FGF19_HUMAN
ID FGF19_HUMAN Reviewed; 216 AA.
AC O95750;
DT 01-DEC-2000, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-1999, sequence version 1.
DT 03-AUG-2022, entry version 192.
DE RecName: Full=Fibroblast growth factor 19;
DE Short=FGF-19;
DE Flags: Precursor;
GN Name=FGF19; ORFNames=UNQ334/PRO533;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Brain;
RX PubMed=9931477; DOI=10.1016/s0167-4781(98)00255-3;
RA Nishimura T., Utsunomiya Y., Hoshikawa M., Ohuchi H., Itoh N.;
RT "Structure and expression of a novel human FGF, FGF-19, expressed in the
RT fetal brain.";
RL Biochim. Biophys. Acta 1444:148-151(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, INTERACTION WITH FGFR4, AND
RP RECEPTOR SPECIFICITY.
RX PubMed=10525310; DOI=10.1006/cyto.1999.0485;
RA Xie M.-H., Holcomb I., Deuel B., Dowd P., Huang A., Vagts A., Foster J.,
RA Liang J., Brush J., Gu Q., Hillan K., Goddard A., Gurney A.L.;
RT "FGF-19, a novel fibroblast growth factor with unique specificity for
RT FGFR4.";
RL Cytokine 11:729-735(1999).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=12975309; DOI=10.1101/gr.1293003;
RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J.,
RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P.,
RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S., Huang A.,
RA Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D.,
RA Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L.,
RA Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C.,
RA Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J.,
RA Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M.;
RT "The secreted protein discovery initiative (SPDI), a large-scale effort to
RT identify novel human secreted and transmembrane proteins: a bioinformatics
RT assessment.";
RL Genome Res. 13:2265-2270(2003).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Colon;
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 project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP PROTEIN SEQUENCE OF 25-39.
RX PubMed=15340161; DOI=10.1110/ps.04682504;
RA Zhang Z., Henzel W.J.;
RT "Signal peptide prediction based on analysis of experimentally verified
RT cleavage sites.";
RL Protein Sci. 13:2819-2824(2004).
RN [7]
RP INDUCTION BY NR1H4, AND FUNCTION.
RX PubMed=12815072; DOI=10.1101/gad.1083503;
RA Holt J.A., Luo G., Billin A.N., Bisi J., McNeill Y.Y., Kozarsky K.F.,
RA Donahee M., Wang D.Y., Mansfield T.A., Kliewer S.A., Goodwin B.,
RA Jones S.A.;
RT "Definition of a novel growth factor-dependent signal cascade for the
RT suppression of bile acid biosynthesis.";
RL Genes Dev. 17:1581-1591(2003).
RN [8]
RP INTERACTION WITH FGFR1; FGFR2; FGFR3 AND FGFR4, AND FUNCTION IN STIMULATION
RP OF CELL PROLIFERATION.
RX PubMed=16597617; DOI=10.1074/jbc.m601252200;
RA Zhang X., Ibrahimi O.A., Olsen S.K., Umemori H., Mohammadi M., Ornitz D.M.;
RT "Receptor specificity of the fibroblast growth factor family. The complete
RT mammalian FGF family.";
RL J. Biol. Chem. 281:15694-15700(2006).
RN [9]
RP FUNCTION, AND INTERACTION WITH FGFR4 AND KLB.
RX PubMed=17623664; DOI=10.1074/jbc.m704165200;
RA Kurosu H., Choi M., Ogawa Y., Dickson A.S., Goetz R., Eliseenkova A.V.,
RA Mohammadi M., Rosenblatt K.P., Kliewer S.A., Kuro-o M.;
RT "Tissue-specific expression of betaKlotho and fibroblast growth factor
RT (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21.";
RL J. Biol. Chem. 282:26687-26695(2007).
RN [10]
RP INTERACTION WITH FGFR4; KL AND KLB.
RX PubMed=18829467; DOI=10.1074/jbc.m803319200;
RA Wu X., Lemon B., Li X., Gupte J., Weiszmann J., Stevens J., Hawkins N.,
RA Shen W., Lindberg R., Chen J.-L., Tian H., Li Y.;
RT "C-terminal tail of FGF19 determines its specificity toward Klotho co-
RT receptors.";
RL J. Biol. Chem. 283:33304-33309(2008).
RN [11]
RP FUNCTION.
RX PubMed=19085950; DOI=10.1002/hep.22627;
RA Song K.H., Li T., Owsley E., Strom S., Chiang J.Y.;
RT "Bile acids activate fibroblast growth factor 19 signaling in human
RT hepatocytes to inhibit cholesterol 7alpha-hydroxylase gene expression.";
RL Hepatology 49:297-305(2009).
