ID FFAR4_HUMAN Reviewed; 377 AA. AC Q5NUL3; Q495H1; Q5VY25; Q5VY26; Q7Z605; Q86SM7; DT 10-MAY-2005, integrated into UniProtKB/Swiss-Prot. DT 10-MAY-2005, sequence version 2. DT 25-APR-2018, entry version 120. DE RecName: Full=Free fatty acid receptor 4; DE AltName: Full=G-protein coupled receptor 120; DE AltName: Full=G-protein coupled receptor 129; DE AltName: Full=G-protein coupled receptor GT01; DE AltName: Full=G-protein coupled receptor PGR4; DE AltName: Full=Omega-3 fatty acid receptor 1; GN Name=FFAR4; Synonyms=GPR120, GPR129, O3FAR1, PGR4; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RX PubMed=14623098; DOI=10.1016/S0014-5793(03)01196-7; RA Fredriksson R., Hoeglund P.J., Gloriam D.E.I., Lagerstroem M.C., RA Schioeth H.B.; RT "Seven evolutionarily conserved human rhodopsin G protein-coupled RT receptors lacking close relatives."; RL FEBS Lett. 554:381-388(2003). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, TISSUE SPECIFICITY, RP AND VARIANT CYS-67. RX PubMed=15619630; DOI=10.1038/nm1168; RA Hirasawa A., Tsumaya K., Awaji T., Katsuma S., Adachi T., Yamada M., RA Sugimoto Y., Miyazaki S., Tsujimoto G.; RT "Free fatty acids regulate gut incretin glucagon-like peptide-1 RT secretion through GPR120."; RL Nat. Med. 11:90-94(2005). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15164054; DOI=10.1038/nature02462; RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L., RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K., RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L., RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P., RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J., RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., RA Brown J.Y., Burford D.C., Burrill W., Burton J., Cahill P., Camire D., RA Carter N.P., Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., RA Corby N., Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., RA Frankish A., Frankland J.A., Garner P., Garnett J., Gribble S., RA Griffiths C., Grocock R., Gustafson E., Hammond S., Harley J.L., RA Hart E., Heath P.D., Ho T.P., Hopkins B., Horne J., Howden P.J., RA Huckle E., Hynds C., Johnson C., Johnson D., Kana A., Kay M., RA Kimberley A.M., Kershaw J.K., Kokkinaki M., Laird G.K., Lawlor S., RA Lee H.M., Leongamornlert D.A., Laird G., Lloyd C., Lloyd D.M., RA Loveland J., Lovell J., McLaren S., McLay K.E., McMurray A., RA Mashreghi-Mohammadi M., Matthews L., Milne S., Nickerson T., RA Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., Peck A.I., RA Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., Ross M.T., RA Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., RA Tracey A., Tromans A., Tsolas J., Wall M., Walsh J., Wang H., RA Weinstock K., West A.P., Willey D.L., Whitehead S.L., Wilming L., RA Wray P.W., Young L., Chen Y., Lovering R.C., Moschonas N.K., RA Siebert R., Fechtel K., Bentley D., Durbin R.M., Hubbard T., RA Doucette-Stamm L., Beck S., Smith D.R., Rogers J.; RT "The DNA sequence and comparative analysis of human chromosome 10."; RL Nature 429:375-381(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R., RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., RA Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). 