ID FGF21_HUMAN Reviewed; 209 AA. AC Q9NSA1; Q8N683; DT 27-APR-2001, integrated into UniProtKB/Swiss-Prot. DT 01-OCT-2000, sequence version 1. DT 24-JAN-2024, entry version 178. DE RecName: Full=Fibroblast growth factor 21; DE Short=FGF-21; DE Flags: Precursor; GN Name=FGF21; ORFNames=UNQ3115/PRO10196; 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]. RX PubMed=10858549; DOI=10.1016/s0167-4781(00)00067-1; RA Nishimura T., Nakatake Y., Konishi M., Itoh N.; RT "Identification of a novel FGF, FGF-21, preferentially expressed in the RT liver."; RL Biochim. Biophys. Acta 1492:203-206(2000). RN [2] 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 [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS SER-141 AND PRO-174. RG NIEHS SNPs program; RL Submitted (JUL-2006) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Lung; 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 29-43. 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 FUNCTION, AND INTERACTION WITH FGFR4 AND KLB. RX PubMed=15902306; DOI=10.1172/jci23606; RA Kharitonenkov A., Shiyanova T.L., Koester A., Ford A.M., Micanovic R., RA Galbreath E.J., Sandusky G.E., Hammond L.J., Moyers J.S., Owens R.A., RA Gromada J., Brozinick J.T., Hawkins E.D., Wroblewski V.J., Li D.-S., RA Mehrbod F., Jaskunas S.R., Shanafelt A.B.; RT "FGF-21 as a novel metabolic regulator."; RL J. Clin. Invest. 115:1627-1635(2005). RN [8] RP FUNCTION. 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 [9] RP INTERACTION WITH 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 [10] RP INTERACTION WITH KLB. RX PubMed=19117008; DOI=10.1002/jcp.21675; RA Micanovic R., Raches D.W., Dunbar J.D., Driver D.A., Bina H.A., RA Dickinson C.D., Kharitonenkov A.; RT "Different roles of N- and C- termini in the functional activity of RT FGF21."; RL J. Cell. Physiol. 219:227-234(2009). RN [11] 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). CC -!- FUNCTION: Stimulates glucose uptake in differentiated adipocytes via CC the induction of glucose transporter SLC2A1/GLUT1 expression (but not CC SLC2A4/GLUT4 expression). Activity requires the presence of KLB. CC Regulates systemic glucose homeostasis and insulin sensitivity. CC {ECO:0000250|UniProtKB:Q9JJN1, ECO:0000269|PubMed:15902306, CC ECO:0000269|PubMed:17623664}. CC -!- SUBUNIT: Interacts (via C-terminus) with KLB; this interaction is CC direct. Interacts with FGFR4. {ECO:0000269|PubMed:15902306, CC ECO:0000269|PubMed:18829467, ECO:0000269|PubMed:19117008}. CC -!- INTERACTION: CC Q9NSA1; P46379-2: BAG6; NbExp=3; IntAct=EBI-3909329, EBI-10988864; CC Q9NSA1; P55212: CASP6; NbExp=3; IntAct=EBI-3909329, EBI-718729; CC Q9NSA1; O14645: DNALI1; NbExp=3; IntAct=EBI-3909329, EBI-395638; CC Q9NSA1; Q0VDC6: FKBP1A; NbExp=3; IntAct=EBI-3909329, EBI-10226858; CC Q9NSA1; P54652: HSPA2; NbExp=4; IntAct=EBI-3909329, EBI-356991; CC Q9NSA1; Q86Z14: KLB; NbExp=2; IntAct=EBI-3909329, EBI-8515198; CC Q9NSA1; O14901: KLF11; NbExp=3; IntAct=EBI-3909329, EBI-948266; CC Q9NSA1; P13473-2: LAMP2; NbExp=3; IntAct=EBI-3909329, EBI-21591415; CC Q9NSA1; O43765: SGTA; NbExp=3; IntAct=EBI-3909329, EBI-347996; CC Q9NSA1; Q96EQ0: SGTB; NbExp=3; IntAct=EBI-3909329, EBI-744081; CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000250|UniProtKB:Q9JJN1}. CC -!- SIMILARITY: Belongs to the heparin-binding growth factors family. CC {ECO:0000305}. CC -!