RN [12]
RP REVIEW.
RX PubMed=20094046; DOI=10.1038/nrc2780;
RA Turner N., Grose R.;
RT "Fibroblast growth factor signalling: from development to cancer.";
RL Nat. Rev. Cancer 10:116-129(2010).
RN [13]
RP INTERACTION WITH MALRD1.
RX PubMed=23747249; DOI=10.1016/j.cmet.2013.04.007;
RA Vergnes L., Lee J.M., Chin R.G., Auwerx J., Reue K.;
RT "Diet1 functions in the FGF15/19 enterohepatic signaling axis to modulate
RT bile acid and lipid levels.";
RL Cell Metab. 17:916-928(2013).
RN [14]
RP X-RAY CRYSTALLOGRAPHY (1.3 ANGSTROMS) OF 39-196, AND DISULFIDE BONDS.
RX PubMed=14730967; DOI=10.1021/bi035320k;
RA Harmer N.J., Pellegrini L., Chirgadze D., Fernandez-Recio J.,
RA Blundell T.L.;
RT "The crystal structure of fibroblast growth factor (FGF) 19 reveals novel
RT features of the FGF family and offers a structural basis for its unusual
RT receptor affinity.";
RL Biochemistry 43:629-640(2004).
RN [15]
RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 23-216, AND INTERACTION WITH KLB.
RX PubMed=17339340; DOI=10.1128/mcb.02249-06;
RA Goetz R., Beenken A., Ibrahimi O.A., Kalinina J., Olsen S.K.,
RA Eliseenkova A.V., Xu C., Neubert T.A., Zhang F., Linhardt R.J., Yu X.,
RA White K.E., Inagaki T., Kliewer S.A., Yamamoto M., Kurosu H., Ogawa Y.,
RA Kuro-o M., Lanske B., Razzaque M.S., Mohammadi M.;
RT "Molecular insights into the klotho-dependent, endocrine mode of action of
RT fibroblast growth factor 19 subfamily members.";
RL Mol. Cell. Biol. 27:3417-3428(2007).
CC -!- FUNCTION: Involved in the suppression of bile acid biosynthesis through
CC down-regulation of CYP7A1 expression, following positive regulation of
CC the JNK and ERK1/2 cascades. Stimulates glucose uptake in adipocytes.
CC Activity requires the presence of KLB and FGFR4.
CC {ECO:0000269|PubMed:12815072, ECO:0000269|PubMed:16597617,
CC ECO:0000269|PubMed:17623664, ECO:0000269|PubMed:19085950}.
CC -!- SUBUNIT: Interacts with FGFR1, FGFR2, FGFR3 and FGFR4. Affinity between
CC fibroblast growth factors (FGFs) and their receptors is increased by
CC KL, KLB and heparan sulfate glycosaminoglycans that function as
CC coreceptors. Interacts with KL; this interaction is direct. Interacts
CC with KLB; this interaction is direct. Interacts with FGFR4 in the
CC presence of heparin, KL or KLB. Interacts with MALRD1
CC (PubMed:23747249). {ECO:0000269|PubMed:10525310,
CC ECO:0000269|PubMed:16597617, ECO:0000269|PubMed:17339340,
CC ECO:0000269|PubMed:17623664, ECO:0000269|PubMed:18829467,
CC ECO:0000269|PubMed:23747249}.
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- TISSUE SPECIFICITY: Expressed in fetal brain, cartilage, retina, and
CC adult gall bladder. {ECO:0000269|PubMed:10525310}.
CC -!- INDUCTION: Induced by the bile acids receptor NR1H4 that binds and
CC activates a NR1H4-responsive element within intron 2.
CC {ECO:0000269|PubMed:12815072}.
CC -!- MISCELLANEOUS: Contrarily to other members of the family that can bind
CC several FGF receptors FGF19 is specific for FGFR4.
CC -!- SIMILARITY: Belongs to the heparin-binding growth factors family.
CC {ECO:0000305}.
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DR EMBL; AB018122; BAA75500.1; -; mRNA.
DR EMBL; AF110400; AAD45973.1; -; mRNA.
DR EMBL; AY358302; AAQ88669.1; -; mRNA.
DR EMBL; BT006729; AAP35375.1; -; mRNA.
DR EMBL; BC017664; AAH17664.1; -; mRNA.
DR CCDS; CCDS8193.1; -.
DR RefSeq; NP_005108.1; NM_005117.2.
DR PDB; 1PWA; X-ray; 1.30 A; A=39-196.
DR PDB; 2P23; X-ray; 1.80 A; A/B=23-216.
