FGFR4_HUMAN
ID FGFR4_HUMAN Reviewed; 802 AA.
AC P22455; G3JVM2; G3JVM5; G3JVM7; G3JVM9; O43785; Q14309; Q71TW8; Q8TDA0;
AC Q96KE5;
DT 01-AUG-1991, integrated into UniProtKB/Swiss-Prot.
DT 27-APR-2001, sequence version 2.
DT 03-AUG-2022, entry version 231.
DE RecName: Full=Fibroblast growth factor receptor 4;
DE Short=FGFR-4;
DE EC=2.7.10.1;
DE AltName: CD_antigen=CD334;
DE Flags: Precursor;
GN Name=FGFR4; Synonyms=JTK2, TKF;
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 1).
RX PubMed=1709094; DOI=10.1002/j.1460-2075.1991.tb07654.x;
RA Partanen J.M., Maekelae T.P., Eerola E., Korhonen J., Hirvonen H.,
RA Claesson-Welsh L., Alitalo K.;
RT "FGFR-4, a novel acidic fibroblast growth factor receptor with a distinct
RT expression pattern.";
RL EMBO J. 10:1347-1354(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND FUNCTION AS RECEPTOR FOR FGF1
RP AND FGF2.
RC TISSUE=Mammary gland;
RX PubMed=7680645; DOI=10.1016/s0021-9258(18)53334-2;
RA Ron D., Reich R., Chedid M., Lengel C., Cohen O.E., Chan A.M., Neufeld G.,
RA Miki T., Tronick S.R.;
RT "Fibroblast growth factor receptor 4 is a high affinity receptor for both
RT acidic and basic fibroblast growth factor but not for keratinocyte growth
RT factor.";
RL J. Biol. Chem. 268:5388-5394(1993).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), VARIANT LEU-136, TISSUE
RP SPECIFICITY, AND SUBCELLULAR LOCATION.
RC TISSUE=Intestine;
RX PubMed=10631118; DOI=10.1006/bbrc.1999.2010;
RA Takaishi S., Sawada M., Morita Y., Seno H., Fukuzawa H., Chiba T.;
RT "Identification of a novel alternative splicing of human FGF receptor 4:
RT soluble-form splice variant expressed in human gastrointestinal epithelial
RT cells.";
RL Biochem. Biophys. Res. Commun. 267:658-662(2000).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=9457674; DOI=10.1007/s003359900703;
RA Kostrzewa M., Muller U.;
RT "Genomic structure and complete sequence of the human FGFR4 gene.";
RL Mamm. Genome 9:131-135(1998).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), SUBCELLULAR LOCATION (ISOFORM 3),
RP INVOLVEMENT IN CANCER, AND VARIANT ARG-388.
RC TISSUE=Pituitary;
RX PubMed=11781352; DOI=10.1172/jci14036;
RA Ezzat S., Zheng L., Zhu X.F., Wu G.E., Asa S.L.;
RT "Targeted expression of a human pituitary tumor-derived isoform of FGF
RT receptor-4 recapitulates pituitary tumorigenesis.";
RL J. Clin. Invest. 109:69-78(2002).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANTS ILE-10 AND LEU-136,
RP INVOLVEMENT IN CANCER, AND VARIANT ARG-388.
RX PubMed=21882254; DOI=10.1002/mc.20848;
RA Marshall A.D., van der Ent M.A., Grosveld G.C.;
RT "PAX3-FOXO1 and FGFR4 in alveolar rhabdomyosarcoma.";
RL Mol. Carcinog. 51:807-815(2012).
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT LEU-136.
RA Lind D.L., Cox D.R.;
RT "Sequence variation in fibroblast growth factor receptors 3 and 4.";
RL Submitted (FEB-2002) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS ILE-10; LEU-136 AND
RP ARG-388.
RG NIEHS SNPs program;
RL Submitted (APR-2007) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15372022; DOI=10.1038/nature02919;
RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S.,
RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M.,
RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.,
RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M.,
RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M.,
RA Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T.,
RA Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A.,
RA Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R.,
RA Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L.,
RA Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N.,
RA Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J.,
RA Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A.,
RA Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M.;
RT "The DNA sequence and comparative analysis of human chromosome 5.";
RL Nature 431:268-274(2004).