- WEB RESOURCE: Name=NIEHS-SNPs; CC URL="http://egp.gs.washington.edu/data/fgf21/"; 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; AB021975; BAA99415.1; -; mRNA. DR EMBL; AY359086; AAQ89444.1; -; mRNA. DR EMBL; DQ847413; ABI75345.1; -; Genomic_DNA. DR EMBL; CH471177; EAW52402.1; -; Genomic_DNA. DR EMBL; BC018404; AAH18404.1; -; mRNA. DR CCDS; CCDS12734.1; -. DR RefSeq; NP_061986.1; NM_019113.3. DR PDB; 5VAQ; X-ray; 2.61 A; C=186-209. DR PDB; 6M6E; NMR; -; A=42-169. DR PDB; 6M6F; NMR; -; A=42-164. DR PDBsum; 5VAQ; -. DR PDBsum; 6M6E; -. DR PDBsum; 6M6F; -. DR AlphaFoldDB; Q9NSA1; -. DR SMR; Q9NSA1; -. DR BioGRID; 117672; 11. DR CORUM; Q9NSA1; -. DR IntAct; Q9NSA1; 14. DR MINT; Q9NSA1; -. DR STRING; 9606.ENSP00000471477; -. DR BioMuta; FGF21; -. DR DMDM; 13626703; -. DR MassIVE; Q9NSA1; -. DR PaxDb; 9606-ENSP00000471477; -. DR PeptideAtlas; Q9NSA1; -. DR Antibodypedia; 31805; 942 antibodies from 38 providers. DR DNASU; 26291; -. DR Ensembl; ENST00000222157.5; ENSP00000222157.3; ENSG00000105550.10. DR Ensembl; ENST00000593756.6; ENSP00000471477.1; ENSG00000105550.10. DR GeneID; 26291; -. DR KEGG; hsa:26291; -. DR MANE-Select; ENST00000593756.6; ENSP00000471477.1; NM_019113.4; NP_061986.1. DR UCSC; uc002pkn.2; human. DR AGR; HGNC:3678; -. DR CTD; 26291; -. DR DisGeNET; 26291; -. DR GeneCards; FGF21; -. DR HGNC; HGNC:3678; FGF21. DR HPA; ENSG00000105550; Tissue enriched (liver). DR MIM; 609436; gene. DR neXtProt; NX_Q9NSA1; -. DR OpenTargets; ENSG00000105550; -. DR PharmGKB; PA28117; -. DR VEuPathDB; HostDB:ENSG00000105550; -. DR eggNOG; KOG3885; Eukaryota. DR GeneTree; ENSGT00940000161866; -. DR HOGENOM; CLU_094251_2_0_1; -. DR InParanoid; Q9NSA1; -. DR OMA; CQAYPIP; -. DR OrthoDB; 4138817at2759; -. DR PhylomeDB; Q9NSA1; -. DR TreeFam; TF335872; -. DR PathwayCommons; Q9NSA1; -. DR Reactome; R-HSA-189200; Cellular hexose transport. DR Reactome; R-HSA-8963889; Assembly of active LPL and LIPC lipase complexes. DR SignaLink; Q9NSA1; -. DR SIGNOR; Q9NSA1; -. DR BioGRID-ORCS; 26291; 8 hits in 1145 CRISPR screens. DR GeneWiki; FGF21; -. DR GenomeRNAi; 26291; -. DR Pharos; Q9NSA1; Tbio. DR PRO; PR:Q9NSA1; -. DR Proteomes; UP000005640; Chromosome 19. DR RNAct; Q9NSA1; Protein. DR Bgee; ENSG00000105550; Expressed in right lobe of liver and 32 other cell types or tissues. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0005576; C:extracellular region; TAS:ProtInc. 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:0009887; P:animal organ morphogenesis; IBA:GO_Central. DR GO; GO:0030154; P:cell differentiation; IBA:GO_Central. DR GO; GO:0007267; P:cell-cell signaling; TAS:ProtInc. DR GO; GO:0071377; P:cellular response to glucagon stimulus; IEA:Ensembl. DR GO; GO:0071333; P:cellular response to glucose stimulus; IEA:Ensembl. DR GO; GO:0071404; P:cellular response to low-density lipoprotein particle stimulus; IEA:Ensembl. DR GO; GO:0071466; P:cellular response to xenobiotic stimulus; IEA:Ensembl. DR GO; GO:0030968; P:endoplasmic reticulum unfolded protein response; IEA:Ensembl. DR GO; GO:0072577; P:endothelial cell apoptotic process; IEA:Ensembl. DR GO; GO:0008543; P:fibroblast growth factor receptor signaling pathway; IBA:GO_Central. DR GO; GO:2000352; P:negative regulation of endothelial cell apoptotic process; IEA:Ensembl. DR GO; GO:0008284; P:positive regulation of cell population proliferation; IBA:GO_Central. DR GO; GO:0120162; P:positive regulation of cold-induced thermogenesis; ISS:YuBioLab. 