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 16-SEP-2015, entry version 153. 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; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; 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- RT 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., RA Terada M., Sugimura T.; RT "Genomic sequence of hst, a transforming gene encoding a protein RT homologous to fibroblast growth factors and the int-2-encoded RT 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., RA Sugimura T.; RT "cDNA sequence of human transforming gene hst and identification of RT the 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., RA Basilico C.; RT "An oncogene isolated by transfection of Kaposi's sarcoma DNA encodes RT a 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., RA Coulier F., 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., RA Basilico C., Mohammadi M.; RT "Identification of receptor and heparin binding sites in fibroblast RT growth 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. CC Required for normal limb and cardiac valve development during CC embryogenesis. {ECO:0000269|PubMed:8663044}. CC -!- SUBUNIT: Interacts with FGFR1, FGFR2, FGFR3 and FGFR4. Affinity CC between fibroblast growth factors (FGFs) and their receptors is CC increased by heparan sulfate glycosaminoglycans that function as CC coreceptors. {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 Note=Antagonist of isoform 1, shutting down FGF4-induced Erk1/2 CC phosphorylation.; CC -!- SIMILARITY: Belongs to the heparin-binding growth factors family. CC {ECO:0000305}. 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; 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. [P08620-2] DR RefSeq; XP_006718538.1; XM_006718475.2. [P08620-1] DR UniGene; Hs.1755; -. DR PDB; 1IJT; X-ray; 1.80 A; A=79-206. DR PDBsum; 1IJT; -. DR ProteinModelPortal; P08620; -. DR SMR; P08620; 79-206. DR DIP; DIP-4017N; -. DR STRING; 9606.ENSP00000168712; -. DR BindingDB; P08620; -. DR ChEMBL; CHEMBL3286072; -. DR DrugBank; DB00686; Pentosan Polysulfate. DR PhosphoSite; P08620; -. DR BioMuta; FGF4; -. DR DMDM; 122750; -. DR PaxDb; P08620; -. DR PRIDE; P08620; -. DR DNASU; 2249; -. DR Ensembl; ENST00000168712; ENSP00000168712; ENSG00000075388. [P08620-1] DR GeneID; 2249; -. DR KEGG; hsa:2249; -. DR UCSC; uc001opg.1; human. [P08620-1] DR CTD; 2249; -. DR GeneCards; GC11M069762; -. DR HGNC; HGNC:3682; FGF4. DR HPA; HPA011209; -. DR MIM; 164980; gene. DR neXtProt; NX_P08620; -. DR PharmGKB; PA28121; -. DR eggNOG; NOG290420; -. DR GeneTree; ENSGT00760000118859; -. DR HOGENOM; HOG000236341; -. DR HOVERGEN; HBG007580; -. DR InParanoid; P08620; -. DR KO; K04358; -. DR OMA; YNAYESH; -. DR OrthoDB; EOG7992S1; -. DR PhylomeDB; P08620; -. DR TreeFam; TF317805; -. 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-2033514; FGFR3 mutant receptor 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-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-5673001; RAF/MAP kinase cascade. DR SignaLink; P08620; -. DR EvolutionaryTrace; P08620; -. DR GeneWiki; FGF4; -. DR GenomeRNAi; 2249; -. DR NextBio; 35478625; -. DR PRO; PR:P08620; -. DR Proteomes; UP000005640; Chromosome 11. DR Bgee; P08620; -. DR CleanEx; HS_FGF4; -. DR Genevisible; P08620; HS. DR GO; GO:0005576; C:extracellular region; TAS:Reactome. DR GO; GO:0005622; C:intracellular; TAS:GOC. DR GO; GO:0008083; F:growth factor activity; TAS:ProtInc. DR GO; GO:0008201; F:heparin binding; IEA:UniProtKB-KW. DR GO; GO:0060561; P:apoptotic process involved in morphogenesis; IEA:Ensembl. DR GO; GO:0001502; P:cartilage condensation; IEA:Ensembl. DR GO; GO:0007267; P:cell-cell signaling; TAS:ProtInc. 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:0007173; P:epidermal growth factor receptor signaling pathway; TAS:Reactome. DR GO; GO:0038095; P:Fc-epsilon receptor signaling pathway; TAS:Reactome. DR GO; GO:0008543; P:fibroblast growth factor receptor signaling pathway; IGI:MGI. DR GO; GO:0045087; P:innate immune response; TAS:Reactome. DR GO; GO:0008286; P:insulin receptor signaling pathway; TAS:Reactome. 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:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome. DR GO; GO:0042475; P:odontogenesis of dentin-containing tooth; IEA:Ensembl. DR GO; GO:0048015; P:phosphatidylinositol-mediated signaling; TAS:Reactome. DR GO; GO:0051781; P:positive regulation of cell division; IEA:UniProtKB-KW. DR GO; GO:0008284; P:positive regulation of cell proliferation; IGI:MGI. DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IDA:UniProtKB. DR GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IEA:Ensembl. 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:0019827; P:stem cell maintenance; IEA:Ensembl. DR InterPro; IPR008996; Cytokine_IL1-like. DR InterPro; IPR028239; FGF4. DR InterPro; IPR002209; Fibroblast_GF_fam. DR InterPro; IPR028142; IL-1_fam/FGF_fam. DR PANTHER; PTHR11486; PTHR11486; 1. DR PANTHER; PTHR11486:SF31; PTHR11486:SF31; 1. DR PRINTS; PR00263; HBGFFGF. DR PRINTS; PR00262; IL1HBGF. 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; Complete proteome; KW Developmental protein; Differentiation; Growth factor; KW Heparin-binding; Mitogen; Proto-oncogene; Reference proteome; KW Secreted; Signal. FT SIGNAL 1 30 {ECO:0000255}. FT CHAIN 31 206 Fibroblast growth factor 4. FT /FTId=PRO_0000008953. FT VAR_SEQ 114 206 SLLELSPVERGVVSIFGVASRFFVAMSSKGKLYGSPFFTDE FT CTFKEILLPNNYNAYESYKYPGMFIALSKNGKTKKGNRVSP FT TMKVTHFLPRL -> TLLHR (in isoform 2). FT {ECO:0000303|PubMed:18192227}. FT /FTId=VSP_053541. FT STRAND 82 88 {ECO:0000244|PDB:1IJT}. FT STRAND 94 98 {ECO:0000244|PDB:1IJT}. FT STRAND 104 109 {ECO:0000244|PDB:1IJT}. FT HELIX 112 114 {ECO:0000244|PDB:1IJT}. FT STRAND 116 122 {ECO:0000244|PDB:1IJT}. FT STRAND 125 130 {ECO:0000244|PDB:1IJT}. FT TURN 131 134 {ECO:0000244|PDB:1IJT}. FT STRAND 135 139 {ECO:0000244|PDB:1IJT}. FT STRAND 145 150 {ECO:0000244|PDB:1IJT}. FT STRAND 155 161 {ECO:0000244|PDB:1IJT}. FT HELIX 163 165 {ECO:0000244|PDB:1IJT}. FT STRAND 167 174 {ECO:0000244|PDB:1IJT}. FT STRAND 185 187 {ECO:0000244|PDB:1IJT}. FT HELIX 190 192 {ECO:0000244|PDB:1IJT}. FT HELIX 198 200 {ECO:0000244|PDB:1IJT}. FT STRAND 202 205 {ECO:0000244|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 //