR00237. GPCRRHODOPSN.
PR01428. PROTEASEAR.
PR01152. PROTEASEAR2.
PROSITEiPS50262. G_PROTEIN_RECEP_F1_2. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

  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. 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.

Entry informationi

Entry nameiPAR2_MOUSE
AccessioniPrimary (citable) accession number: P55086
Entry historyi
Integrated into UniProtKB/Swiss-Prot: October 1, 1996
Last sequence update: October 1, 1996
Last modified: July 22, 2015
This is version 123 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

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

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. 7-transmembrane G-linked receptors
    List of 7-transmembrane G-linked receptor entries
  2. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  3. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.