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 RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 49-312 (ISOFORM 2). RX PubMed=12679517; DOI=10.1073/pnas.0230374100; RA Vassilatis D.K., Hohmann J.G., Zeng H., Li F., Ranchalis J.E., RA Mortrud M.T., Brown A., Rodriguez S.S., Weller J.R., Wright A.C., RA Bergmann J.E., Gaitanaris G.A.; RT "The G protein-coupled receptor repertoires of human and mouse."; RL Proc. Natl. Acad. Sci. U.S.A. 100:4903-4908(2003). RN [7] RP TISSUE SPECIFICITY, AND DEVELOPMENTAL STAGE. RX PubMed=17250804; DOI=10.1016/j.bbrc.2007.01.028; RA Gotoh C., Hong Y.H., Iga T., Hishikawa D., Suzuki Y., Song S.H., RA Choi K.C., Adachi T., Hirasawa A., Tsujimoto G., Sasaki S., Roh S.G.; RT "The regulation of adipogenesis through GPR120."; RL Biochem. Biophys. Res. Commun. 354:591-597(2007). RN [8] RP PHOSPHORYLATION. RX PubMed=20471368; DOI=10.1016/j.bbrc.2010.05.057; RA Burns R.N., Moniri N.H.; RT "Agonism with the omega-3 fatty acids alpha-linolenic acid and RT docosahexaenoic acid mediates phosphorylation of both the short and RT long isoforms of the human GPR120 receptor."; RL Biochem. Biophys. Res. Commun. 396:1030-1035(2010). RN [9] RP INVOLVEMENT IN BMIQ10, VARIANTS CYS-67 AND HIS-270, AND ASSOCIATION OF RP VARIANT HIS-270 WITH RISK OF OBESITY. RX PubMed=22343897; DOI=10.1038/nature10798; RA Ichimura A., Hirasawa A., Poulain-Godefroy O., Bonnefond A., Hara T., RA Yengo L., Kimura I., Leloire A., Liu N., Iida K., Choquet H., RA Besnard P., Lecoeur C., Vivequin S., Ayukawa K., Takeuchi M., RA Ozawa K., Tauber M., Maffeis C., Morandi A., Buzzetti R., Elliott P., RA Pouta A., Jarvelin M.R., Korner A., Kiess W., Pigeyre M., Caiazzo R., RA Van Hul W., Van Gaal L., Horber F., Balkau B., Levy-Marchal C., RA Rouskas K., Kouvatsi A., Hebebrand J., Hinney A., Scherag A., RA Pattou F., Meyre D., Koshimizu T.A., Wolowczuk I., Tsujimoto G., RA Froguel P.; RT "Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and RT human."; RL Nature 483:350-354(2012). CC -!- FUNCTION: Receptor for medium and long-chain free fatty acids CC (FFAs). Signals via a G(q)/G(11)-coupled pathway. Acts as a CC receptor for omega-3 fatty acids and mediates robust anti- CC inflammatory effects, particularly in macrophages and fat cells. CC The anti-inflammatory effects involve inhibition of TAK1 through a CC beta-arrestin 2 (ARRB2)/TAB1-dependent effect, but independent of CC the G(q)/G(11)-coupled pathway. Mediates potent insulin CC sensitizing and antidiabetic effects by repressing macrophage- CC induced tissue inflammation. May mediate the taste of fatty acids. CC Mediates FFA-induced inhibition of apoptosis in enteroendocrine CC cells. May play a role in the regulation of adipocyte development CC and differentiation. {ECO:0000269|PubMed:15619630}. CC -!- SUBUNIT: Interacts with ARRB2 following docosahexaenoic acid (DHA) CC stimulation. {ECO:0000250}. CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250}; Multi-pass CC membrane protein {ECO:0000250}. Note=Colocalized with ARRB2 CC following DHA treatment. {ECO:0000250}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q5NUL3-1; Sequence=Displayed; CC Note=Specific to human.; CC Name=2; CC IsoId=Q5NUL3-2; Sequence=VSP_013684; CC -!- TISSUE SPECIFICITY: Abundant expression in the intestinal tract. CC Highly expressed in adipose tissue, small intestine and pancreas. CC {ECO:0000269|PubMed:15619630, ECO:0000269|PubMed:17250804}. CC -!