DR PDB; 6KTR; X-ray; 2.60 A; C/D=23-216.
DR PDB; 6NFJ; X-ray; 3.19 A; C/F=167-216.
DR PDBsum; 1PWA; -.
DR PDBsum; 2P23; -.
DR PDBsum; 6KTR; -.
DR PDBsum; 6NFJ; -.
DR AlphaFoldDB; O95750; -.
DR SMR; O95750; -.
DR BioGRID; 115290; 7.
DR CORUM; O95750; -.
DR DIP; DIP-6039N; -.
DR IntAct; O95750; 2.
DR STRING; 9606.ENSP00000294312; -.
DR DrugBank; DB01109; Heparin.
DR iPTMnet; O95750; -.
DR PhosphoSitePlus; O95750; -.
DR BioMuta; FGF19; -.
DR MassIVE; O95750; -.
DR PaxDb; O95750; -.
DR PeptideAtlas; O95750; -.
DR PRIDE; O95750; -.
DR ProteomicsDB; 51021; -.
DR Antibodypedia; 30654; 443 antibodies from 34 providers.
DR DNASU; 9965; -.
DR Ensembl; ENST00000294312.4; ENSP00000294312.3; ENSG00000162344.4.
DR GeneID; 9965; -.
DR KEGG; hsa:9965; -.
DR MANE-Select; ENST00000294312.4; ENSP00000294312.3; NM_005117.3; NP_005108.1.
DR UCSC; uc001opf.4; human.
DR CTD; 9965; -.
DR DisGeNET; 9965; -.
DR GeneCards; FGF19; -.
DR HGNC; HGNC:3675; FGF19.
DR HPA; ENSG00000162344; Tissue enriched (gallbladder).
DR MIM; 603891; gene.
DR neXtProt; NX_O95750; -.
DR OpenTargets; ENSG00000162344; -.
DR PharmGKB; PA28114; -.
DR VEuPathDB; HostDB:ENSG00000162344; -.
DR eggNOG; KOG3885; Eukaryota.
DR GeneTree; ENSGT00940000160601; -.
DR HOGENOM; CLU_094251_1_0_1; -.
DR InParanoid; O95750; -.
DR OMA; CTFREQI; -.
DR OrthoDB; 1157034at2759; -.
DR PhylomeDB; O95750; -.
DR TreeFam; TF335872; -.
DR PathwayCommons; O95750; -.
DR Reactome; R-HSA-109704; PI3K Cascade.
DR Reactome; R-HSA-1257604; PIP3 activates AKT signaling.
DR Reactome; R-HSA-1307965; betaKlotho-mediated ligand binding.
DR Reactome; R-HSA-190322; FGFR4 ligand binding and activation.
DR Reactome; R-HSA-2219530; Constitutive Signaling by Aberrant PI3K in Cancer.
DR Reactome; R-HSA-5654228; Phospholipase C-mediated cascade, FGFR4.
DR Reactome; R-HSA-5654712; FRS-mediated FGFR4 signaling.
DR Reactome; R-HSA-5654719; SHC-mediated cascade:FGFR4.
DR Reactome; R-HSA-5654720; PI-3K cascade:FGFR4.
DR Reactome; R-HSA-5654733; Negative regulation of FGFR4 signaling.
DR Reactome; R-HSA-5673001; RAF/MAP kinase cascade.
DR Reactome; R-HSA-6811558; PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling.
DR SignaLink; O95750; -.
DR SIGNOR; O95750; -.
DR BioGRID-ORCS; 9965; 14 hits in 1010 CRISPR screens.
DR ChiTaRS; FGF19; human.
DR EvolutionaryTrace; O95750; -.
DR GeneWiki; FGF19; -.
DR GenomeRNAi; 9965; -.
DR Pharos; O95750; Tbio.
DR PRO; PR:O95750; -.
DR Proteomes; UP000005640; Chromosome 11.
DR RNAct; O95750; protein.
DR Bgee; ENSG00000162344; Expressed in gall bladder and 20 other tissues.
DR Genevisible; O95750; HS.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IBA:GO_Central.
DR GO; GO:0005104; F:fibroblast growth factor receptor binding; IPI:UniProtKB.
DR GO; GO:0008083; F:growth factor activity; IBA:GO_Central.
DR GO; GO:0009887; P:animal organ morphogenesis; IBA:GO_Central.
DR GO; GO:0015721; P:bile acid and bile salt transport; IEA:Ensembl.
DR GO; GO:0030154; P:cell differentiation; IBA:GO_Central.
DR GO; GO:0008543; P:fibroblast growth factor receptor signaling pathway; IGI:MGI.