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANT LEU-136.
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 [11]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Muscle;
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 [12]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 609-676.
RC TISSUE=Blood;
RX PubMed=2247464; DOI=10.1073/pnas.87.22.8913;
RA Partanen J., Maekelae T.P., Alitalo R., Lehvaeslaiho H., Alitalo K.;
RT "Putative tyrosine kinases expressed in K-562 human leukemia cells.";
RL Proc. Natl. Acad. Sci. U.S.A. 87:8913-8917(1990).
RN [13]
RP PROTEIN SEQUENCE OF 22-38.
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 [14]
RP FUNCTION AS FGF1 RECEPTOR AND IN ACTIVATION OF SIGNALING VIA PLCG1 AND
RP PIK3R1, INTERACTION WITH PLCG1, PHOSPHORYLATION AT TYR-754, AND MUTAGENESIS
RP OF TYR-754.
RX PubMed=7518429; DOI=10.1016/s0021-9258(17)32309-8;
RA Vainikka S., Joukov V., Wennstrom S., Bergman M., Pelicci P.G., Alitalo K.;
RT "Signal transduction by fibroblast growth factor receptor-4 (FGFR-4).
RT Comparison with FGFR-1.";
RL J. Biol. Chem. 269:18320-18326(1994).
RN [15]
RP INTERACTION WITH FGF1; FGF2; FGF4; FGF6; FGF8 AND FGF9, AND FUNCTION IN
RP CELL 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 [16]
RP FUNCTION IN CELL DIFFERENTIATION, MUTAGENESIS OF LYS-503, CATALYTIC
RP ACTIVITY, AND IDENTIFICATION IN A COMPLEX WITH NCAM1; CDH2; PLCG1; FRS2;
RP SRC; SHC; GAP43 AND CTTN.
RX PubMed=11433297; DOI=10.1038/35083041;
RA Cavallaro U., Niedermeyer J., Fuxa M., Christofori G.;
RT "N-CAM modulates tumour-cell adhesion to matrix by inducing FGF-receptor
RT signalling.";
RL Nat. Cell Biol. 3:650-657(2001).
RN [17]
RP INVOLVEMENT IN CANCER.
RX PubMed=11830541;
RA Bange J., Prechtl D., Cheburkin Y., Specht K., Harbeck N., Schmitt M.,
RA Knyazeva T., Mueller S., Gaertner S., Sures I., Wang H., Imyanitov E.,
RA Haering H.U., Knayzev P., Iacobelli S., Hoefler H., Ullrich A.;
RT "Cancer progression and tumor cell motility are associated with the FGFR4
RT Arg(388) allele.";
RL Cancer Res. 62:840-847(2002).
RN [18]
RP INTERACTION WITH FGF1; FGF17; FGF18; FGF19; FGF21 AND FGF23, AND FUNCTION
RP IN STIMULATION 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 [19]
RP INTERACTION WITH FGF19; FGF21 AND KLB, AND FUNCTION IN SIGNALING AND IN
RP REGULATION OF CYP7A1 AND BILE ACID SYNTHESIS.
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 [20]
RP FUNCTION IN STAT1 PHOSPHORYLATION, CATALYTIC ACTIVITY, MUTAGENESIS OF
RP LYS-503, GLYCOSYLATION, AND PHOSPHORYLATION.
RX PubMed=17311277; DOI=10.1002/jcp.21014;
RA Citores L., Bai L., Sorensen V., Olsnes S.;
RT "Fibroblast growth factor receptor-induced phosphorylation of STAT1 at the
RT Golgi apparatus without translocation to the nucleus.";
RL J. Cell. Physiol. 212:148-156(2007).
RN [21]
RP INVOLVEMENT IN CANCER, AND VARIANT ARG-388.
RX PubMed=18756523; DOI=10.1002/ijc.23578;
RA Ma Z., Tsuchiya N., Yuasa T., Inoue T., Kumazawa T., Narita S.,
RA Horikawa Y., Tsuruta H., Obara T., Saito M., Satoh S., Ogawa O.,
RA Habuchi T.;
RT "Polymorphisms of fibroblast growth factor receptor 4 have association with
RT the development of prostate cancer and benign prostatic hyperplasia and the
RT progression of prostate cancer in a Japanese population.";
RL Int. J. Cancer 123:2574-2579(2008).