- DEVELOPMENTAL STAGE: Expression detected in differentiated CC adipocytes but not in preadipocytes. CC {ECO:0000269|PubMed:17250804}. CC -!- PTM: Phosphorylated. FFA stimulation facilitates phosphorylation. CC {ECO:0000269|PubMed:20471368}. CC -!- POLYMORPHISM: Genetic variations in FFAR4 define the body mass CC index quantitative trait locus 10 (BMIQ10) [MIM:607514]. Variance CC in body mass index is a susceptibility factor for obesity. CC -!- MISCELLANEOUS: It has been shown that FFA alpha-linolenic acid CC stimulates secretion of glucagon-like peptide 1 (GLP-1) from the CC gastro-intestinal tract (PubMed:15619630). However, this ligand is CC an agonist of both FFAR4 and FFAR1 and the latter has been shown CC to mediate GLP-1 release too (PubMed:18519800). So the precise CC role of FFAR4 in mediating needs to be confirmed. CC {ECO:0000305|PubMed:15619630}. CC -!- SIMILARITY: Belongs to the G-protein coupled receptor 1 family. CC {ECO:0000255|PROSITE-ProRule:PRU00521}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AY288417; AAP72126.1; -; mRNA. DR EMBL; AB115768; BAD83368.1; -; mRNA. DR EMBL; AL356214; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471066; EAW50069.1; -; Genomic_DNA. DR EMBL; BC101175; AAI01176.1; -; mRNA. DR EMBL; AY255573; AAO85085.1; -; mRNA. DR CCDS; CCDS31248.1; -. [Q5NUL3-1] DR CCDS; CCDS55720.1; -. [Q5NUL3-2] DR RefSeq; NP_001182684.1; NM_001195755.1. [Q5NUL3-2] DR RefSeq; NP_859529.2; NM_181745.3. [Q5NUL3-1] DR UniGene; Hs.661022; -. DR ProteinModelPortal; Q5NUL3; -. DR STRING; 9606.ENSP00000360538; -. DR BindingDB; Q5NUL3; -. DR ChEMBL; CHEMBL5339; -. DR DrugBank; DB05793; PRO-542. DR DrugBank; DB05435; TNX-355. DR GuidetoPHARMACOLOGY; 127; -. DR SwissLipids; SLP:000001562; -. [Q5NUL3-2] DR iPTMnet; Q5NUL3; -. DR PhosphoSitePlus; Q5NUL3; -. DR BioMuta; FFAR4; -. DR DMDM; 82581671; -. DR PaxDb; Q5NUL3; -. DR PeptideAtlas; Q5NUL3; -. DR PRIDE; Q5NUL3; -. DR Ensembl; ENST00000371481; ENSP00000360536; ENSG00000186188. [Q5NUL3-2] DR Ensembl; ENST00000371483; ENSP00000360538; ENSG00000186188. [Q5NUL3-1] DR GeneID; 338557; -. DR KEGG; hsa:338557; -. DR UCSC; uc010qnt.2; human. [Q5NUL3-1] DR CTD; 338557; -. DR DisGeNET; 338557; -. DR EuPathDB; HostDB:ENSG00000186188.10; -. DR GeneCards; FFAR4; -. DR HGNC; HGNC:19061; FFAR4. DR HPA; HPA042563; -. DR MalaCards; FFAR4; -. DR MIM; 607514; phenotype. DR MIM; 609044; gene. DR neXtProt; NX_Q5NUL3; -. DR OpenTargets; ENSG00000186188; -. DR PharmGKB; PA134924595; -. DR eggNOG; KOG3656; Eukaryota. DR eggNOG; ENOG410XRW9; LUCA. DR GeneTree; ENSGT00390000009371; -. DR HOVERGEN; HBG051775; -. DR InParanoid; Q5NUL3; -. DR KO; K08425; -. DR OMA; CADLLFT; -. DR OrthoDB; EOG091G0CDY; -. DR PhylomeDB; Q5NUL3; -. DR TreeFam; TF336844; -. DR Reactome; R-HSA-381771; Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1). DR Reactome; R-HSA-416476; G alpha (q) signalling events. DR Reactome; R-HSA-444209; Free fatty acid receptors. DR GeneWiki; GPR120; -. DR GenomeRNAi; 338557; -. DR PRO; PR:Q5NUL3; -. DR Proteomes; UP000005640; Chromosome 10. DR Bgee; ENSG00000186188; -. DR CleanEx; HS_GPR120; -. DR ExpressionAtlas; Q5NUL3; baseline and differential. DR Genevisible; Q5NUL3; HS. DR GO; GO:0030139; C:endocytic vesicle; IEA:Ensembl. DR GO; GO:0005887; C:integral component of plasma