DR GO; GO:0007507; P:heart development; IEA:Ensembl.
DR GO; GO:0070858; P:negative regulation of bile acid biosynthetic process; IDA:UniProtKB.
DR GO; GO:0010629; P:negative regulation of gene expression; IDA:UniProtKB.
DR GO; GO:0007399; P:nervous system development; TAS:ProtInc.
DR GO; GO:0001755; P:neural crest cell migration; IEA:Ensembl.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; IGI:MGI.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IDA:UniProtKB.
DR GO; GO:0010628; P:positive regulation of gene expression; IBA:GO_Central.
DR GO; GO:0046326; P:positive regulation of glucose import; IDA:UniProtKB.
DR GO; GO:0046330; P:positive regulation of JNK cascade; IDA:UniProtKB.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; IDA:UniProtKB.
DR GO; GO:0030334; P:regulation of cell migration; IBA:GO_Central.
DR GO; GO:0009617; P:response to bacterium; IEA:Ensembl.
DR GO; GO:0045471; P:response to ethanol; IEA:Ensembl.
DR GO; GO:0014070; P:response to organic cyclic compound; IEA:Ensembl.
DR CDD; cd00058; FGF; 1.
DR InterPro; IPR035444; FGF15/19/21.
DR InterPro; IPR028303; FGF15/FGF19.
DR InterPro; IPR002209; Fibroblast_GF_fam.
DR InterPro; IPR008996; IL1/FGF.
DR PANTHER; PTHR11486; PTHR11486; 1.
DR PANTHER; PTHR11486:SF74; PTHR11486:SF74; 1.
DR Pfam; PF00167; FGF; 1.
DR PIRSF; PIRSF037961; FGF-19_FGF-21; 1.
DR PRINTS; PR00263; HBGFFGF.
DR SMART; SM00442; FGF; 1.
DR SUPFAM; SSF50353; SSF50353; 1.
DR PROSITE; PS00247; HBGF_FGF; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Direct protein sequencing; Disulfide bond; Growth factor;
KW Reference proteome; Secreted; Signal.
FT SIGNAL 1..24
FT /evidence="ECO:0000269|PubMed:15340161"
FT CHAIN 25..216
FT /note="Fibroblast growth factor 19"
FT /id="PRO_0000008993"
FT DISULFID 58..70
FT /evidence="ECO:0000269|PubMed:14730967"
FT DISULFID 102..120
FT /evidence="ECO:0000269|PubMed:14730967"
FT STRAND 42..49
FT /evidence="ECO:0007829|PDB:1PWA"
FT STRAND 58..62
FT /evidence="ECO:0007829|PDB:1PWA"
FT STRAND 66..73
FT /evidence="ECO:0007829|PDB:1PWA"
FT HELIX 76..78
FT /evidence="ECO:0007829|PDB:1PWA"
FT STRAND 80..86
FT /evidence="ECO:0007829|PDB:1PWA"
FT STRAND 89..94
FT /evidence="ECO:0007829|PDB:1PWA"
FT TURN 95..97
FT /evidence="ECO:0007829|PDB:1PWA"
FT STRAND 100..103
FT /evidence="ECO:0007829|PDB:1PWA"
FT HELIX 105..107
FT /evidence="ECO:0007829|PDB:1PWA"
FT STRAND 109..114
FT /evidence="ECO:0007829|PDB:1PWA"
FT HELIX 117..120
FT /evidence="ECO:0007829|PDB:1PWA"
FT STRAND 121..126
FT /evidence="ECO:0007829|PDB:1PWA"
FT STRAND 132..136
FT /evidence="ECO:0007829|PDB:1PWA"
FT TURN 137..140
FT /evidence="ECO:0007829|PDB:1PWA"
FT HELIX 150..152
FT /evidence="ECO:0007829|PDB:2P23"
FT HELIX 153..156
FT /evidence="ECO:0007829|PDB:2P23"
FT STRAND 165..168
FT /evidence="ECO:0007829|PDB:1PWA"
SQ SEQUENCE 216 AA; 24003 MW; E0BCBC9C220F9832 CRC64;
MRSGCVVVHV WILAGLWLAV AGRPLAFSDA GPHVHYGWGD PIRLRHLYTS GPHGLSSCFL
RIRADGVVDC ARGQSAHSLL EIKAVALRTV AIKGVHSVRY LCMGADGKMQ GLLQYSEEDC
AFEEEIRPDG YNVYRSEKHR LPVSLSSAKQ RQLYKNRGFL PLSHFLPMLP MVPEEPEDLR
GHLESDMFSS PLETDSMDPF GLVTGLEAVR SPSFEK