RN [22]
RP CATALYTIC ACTIVITY, FUNCTION AS FGF1 RECEPTOR AND IN ACTIVATION OF PLCG1;
RP FRS2; MAPK1/ERK2 AND MAPK3/ERK1, ACTIVITY REGULATION, UBIQUITINATION, AND
RP SUBCELLULAR LOCATION.
RX PubMed=18480409; DOI=10.1091/mbc.e07-12-1219;
RA Haugsten E.M., Malecki J., Bjorklund S.M., Olsnes S., Wesche J.;
RT "Ubiquitination of fibroblast growth factor receptor 1 is required for its
RT intracellular sorting but not for its endocytosis.";
RL Mol. Biol. Cell 19:3390-3403(2008).
RN [23]
RP CATALYTIC ACTIVITY, FUNCTION AS FGF2 RECEPTOR AND IN STIMULATION OF CELL
RP PROLIFERATION, SUBCELLULAR LOCATION, INTERACTION WITH FGF2 AND HIP1,
RP PHOSPHORYLATION AT TYR-642 AND TYR-643, INVOLVEMENT IN CANCER, AND
RP CHARACTERIZATION OF VARIANT ARG-388.
RX PubMed=18670643; DOI=10.1593/neo.08450;
RA Wang J., Yu W., Cai Y., Ren C., Ittmann M.M.;
RT "Altered fibroblast growth factor receptor 4 stability promotes prostate
RT cancer progression.";
RL Neoplasia 10:847-856(2008).
RN [24]
RP INVOLVEMENT IN CANCER.
RX PubMed=20638838; DOI=10.1016/j.ejca.2010.06.017;
RA Xu W., Li Y., Wang X., Chen B., Wang Y., Liu S., Xu J., Zhao W., Wu J.;
RT "FGFR4 transmembrane domain polymorphism and cancer risk: a meta-analysis
RT including 8555 subjects.";
RL Eur. J. Cancer 46:3332-3338(2010).
RN [25]
RP FUNCTION IN FGF19 SIGNALING AND IN REGULATION OF BILE ACID SYNTHESIS VIA
RP CYP7A1, INTERACTION WITH FGF19; KL AND KLB, AUTOPHOSPHORYLATION,
RP SUBCELLULAR LOCATION, AND GLYCOSYLATION.
RX PubMed=20683963; DOI=10.1002/hep.23708;
RA Triantis V., Saeland E., Bijl N., Oude-Elferink R.P., Jansen P.L.;
RT "Glycosylation of fibroblast growth factor receptor 4 is a key regulator of
RT fibroblast growth factor 19-mediated down-regulation of cytochrome P450
RT 7A1.";
RL Hepatology 52:656-666(2010).
RN [26]
RP FUNCTION IN HEPATOCYTE PROLIFERATION AND FGF19 SIGNALING.
RX PubMed=20018895; DOI=10.1074/jbc.m109.068783;
RA Wu X., Ge H., Lemon B., Vonderfecht S., Weiszmann J., Hecht R., Gupte J.,
RA Hager T., Wang Z., Lindberg R., Li Y.;
RT "FGF19-induced hepatocyte proliferation is mediated through FGFR4
RT activation.";
RL J. Biol. Chem. 285:5165-5170(2010).
RN [27]
RP FUNCTION IN DOWN-REGULATION OF MMP14, AUTOPHOSPHORYLATION, AND INTERACTION
RP WITH MMP14.
RX PubMed=20798051; DOI=10.1073/pnas.0914459107;
RA Sugiyama N., Varjosalo M., Meller P., Lohi J., Chan K.M., Zhou Z.,
RA Alitalo K., Taipale J., Keski-Oja J., Lehti K.;
RT "FGF receptor-4 (FGFR4) polymorphism acts as an activity switch of a
RT membrane type 1 matrix metalloproteinase-FGFR4 complex.";
RL Proc. Natl. Acad. Sci. U.S.A. 107:15786-15791(2010).
RN [28]
RP INVOLVEMENT IN CANCER, AND VARIANT ARG-388.
