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P55086

- PAR2_MOUSE

UniProt

P55086 - PAR2_MOUSE

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Protein

Proteinase-activated receptor 2

Gene
F2rl1, Gpcr11, Gpr11, Par2
Organism
Mus musculus (Mouse)
Status
Reviewed - 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.5 Publications

Sites

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

GO - Molecular functioni

  1. G-protein alpha-subunit binding Source: UniProtKB
  2. G-protein beta-subunit binding Source: UniProtKB
  3. G-protein coupled receptor activity Source: UniProtKB
  4. heterotrimeric G-protein binding Source: UniProtKB
  5. thrombin receptor activity Source: InterPro

GO - Biological processi

  1. blood coagulation Source: InterPro
  2. chemokine (C-C motif) ligand 2 secretion Source: UniProtKB
  3. chemokine secretion Source: UniProtKB
  4. defense response to virus Source: UniProtKB
  5. establishment of endothelial barrier Source: Ensembl
  6. inflammatory response Source: UniProtKB-KW
  7. innate immune response Source: UniProtKB-KW
  8. interferon-gamma secretion Source: UniProtKB
  9. interleukin-10 secretion Source: UniProtKB
  10. interleukin-1 beta secretion Source: UniProtKB
  11. leukocyte migration Source: UniProtKB
  12. leukocyte proliferation Source: UniProtKB
  13. mature dendritic cell differentiation Source: UniProtKB
  14. negative regulation of chemokine secretion Source: Ensembl
  15. negative regulation of JNK cascade Source: Ensembl
  16. negative regulation of toll-like receptor 3 signaling pathway Source: Ensembl
  17. negative regulation of tumor necrosis factor-mediated signaling pathway Source: Ensembl
  18. neutrophil activation Source: UniProtKB
  19. positive regulation of actin filament depolymerization Source: Ensembl
  20. positive regulation of cell migration Source: UniProtKB
  21. positive regulation of chemotaxis Source: UniProtKB
  22. positive regulation of cytokine secretion involved in immune response Source: UniProtKB
  23. positive regulation of cytosolic calcium ion concentration Source: UniProtKB
  24. positive regulation of eosinophil degranulation Source: Ensembl
  25. positive regulation of ERK1 and ERK2 cascade Source: UniProtKB
  26. positive regulation of glomerular filtration Source: UniProtKB
  27. positive regulation of I-kappaB kinase/NF-kappaB signaling Source: UniProtKB
  28. positive regulation of interleukin-6 secretion Source: UniProtKB
  29. positive regulation of interleukin-8 secretion Source: UniProtKB
  30. positive regulation of JNK cascade Source: Ensembl
  31. positive regulation of leukocyte chemotaxis Source: Ensembl
  32. positive regulation of neutrophil mediated killing of gram-negative bacterium Source: Ensembl
  33. positive regulation of phagocytosis, engulfment Source: Ensembl
  34. positive regulation of phosphatidylinositol 3-kinase signaling Source: UniProtKB
  35. positive regulation of positive chemotaxis Source: Ensembl
  36. positive regulation of pseudopodium assembly Source: UniProtKB
  37. positive regulation of renin secretion into blood stream Source: UniProtKB
  38. positive regulation of Rho protein signal transduction Source: UniProtKB
  39. positive regulation of superoxide anion generation Source: UniProtKB
  40. positive regulation of toll-like receptor 2 signaling pathway Source: Ensembl
  41. positive regulation of toll-like receptor 3 signaling pathway Source: Ensembl
  42. positive regulation of toll-like receptor 4 signaling pathway Source: Ensembl
  43. positive regulation of transcription from RNA polymerase II promoter Source: Ensembl
  44. positive regulation of vasodilation Source: UniProtKB
  45. regulation of blood coagulation Source: Ensembl
  46. regulation of I-kappaB kinase/NF-kappaB signaling Source: UniProtKB
  47. regulation of JNK cascade Source: UniProtKB
  48. T cell activation involved in immune response Source: UniProtKB
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_207651. 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: Chromosome 13

Organism-specific databases

MGIiMGI:101910. F2rl1.

Subcellular locationi

Topology

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

GO - Cellular componenti

  1. integral component of plasma membrane Source: Ensembl
  2. pseudopodium Source: UniProtKB
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 – 2525 Reviewed predictionAdd
BLAST
Propeptidei26 – 3813Removed for receptor activation By similarityPRO_0000012752Add
BLAST
Chaini39 – 399361Proteinase-activated receptor 2PRO_0000012753Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Glycosylationi33 – 331N-linked (GlcNAc...) Reviewed prediction
Disulfide bondi150 ↔ 228 By similarity
Glycosylationi224 – 2241N-linked (GlcNAc...) Reviewed prediction
Lipidationi363 – 3631S-palmitoyl cysteine By 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.
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.