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:1905599; P:positive regulation of low-density lipoprotein receptor activity; NAS:BHF-UCL. DR GO; GO:0090080; P:positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway; IEA:Ensembl. DR GO; GO:0001934; P:positive regulation of protein phosphorylation; IBA:GO_Central. DR GO; GO:0010898; P:positive regulation of triglyceride catabolic process; IEA:Ensembl. DR GO; GO:0030334; P:regulation of cell migration; IBA:GO_Central. DR GO; GO:0010988; P:regulation of low-density lipoprotein particle clearance; NAS:BHF-UCL. DR GO; GO:0014823; P:response to activity; IEA:Ensembl. DR GO; GO:1904640; P:response to methionine; IEA:Ensembl. DR GO; GO:0031667; P:response to nutrient levels; IEA:Ensembl. DR GO; GO:0007165; P:signal transduction; TAS:ProtInc. DR Gene3D; 2.80.10.50; -; 1. DR InterPro; IPR035444; FGF15/19/21. DR InterPro; IPR002209; Fibroblast_GF_fam. DR InterPro; IPR008996; IL1/FGF. DR PANTHER; PTHR11486; FIBROBLAST GROWTH FACTOR; 1. DR PANTHER; PTHR11486:SF81; FIBROBLAST GROWTH FACTOR 21; 1. DR Pfam; PF00167; FGF; 1. DR PIRSF; PIRSF037961; FGF-19_FGF-21; 1. DR PRINTS; PR00263; HBGFFGF. DR PRINTS; PR00262; IL1HBGF. DR SMART; SM00442; FGF; 1. DR SUPFAM; SSF50353; Cytokine; 1. DR PROSITE; PS00247; HBGF_FGF; 1. DR Genevisible; Q9NSA1; HS. PE 1: Evidence at protein level; KW 3D-structure; Direct protein sequencing; Growth factor; Reference proteome; KW Secreted; Signal. FT SIGNAL 1..28 FT /evidence="ECO:0000269|PubMed:15340161" FT CHAIN 29..209 FT /note="Fibroblast growth factor 21" FT /id="PRO_0000008994" FT REGION 143..209 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 159..184 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 194..209 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT VARIANT 141 FT /note="G -> S (in dbSNP:rs41308776)" FT /evidence="ECO:0000269|Ref.3" FT /id="VAR_055375" FT VARIANT 174 FT /note="L -> P (in dbSNP:rs739320)" FT /evidence="ECO:0000269|Ref.3" FT /id="VAR_049064" FT CONFLICT 23 FT /note="Missing (in Ref. 2; AAQ89444)" FT /evidence="ECO:0000305" FT STRAND 44..51 FT /evidence="ECO:0007829|PDB:6M6E" FT HELIX 52..55 FT /evidence="ECO:0007829|PDB:6M6E" FT STRAND 60..63 FT /evidence="ECO:0007829|PDB:6M6E" FT STRAND 69..74 FT /evidence="ECO:0007829|PDB:6M6E" FT HELIX 77..79 FT /evidence="ECO:0007829|PDB:6M6E" FT STRAND 80..87 FT /evidence="ECO:0007829|PDB:6M6E" FT STRAND 90..95 FT /evidence="ECO:0007829|PDB:6M6E" FT TURN 96..98 FT /evidence="ECO:0007829|PDB:6M6E" FT STRAND 101..104 FT /evidence="ECO:0007829|PDB:6M6E" FT STRAND 110..115 FT /evidence="ECO:0007829|PDB:6M6E" FT HELIX 118..121 FT /evidence="ECO:0007829|PDB:6M6E" FT STRAND 123..127 FT /evidence="ECO:0007829|PDB:6M6E" FT STRAND 133..136 FT /evidence="ECO:0007829|PDB:6M6E" FT TURN 138..140 FT /evidence="ECO:0007829|PDB:6M6E" FT STRAND 152..154 FT /evidence="ECO:0007829|PDB:6M6E" FT STRAND 164..168 FT /evidence="ECO:0007829|PDB:6M6E" FT STRAND 190..192 FT /evidence="ECO:0007829|PDB:5VAQ" FT TURN 205..208 FT /evidence="ECO:0007829|PDB:5VAQ" SQ SEQUENCE 209 AA; 22300 MW; 27925C52A0023823 CRC64; MDSDETGFEH SGLWVSVLAG LLLGACQAHP IPDSSPLLQF GGQVRQRYLY TDDAQQTEAH LEIREDGTVG GAADQSPESL LQLKALKPGV IQILGVKTSR FLCQRPDGAL YGSLHFDPEA CSFRELLLED GYNVYQSEAH GLPLHLPGNK SPHRDPAPRG PARFLPLPGL PPALPEPPGI LAPQPPDVGS SDPLSMVGPS QGRSPSYAS //