RX PubMed=21349172; DOI=10.1186/1471-2407-11-84;
RA Xu B., Tong N., Chen S.Q., Hua L.X., Wang Z.J., Zhang Z.D., Chen M.;
RT "FGFR4 Gly388Arg polymorphism contributes to prostate cancer development
RT and progression: a meta-analysis of 2618 cases and 2305 controls.";
RL BMC Cancer 11:84-84(2011).
RN [29]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [30]
RP INVOLVEMENT IN CANCER.
RX PubMed=21412156; DOI=10.1097/cej.0b013e3283457274;
RA Frullanti E., Berking C., Harbeck N., Jezequel P., Haugen A., Mawrin C.,
RA Parise O. Jr., Sasaki H., Tsuchiya N., Dragani T.A.;
RT "Meta and pooled analyses of FGFR4 Gly388Arg polymorphism as a cancer
RT prognostic factor.";
RL Eur. J. Cancer Prev. 20:340-347(2011).
RN [31]
RP FUNCTION IN FGF19 SIGNALING, FUNCTION IN STIMULATION OF CELL PROLIFERATION
RP AND ACTIVATION OF MAPK1/ERK2 AND MAPK3/ERK1, AND INTERACTION WITH FGF19;
RP KLB AND SULFATED GLYCOSAMINOGLYCANS.
RX PubMed=21653700; DOI=10.1074/jbc.m111.251140;
RA Nakamura M., Uehara Y., Asada M., Honda E., Nagai N., Kimata K., Suzuki M.,
RA Imamura T.;
RT "Sulfated glycosaminoglycans are required for specific and sensitive
RT fibroblast growth factor (FGF) 19 signaling via FGF receptor 4 and
RT betaKlotho.";
RL J. Biol. Chem. 286:26418-26423(2011).
RN [32]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-573, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [33]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-573, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [34]
RP INTERACTION WITH STAT3, INVOLVEMENT IN CANCER, CHARACTERIZATION OF VARIANT
RP ARG-388, AND PHOSPHORYLATION AT TYR-390.
RX PubMed=26675719; DOI=10.1038/nature16449;
RA Ulaganathan V.K., Sperl B., Rapp U.R., Ullrich A.;
RT "Germline variant FGFR4 p.G388R exposes a membrane-proximal STAT3 binding
RT site.";
RL Nature 528:570-574(2015).
RN [35]
RP VARIANTS [LARGE SCALE ANALYSIS] ILE-10; LEU-136; ALA-179; SER-426; ASN-516;
RP MET-550; THR-712 AND ASN-772.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G.,
RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S.,
RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G.,
RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K.,
RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D.,
RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R.,
RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A.,
RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F.,
RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F.,
RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G.,
RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R.,
RA Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
RN [36]
RP REVIEW ON LIGAND SELECTIVITY AND SIGNALING.
RX PubMed=15863030; DOI=10.1016/j.cytogfr.2005.01.001;
RA Eswarakumar V.P., Lax I., Schlessinger J.;
RT "Cellular signaling by fibroblast growth factor receptors.";
RL Cytokine Growth Factor Rev. 16:139-149(2005).
RN [37]
RP REVIEW ON FUNCTION IN FGF SIGNALING.
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 [38]
RP CHARACTERIZATION OF VARIANT ARG-388, AND FUNCTION IN TUMOR CELL INVASION.
RX PubMed=20876804; DOI=10.1158/0008-5472.can-10-1223;
RA Sugiyama N., Varjosalo M., Meller P., Lohi J., Hyytiainen M., Kilpinen S.,
RA Kallioniemi O., Ingvarsen S., Engelholm L.H., Taipale J., Alitalo K.,
RA Keski-Oja J., Lehti K.;
RT "Fibroblast growth factor receptor 4 regulates tumor invasion by coupling
RT fibroblast growth factor signaling to extracellular matrix degradation.";
RL Cancer Res. 70:7851-7861(2010).
