FGF4_HUMAN
ID FGF4_HUMAN Reviewed; 206 AA.
AC P08620; B7U994;
DT 01-AUG-1988, integrated into UniProtKB/Swiss-Prot.
DT 01-AUG-1988, sequence version 1.
DT 03-AUG-2022, entry version 196.
DE RecName: Full=Fibroblast growth factor 4;
DE Short=FGF-4;
DE AltName: Full=Heparin secretory-transforming protein 1;
DE Short=HST;
DE Short=HST-1;
DE Short=HSTF-1;
DE AltName: Full=Heparin-binding growth factor 4;
DE Short=HBGF-4;
DE AltName: Full=Transforming protein KS3;
DE Flags: Precursor;
GN Name=FGF4; Synonyms=HST, HSTF1, KS3;
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] (ISOFORM 2), AND ALTERNATIVE SPLICING.
RX PubMed=18192227; DOI=10.1634/stemcells.2007-1037;
RA Mayshar Y., Rom E., Chumakov I., Kronman A., Yayon A., Benvenisty N.;
RT "Fibroblast growth factor 4 and its novel splice isoform have opposing
RT effects on the maintenance of human embryonic stem cell self-renewal.";
RL Stem Cells 26:767-774(2008).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=2959959; DOI=10.1073/pnas.84.20.7305;
RA Yoshida T., Miyagawa K., Odagiri H., Sakamoto H., Little P.F.R., Terada M.,
RA Sugimura T.;
RT "Genomic sequence of hst, a transforming gene encoding a protein homologous
RT to fibroblast growth factors and the int-2-encoded protein.";
RL Proc. Natl. Acad. Sci. U.S.A. 84:7305-7309(1987).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=2953031; DOI=10.1073/pnas.84.9.2980;
RA Taira M., Yoshida T., Miyagawa K., Sakamoto H., Terada M., Sugimura T.;
RT "cDNA sequence of human transforming gene hst and identification of the
RT coding sequence required for transforming activity.";
RL Proc. Natl. Acad. Sci. U.S.A. 84:2980-2984(1987).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=2957062; DOI=10.1016/0092-8674(87)90331-x;
RA Delli-Bovi P., Curatola A.M., Kern F.G., Greco A., Ittmann M., Basilico C.;
RT "An oncogene isolated by transfection of Kaposi's sarcoma DNA encodes a
RT growth factor that is a member of the FGF family.";
RL Cell 50:729-737(1987).
RN [5]
RP INTERACTION WITH FGFR1; FGFR2; FGFR3 AND FGFR4, AND FUNCTION IN CELL
RP PROLIFERATION.
RX PubMed=8663044; DOI=10.1074/jbc.271.25.15292;
RA Ornitz D.M., Xu J., Colvin J.S., McEwen D.G., MacArthur C.A., Coulier F.,
RA Gao G., Goldfarb M.;
RT "Receptor specificity of the fibroblast growth factor family.";
RL J. Biol. Chem. 271:15292-15297(1996).
RN [6]
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 [7]
RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 79-206.
RX PubMed=11486033; DOI=10.1128/mcb.21.17.5946-5957.2001;
RA Bellosta P., Iwahori A., Plotnikov A.N., Eliseenkova A.V., Basilico C.,
RA Mohammadi M.;
RT "Identification of receptor and heparin binding sites in fibroblast growth
RT factor 4 by structure-based mutagenesis.";
RL Mol. Cell. Biol. 21:5946-5957(2001).
CC -!- FUNCTION: Plays an important role in the regulation of embryonic
CC development, cell proliferation, and cell differentiation. Required for
CC normal limb and cardiac valve development during embryogenesis.
CC {ECO:0000269|PubMed:8663044}.
CC -!- SUBUNIT: Interacts with FGFR1, FGFR2, FGFR3 and FGFR4. Affinity between
CC fibroblast growth factors (FGFs) and their receptors is increased by
CC heparan sulfate glycosaminoglycans that function as coreceptors.