Keywords - PTMi

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

Proteomic databases

PRIDEiP55086.

PTM databases

PhosphoSiteiP55086.

Expressioni

Gene expression databases

ArrayExpressiP55086.
BgeeiP55086.
CleanExiMM_F2RL1.
GenevestigatoriP55086.

Interactioni

Subunit structurei

Interacts with TLR4, COPS5 and TMED2 By similarity. Interacts with GNAQ, GNA11, GNA12, GNA13 and GNA14.1 Publication

Structurei

3D structure databases

ProteinModelPortaliP55086.
SMRiP55086. Positions 67-354.

Family & Domainsi

Compositional bias

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

Sequence similaritiesi

Keywords - Domaini

Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

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

Family and domain databases

Gene3Di1.20.1070.10. 1 hit.
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

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MRSLSLAWLL GGITLLAASV SCSRTENLAP GRNNSKGRSL IGRLETQPPI    50
TGKGVPVEPG FSIDEFSASI LTGKLTTVFL PVVYIIVFVI GLPSNGMALW 100
IFLFRTKKKH PAVIYMANLA LADLLSVIWF PLKISYHLHG NNWVYGEALC 150
KVLIGFFYGN MYCSILFMTC LSVQRYWVIV NPMGHPRKKA NIAVGVSLAI 200
WLLIFLVTIP LYVMKQTIYI PALNITTCHD VLPEEVLVGD MFNYFLSLAI 250
GVFLFPALLT ASAYVLMIKT LRSSAMDEHS EKKRQRAIRL IITVLAMYFI 300
CFAPSNLLLV VHYFLIKTQR QSHVYALYLV ALCLSTLNSC IDPFVYYFVS 350
KDFRDHARNA LLCRSVRTVN RMQISLSSNK FSRKSGSYSS SSTSVKTSY 399
Length:399
Mass (Da):44,752
Last modified:October 1, 1996 - v1
Checksum:iA93749425ED0B194
GO

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
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:
EMBL
GenBank
DDBJ
Links Updated
Z48043 mRNA. Translation: CAA88097.1 .
CCDSi CCDS26700.1.
PIRi I48705.
RefSeqi NP_032000.3. NM_007974.4.
UniGenei Mm.1614.

3D structure databases

ProteinModelPortali P55086.
SMRi P55086. Positions 67-354.
ModBasei Search...
MobiDBi Search...

Protein family/group databases

GPCRDBi Search...

PTM databases

PhosphoSitei P55086.

Proteomic databases

PRIDEi P55086.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENSMUST00000022185 ; ENSMUSP00000022185 ; ENSMUSG00000021678 .
GeneIDi 14063.
KEGGi mmu:14063.
UCSCi uc011zda.2. mouse.

Organism-specific databases

CTDi 2150.
MGIi MGI:101910. F2rl1.

Phylogenomic databases

eggNOGi NOG145128.
HOGENOMi HOG000116291.
HOVERGENi HBG105658.
InParanoidi P55086.
KOi K04234.
OMAi LAMYLIC.
OrthoDBi EOG7DNNVR.
PhylomeDBi P55086.
TreeFami TF330775.

Enzyme and pathway databases

Reactomei REACT_207651. G alpha (q) signalling events.

Miscellaneous databases

ChiTaRSi F2RL1. mouse.
NextBioi 285036.
PROi P55086.
SOURCEi Search...

Gene expression databases

ArrayExpressi P55086.
Bgeei P55086.
CleanExi MM_F2RL1.
Genevestigatori P55086.

Family and domain databases

Gene3Di 1.20.1070.10. 1 hit.
InterProi IPR000276. GPCR_Rhodpsn.
IPR017452. GPCR_Rhodpsn_7TM.
IPR002281. Pro_rcpt_2.
IPR003912. Protea_act_rcpt.
[Graphical view ]
Pfami PF00001. 7tm_1. 1 hit.
[Graphical view ]
PRINTSi PR00237. GPCRRHODOPSN.
PR01428. PROTEASEAR.
PR01152. PROTEASEAR2.
PROSITEi PS50262. G_PROTEIN_RECEP_F1_2. 1 hit.
[Graphical view ]
ProtoNeti Search...

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: September 3, 2014
This is version 115 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