membrane; IBA:GO_Central. DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB. DR GO; GO:0005504; F:fatty acid binding; ISS:UniProtKB. DR GO; GO:0004930; F:G-protein coupled receptor activity; IBA:GO_Central. DR GO; GO:0008527; F:taste receptor activity; IBA:GO_Central. DR GO; GO:0045444; P:fat cell differentiation; IEA:Ensembl. DR GO; GO:0007186; P:G-protein coupled receptor signaling pathway; TAS:Reactome. DR GO; GO:0046879; P:hormone secretion; IBA:GO_Central. DR GO; GO:0043066; P:negative regulation of apoptotic process; ISS:UniProtKB. DR GO; GO:0050710; P:negative regulation of cytokine secretion; ISS:UniProtKB. DR GO; GO:0050728; P:negative regulation of inflammatory response; ISS:UniProtKB. DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; ISS:UniProtKB. DR GO; GO:0010827; P:regulation of glucose transmembrane transport; ISS:UniProtKB. DR InterPro; IPR000276; GPCR_Rhodpsn. DR InterPro; IPR017452; GPCR_Rhodpsn_7TM. DR Pfam; PF00001; 7tm_1; 1. DR PRINTS; PR00237; GPCRRHODOPSN. DR PROSITE; PS50262; G_PROTEIN_RECEP_F1_2; 1. PE 1: Evidence at protein level; KW Alternative splicing; Cell membrane; Complete proteome; KW G-protein coupled receptor; Glycoprotein; Lipid-binding; Membrane; KW Phosphoprotein; Polymorphism; Receptor; Reference proteome; KW Transducer; Transmembrane; Transmembrane helix. FT CHAIN 1 377 Free fatty acid receptor 4. FT /FTId=PRO_0000069610. FT TOPO_DOM 1 45 Extracellular. {ECO:0000255}. FT TRANSMEM 46 66 Helical; Name=1. {ECO:0000255}. FT TOPO_DOM 67 77 Cytoplasmic. {ECO:0000255}. FT TRANSMEM 78 98 Helical; Name=2. {ECO:0000255}. FT TOPO_DOM 99 112 Extracellular. {ECO:0000255}. FT TRANSMEM 113 133 Helical; Name=3. {ECO:0000255}. FT TOPO_DOM 134 156 Cytoplasmic. {ECO:0000255}. FT TRANSMEM 157 177 Helical; Name=4. {ECO:0000255}. FT TOPO_DOM 178 204 Extracellular. {ECO:0000255}. FT TRANSMEM 205 225 Helical; Name=5. {ECO:0000255}. FT TOPO_DOM 226 284 Cytoplasmic. {ECO:0000255}. FT TRANSMEM 285 305 Helical; Name=6. {ECO:0000255}. FT TOPO_DOM 306 311 Extracellular. {ECO:0000255}. FT TRANSMEM 312 332 Helical; Name=7. {ECO:0000255}. FT TOPO_DOM 333 377 Cytoplasmic. {ECO:0000255}. FT COMPBIAS 67 71 Poly-Arg. FT CARBOHYD 21 21 N-linked (GlcNAc...) asparagine. FT {ECO:0000255}. FT VAR_SEQ 233 248 Missing (in isoform 2). FT {ECO:0000303|PubMed:12679517, FT ECO:0000303|PubMed:15489334}. FT /FTId=VSP_013684. FT VARIANT 67 67 R -> C (in dbSNP:rs61866610). FT {ECO:0000269|PubMed:15619630, FT ECO:0000269|PubMed:22343897}. FT /FTId=VAR_067799. FT VARIANT 270 270 R -> H (polymorphism associated with FT increased risk of obesity; FT dbSNP:rs116454156). FT {ECO:0000269|PubMed:22343897}. FT /FTId=VAR_067800. FT CONFLICT 67 67 Missing (in Ref. 1; AAP72126). FT {ECO:0000305}. FT CONFLICT 274 274 Q -> H (in Ref. 2; BAD83368). FT {ECO:0000305}. FT CONFLICT 297 297 I -> T (in Ref. 2; BAD83368). FT {ECO:0000305}. SQ SEQUENCE 377 AA; 42241 MW; 28BB8C3A939A7EFF CRC64; MSPECARAAG DAPLRSLEQA NRTRFPFFSD VKGDHRLVLA AVETTVLVLI FAVSLLGNVC ALVLVARRRR RGATACLVLN LFCADLLFIS AIPLVLAVRW TEAWLLGPVA CHLLFYVMTL SGSVTILTLA AVSLERMVCI VHLQRGVRGP GRRARAVLLA LIWGYSAVAA LPLCVFFRVV PQRLPGADQE ISICTLIWPT IPGEISWDVS FVTLNFLVPG LVIVISYSKI LQTSEHLLDA RAVVTHSEIT KASRKRLTVS LAYSESHQIR VSQQDFRLFR TLFLLMVSFF IMWSPIIITI LLILIQNFKQ DLVIWPSLFF WVVAFTFANS ALNPILYNMT LCRNEWKKIF CCFWFPEKGA ILTDTSVKRN DLSIISG //