CC {ECO:0000269|PubMed:8663044}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000305}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P08620-1; Sequence=Displayed;
CC Name=2; Synonyms=FGF4si;
CC IsoId=P08620-2; Sequence=VSP_053541;
CC -!- MISCELLANEOUS: [Isoform 2]: Antagonist of isoform 1, shutting down
CC FGF4-induced Erk1/2 phosphorylation. {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the heparin-binding growth factors family.
CC {ECO:0000305}.
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DR EMBL; FJ456981; ACJ68447.1; -; mRNA.
DR EMBL; J02986; AAB59555.1; -; Genomic_DNA.
DR EMBL; M17446; AAA59473.1; -; mRNA.
DR CCDS; CCDS8194.1; -. [P08620-1]
DR PIR; A28417; TVHUHS.
DR RefSeq; NP_001998.1; NM_002007.2. [P08620-1]
DR RefSeq; XP_005273904.1; XM_005273847.1.
DR PDB; 1IJT; X-ray; 1.80 A; A=79-206.
DR PDBsum; 1IJT; -.
DR AlphaFoldDB; P08620; -.
DR SMR; P08620; -.
DR BioGRID; 108540; 41.
DR DIP; DIP-4017N; -.
DR IntAct; P08620; 2.
DR STRING; 9606.ENSP00000168712; -.
DR BindingDB; P08620; -.
DR ChEMBL; CHEMBL3286072; -.
DR DrugBank; DB01109; Heparin.
DR DrugBank; DB00686; Pentosan polysulfate.
DR DrugBank; DB05309; TP-508.
DR iPTMnet; P08620; -.
DR PhosphoSitePlus; P08620; -.
DR BioMuta; FGF4; -.
DR DMDM; 122750; -.
DR jPOST; P08620; -.
DR MassIVE; P08620; -.
DR PaxDb; P08620; -.
DR PeptideAtlas; P08620; -.
DR PRIDE; P08620; -.
DR Antibodypedia; 2159; 455 antibodies from 39 providers.
DR DNASU; 2249; -.
DR Ensembl; ENST00000168712.3; ENSP00000168712.1; ENSG00000075388.4. [P08620-1]
DR GeneID; 2249; -.
DR KEGG; hsa:2249; -.
DR MANE-Select; ENST00000168712.3; ENSP00000168712.1; NM_002007.4; NP_001998.1.
DR UCSC; uc001opg.2; human. [P08620-1]
DR CTD; 2249; -.
DR DisGeNET; 2249; -.
DR GeneCards; FGF4; -.
DR HGNC; HGNC:3682; FGF4.
DR HPA; ENSG00000075388; Not detected.
DR MIM; 164980; gene.
DR neXtProt; NX_P08620; -.
DR OpenTargets; ENSG00000075388; -.
DR PharmGKB; PA28121; -.
DR VEuPathDB; HostDB:ENSG00000075388; -.
DR eggNOG; KOG3885; Eukaryota.
DR GeneTree; ENSGT00940000158825; -.
DR HOGENOM; CLU_081609_4_1_1; -.
DR InParanoid; P08620; -.
DR OMA; YESHTYP; -.
DR OrthoDB; 1183051at2759; -.
DR PhylomeDB; P08620; -.
DR TreeFam; TF317805; -.
DR PathwayCommons; P08620; -.
DR Reactome; R-HSA-109704; PI3K Cascade.
DR Reactome; R-HSA-1257604; PIP3 activates AKT signaling.
DR Reactome; R-HSA-1839122; Signaling by activated point mutants of FGFR1.
DR Reactome; R-HSA-1839130; Signaling by activated point mutants of FGFR3.
DR Reactome; R-HSA-190322; FGFR4 ligand binding and activation.
DR Reactome; R-HSA-190372; FGFR3c ligand binding and activation.
DR Reactome; R-HSA-190373; FGFR1c ligand binding and activation.
DR Reactome; R-HSA-190375; FGFR2c ligand binding and activation.
DR Reactome; R-HSA-2033519; Activated point mutants of FGFR2.
DR Reactome; R-HSA-2219530; Constitutive Signaling by Aberrant PI3K in Cancer.
