P55086 (PAR2_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

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 names

Name:	F2rl1
Synonyms:	Gpcr11, Gpr11, Par2

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	399 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence 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 process	Immunity Inflammatory response Innate immunity
Cellular component	Cell membrane Membrane
Domain	Signal Transmembrane Transmembrane helix
Molecular function	G-protein coupled receptor Receptor Transducer
PTM	Disulfide bond Glycoprotein Lipoprotein Palmitate Phosphoprotein Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	T 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 defense response to virus Inferred from direct assay PubMed 19494303. Source: UniProtKB elevation of cytosolic calcium ion concentration Inferred from direct assay Ref.14. Source: UniProtKB establishment of endothelial barrier Inferred from electronic annotation. Source: Compara 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: Compara negative regulation of chemokine secretion Inferred from electronic annotation. Source: Compara negative regulation of toll-like receptor 3 signaling pathway Inferred from electronic annotation. Source: Compara negative regulation of tumor necrosis factor-mediated signaling pathway Inferred from electronic annotation. Source: Compara 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 cascade Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of JNK cascade Inferred from electronic annotation. Source: Compara 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: Compara 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 eosinophil degranulation Inferred from electronic annotation. Source: Compara 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: Compara positive regulation of neutrophil mediated killing of gram-negative bacterium Inferred from electronic annotation. Source: Compara positive regulation of phagocytosis, engulfment Inferred from electronic annotation. Source: Compara positive regulation of phosphatidylinositol 3-kinase cascade Inferred from direct assay Ref.14. Source: UniProtKB positive regulation of positive chemotaxis Inferred from electronic annotation. Source: Compara 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: Compara positive regulation of toll-like receptor 3 signaling pathway Inferred from electronic annotation. Source: Compara positive regulation of toll-like receptor 4 signaling pathway Inferred from electronic annotation. Source: Compara positive regulation of transcription from RNA polymerase II promoter Inferred from electronic annotation. Source: Compara positive regulation of vasodilation Inferred from direct assay PubMed 21859963. Source: UniProtKB regulation of JNK cascade Inferred from sequence or structural similarity. Source: UniProtKB regulation of blood coagulation Inferred from electronic annotation. Source: Compara
Cellular_component	integral to plasma membrane Inferred from electronic annotation. Source: Compara pseudopodium Inferred from direct assay Ref.6. Source: UniProtKB
Molecular_function	G-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 key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 25	25	Potential
	Propeptide	26 – 38	13	Removed for receptor activation By similarity		PRO_0000012752
	Chain	39 – 399	361	Proteinase-activated receptor 2		PRO_0000012753
Regions
	Topological domain	39 – 77	39	Extracellular Potential
	Transmembrane	78 – 103	26	Helical; Name=1; Potential
	Topological domain	104 – 112	9	Cytoplasmic Potential
	Transmembrane	113 – 132	20	Helical; Name=2; Potential
	Topological domain	133 – 151	19	Extracellular Potential
	Transmembrane	152 – 173	22	Helical; Name=3; Potential
	Topological domain	174 – 192	19	Cytoplasmic Potential
	Transmembrane	193 – 213	21	Helical; Name=4; Potential
	Topological domain	214 – 243	30	Extracellular Potential
	Transmembrane	244 – 262	19	Helical; Name=5; Potential
	Topological domain	263 – 287	25	Cytoplasmic Potential
	Transmembrane	288 – 310	23	Helical; Name=6; Potential
	Topological domain	311 – 325	15	Extracellular Potential
	Transmembrane	326 – 349	24	Helical; Name=7; Potential
	Topological domain	350 – 399	50	Cytoplasmic Potential
	Compositional bias	385 – 394	10	Poly-Ser
Sites
	Site	38 – 39	2	Cleavage; by trypsin By similarity
Amino acid modifications
	Lipidation	363	1	S-palmitoyl cysteine By similarity
	Glycosylation	33	1	N-linked (GlcNAc...) Potential
	Glycosylation	224	1	N-linked (GlcNAc...) Potential
	Disulfide bond	150 ↔ 228		By similarity

Sequences

	Sequence		Length	Mass (Da)
	P55086 [UniParc]. Last modified October 1, 1996. Version 1. Checksum: A93749425ED0B194	FASTA	399	44,752
	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

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.
IPI	IPI00331621.
PIR	I48705.
RefSeq	NP_032000.3. NM_007974.4.
UniGene	Mm.1614.
3D structure databases
ProteinModelPortal	P55086.
SMR	P55086. Positions 67-354.
ModBase	Search...
Protein family/group databases
GPCRDB	Search...
PTM databases
PhosphoSite	P55086.
Proteomic databases
PRIDE	P55086.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000022185; ENSMUSP00000022185; ENSMUSG00000021678.
GeneID	14063.
KEGG	mmu:14063.
Organism-specific databases
CTD	2150.
MGI	MGI:101910. F2rl1.
Phylogenomic databases
eggNOG	NOG145128.
HOGENOM	HOG000116291.
HOVERGEN	HBG105658.
InParanoid	P55086.
KO	K04234.
OMA	LLVVHYF.
OrthoDB	EOG4TB4BH.
Gene expression databases
ArrayExpress	P55086.
Bgee	P55086.
CleanEx	MM_F2RL1.
Genevestigator	P55086.
GermOnline	ENSMUSG00000021678. Mus musculus.
Family and domain databases
InterPro	IPR000276. GPCR_Rhodpsn. IPR017452. GPCR_Rhodpsn_7TM. IPR002281. Pro_rcpt_2. IPR003912. Protea_act_rcpt. [Graphical view]
Pfam	PF00001. 7tm_1. 1 hit. [Graphical view]
PRINTS	PR00237. GPCRRHODOPSN. PR01428. PROTEASEAR. PR01152. PROTEASEAR2.
PROSITE	PS00237. G_PROTEIN_RECEP_F1_1. False negative. PS50262. G_PROTEIN_RECEP_F1_2. 1 hit. [Graphical view]
ProtoNet	Search...
Other
ChiTaRS	F2RL1. mouse.
NextBio	285036.
SOURCE	Search...

Entry information

Entry name

PAR2_MOUSE

Accession

Primary (citable) accession number: P55086

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1996
Last sequence update:	October 1, 1996
Last modified:	May 1, 2013
This is version 105 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program