DR Reactome; R-HSA-5654219; Phospholipase C-mediated cascade: FGFR1.
DR Reactome; R-HSA-5654221; Phospholipase C-mediated cascade, FGFR2.
DR Reactome; R-HSA-5654227; Phospholipase C-mediated cascade, FGFR3.
DR Reactome; R-HSA-5654228; Phospholipase C-mediated cascade, FGFR4.
DR Reactome; R-HSA-5654687; Downstream signaling of activated FGFR1.
DR Reactome; R-HSA-5654688; SHC-mediated cascade:FGFR1.
DR Reactome; R-HSA-5654689; PI-3K cascade:FGFR1.
DR Reactome; R-HSA-5654693; FRS-mediated FGFR1 signaling.
DR Reactome; R-HSA-5654695; PI-3K cascade:FGFR2.
DR Reactome; R-HSA-5654699; SHC-mediated cascade:FGFR2.
DR Reactome; R-HSA-5654700; FRS-mediated FGFR2 signaling.
DR Reactome; R-HSA-5654704; SHC-mediated cascade:FGFR3.
DR Reactome; R-HSA-5654706; FRS-mediated FGFR3 signaling.
DR Reactome; R-HSA-5654710; PI-3K cascade:FGFR3.
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-5654726; Negative regulation of FGFR1 signaling.
DR Reactome; R-HSA-5654727; Negative regulation of FGFR2 signaling.
DR Reactome; R-HSA-5654732; Negative regulation of FGFR3 signaling.
DR Reactome; R-HSA-5654733; Negative regulation of FGFR4 signaling.
DR Reactome; R-HSA-5655253; Signaling by FGFR2 in disease.
DR Reactome; R-HSA-5655302; Signaling by FGFR1 in disease.
DR Reactome; R-HSA-5655332; Signaling by FGFR3 in disease.
DR Reactome; R-HSA-5658623; FGFRL1 modulation of FGFR1 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; P08620; -.
DR SIGNOR; P08620; -.
DR BioGRID-ORCS; 2249; 11 hits in 1073 CRISPR screens.
DR EvolutionaryTrace; P08620; -.
DR GeneWiki; FGF4; -.
DR GenomeRNAi; 2249; -.
DR Pharos; P08620; Tbio.
DR PRO; PR:P08620; -.
DR Proteomes; UP000005640; Chromosome 11.
DR RNAct; P08620; protein.
DR Bgee; ENSG00000075388; Expressed in olfactory bulb and 10 other tissues.
DR Genevisible; P08620; 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; IBA:GO_Central.
DR GO; GO:0008083; F:growth factor activity; IBA:GO_Central.
DR GO; GO:0008201; F:heparin binding; IEA:UniProtKB-KW.
DR GO; GO:0009887; P:animal organ morphogenesis; IBA:GO_Central.
DR GO; GO:0060561; P:apoptotic process involved in morphogenesis; IEA:Ensembl.
DR GO; GO:0001502; P:cartilage condensation; IEA:Ensembl.
DR GO; GO:0030154; P:cell differentiation; IBA:GO_Central.
DR GO; GO:0007267; P:cell-cell signaling; TAS:ProtInc.
DR GO; GO:1990830; P:cellular response to leukemia inhibitory factor; IEA:Ensembl.
DR GO; GO:0060591; P:chondroblast differentiation; IDA:UniProtKB.
DR GO; GO:0060363; P:cranial suture morphogenesis; IEA:Ensembl.
DR GO; GO:0035116; P:embryonic hindlimb morphogenesis; IEA:Ensembl.
DR GO; GO:1904019; P:epithelial cell apoptotic process; IEA:Ensembl.
DR GO; GO:0008543; P:fibroblast growth factor receptor signaling pathway; IGI:MGI.
DR GO; GO:0010463; P:mesenchymal cell proliferation; IDA:UniProtKB.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IEA:Ensembl.
DR GO; GO:0042475; P:odontogenesis of dentin-containing tooth; IEA:Ensembl.
DR GO; GO:0051781; P:positive regulation of cell division; IEA:UniProtKB-KW.
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:0001934; P:positive regulation of protein phosphorylation; IBA:GO_Central.
DR GO; GO:2000648; P:positive regulation of stem cell proliferation; IEA:Ensembl.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IEA:Ensembl.
DR GO; GO:0030334; P:regulation of cell migration; IBA:GO_Central.
DR GO; GO:2000544; P:regulation of endothelial cell chemotaxis to fibroblast growth factor; IDA:UniProtKB.
DR GO; GO:0007165; P:signal transduction; TAS:ProtInc.
DR GO; GO:0035019; P:somatic stem cell population maintenance; IEA:Ensembl.
DR GO; GO:0072089; P:stem cell proliferation; IEA:Ensembl.
DR CDD; cd00058; FGF; 1.
DR InterPro; IPR028239; FGF4.
DR InterPro; IPR002209; Fibroblast_GF_fam.
DR InterPro; IPR008996; IL1/FGF.
DR PANTHER; PTHR11486; PTHR11486; 1.
DR PANTHER; PTHR11486:SF31; PTHR11486:SF31; 1.
DR Pfam; PF00167; FGF; 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; Alternative splicing; Developmental protein; Differentiation;
KW Growth factor; Heparin-binding; Mitogen; Proto-oncogene;
KW Reference proteome; Secreted; Signal.
FT SIGNAL 1..30
FT /evidence="ECO:0000255"
FT CHAIN 31..206
FT /note="Fibroblast growth factor 4"
FT /id="PRO_0000008953"
FT VAR_SEQ 114..206
FT /note="SLLELSPVERGVVSIFGVASRFFVAMSSKGKLYGSPFFTDECTFKEILLPNN
FT YNAYESYKYPGMFIALSKNGKTKKGNRVSPTMKVTHFLPRL -> TLLHR (in
FT isoform 2)"
FT /evidence="ECO:0000303|PubMed:18192227"
FT /id="VSP_053541"
FT STRAND 82..88
FT /evidence="ECO:0007829|PDB:1IJT"
FT STRAND 94..98
FT /evidence="ECO:0007829|PDB:1IJT"
FT STRAND 104..109
FT /evidence="ECO:0007829|PDB:1IJT"
FT HELIX 112..114
FT /evidence="ECO:0007829|PDB:1IJT"
FT STRAND 116..122
FT /evidence="ECO:0007829|PDB:1IJT"
FT STRAND 125..130
FT /evidence="ECO:0007829|PDB:1IJT"
FT TURN 131..134
FT /evidence="ECO:0007829|PDB:1IJT"
FT STRAND 135..139
FT /evidence="ECO:0007829|PDB:1IJT"
FT STRAND 145..150
FT /evidence="ECO:0007829|PDB:1IJT"
FT STRAND 155..161
FT /evidence="ECO:0007829|PDB:1IJT"
FT HELIX 163..165
FT /evidence="ECO:0007829|PDB:1IJT"
FT STRAND 167..174
FT /evidence="ECO:0007829|PDB:1IJT"
FT STRAND 185..187
FT /evidence="ECO:0007829|PDB:1IJT"
FT HELIX 190..192
FT /evidence="ECO:0007829|PDB:1IJT"
FT HELIX 198..200
FT /evidence="ECO:0007829|PDB:1IJT"
FT STRAND 202..205
FT /evidence="ECO:0007829|PDB:1IJT"
SQ SEQUENCE 206 AA; 22048 MW; C7FD54A0272A1569 CRC64;
MSGPGTAAVA LLPAVLLALL APWAGRGGAA APTAPNGTLE AELERRWESL VALSLARLPV
AAQPKEAAVQ SGAGDYLLGI KRLRRLYCNV GIGFHLQALP DGRIGGAHAD TRDSLLELSP
VERGVVSIFG VASRFFVAMS SKGKLYGSPF FTDECTFKEI LLPNNYNAYE SYKYPGMFIA
LSKNGKTKKG NRVSPTMKVT HFLPRL