CC -!- FUNCTION: Tyrosine-protein kinase that acts as cell-surface receptor
CC for fibroblast growth factors and plays a role in the regulation of
CC cell proliferation, differentiation and migration, and in regulation of
CC lipid metabolism, bile acid biosynthesis, glucose uptake, vitamin D
CC metabolism and phosphate homeostasis. Required for normal down-
CC regulation of the expression of CYP7A1, the rate-limiting enzyme in
CC bile acid synthesis, in response to FGF19. Phosphorylates PLCG1 and
CC FRS2. Ligand binding leads to the activation of several signaling
CC cascades. Activation of PLCG1 leads to the production of the cellular
CC signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate.
CC Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and
CC SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the
CC MAP kinase signaling pathway, as well as of the AKT1 signaling pathway.
CC Promotes SRC-dependent phosphorylation of the matrix protease MMP14 and
CC its lysosomal degradation. FGFR4 signaling is down-regulated by
CC receptor internalization and degradation; MMP14 promotes
CC internalization and degradation of FGFR4. Mutations that lead to
CC constitutive kinase activation or impair normal FGFR4 inactivation lead
CC to aberrant signaling. {ECO:0000269|PubMed:11433297,
CC ECO:0000269|PubMed:16597617, ECO:0000269|PubMed:17311277,
CC ECO:0000269|PubMed:17623664, ECO:0000269|PubMed:18480409,
CC ECO:0000269|PubMed:18670643, ECO:0000269|PubMed:20018895,
CC ECO:0000269|PubMed:20683963, ECO:0000269|PubMed:20798051,
CC ECO:0000269|PubMed:20876804, ECO:0000269|PubMed:21653700,
CC ECO:0000269|PubMed:7518429, ECO:0000269|PubMed:7680645,
CC ECO:0000269|PubMed:8663044}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-
CC [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA-
CC COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858,
CC ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.1;
CC Evidence={ECO:0000255|PROSITE-ProRule:PRU10028,
CC ECO:0000269|PubMed:11433297, ECO:0000269|PubMed:17311277,
CC ECO:0000269|PubMed:18480409, ECO:0000269|PubMed:18670643};
CC -!- ACTIVITY REGULATION: Present in an inactive conformation in the absence
CC of bound ligand. Ligand binding leads to dimerization and activation by
CC autophosphorylation on tyrosine residues.
CC {ECO:0000269|PubMed:18480409}.
CC -!- SUBUNIT: Monomer. Homodimer after ligand binding. Interacts with FGF1,
CC FGF2, FGF4, FGF6, FGF8, FGF9, FGF16, FGF17, FGF18, FGF19, FGF21 and
CC FGF23 (in vitro). Binding affinity for FGF family members is enhanced
CC by interactions between FGFs and heparan sulfate proteoglycans.
CC Interacts with KLB; this strongly increases the affinity for FGF19 and
CC FGF23. Affinity for FGF19 is strongly increased by KLB and sulfated
CC glycosaminoglycans. KLB and KL both interact with the core-glycosylated
CC FGFR4 in the endoplasmic reticulum and promote its degradation, so that
CC only FGFR4 with fully mature N-glycans is expressed at the cell
CC surface. Identified in a complex with NCAM1, CDH2, PLCG1, FRS2, SRC,
CC SHC1, GAP43 and CTTN. Interacts with MMP14 and HIP1 (PubMed:11433297,
CC PubMed:16597617, PubMed:17623664, PubMed:18670643, PubMed:20683963,
CC PubMed:20798051, PubMed:21653700, PubMed:7518429, PubMed:8663044).
CC Interacts with STAT3 (PubMed:26675719). {ECO:0000269|PubMed:11433297,
CC ECO:0000269|PubMed:16597617, ECO:0000269|PubMed:17623664,
CC ECO:0000269|PubMed:18670643, ECO:0000269|PubMed:20683963,
CC ECO:0000269|PubMed:20798051, ECO:0000269|PubMed:21653700,
CC ECO:0000269|PubMed:26675719, ECO:0000269|PubMed:7518429,
CC ECO:0000269|PubMed:8663044}.
CC -!- INTERACTION:
CC P22455; P50281: MMP14; NbExp=6; IntAct=EBI-6256193, EBI-992788;
CC -!- SUBCELLULAR LOCATION: Cell membrane; Single-pass type I membrane
CC protein. Endosome. Endoplasmic reticulum. Note=Internalized from the
CC cell membrane to recycling endosomes, and from there back to the cell
CC membrane.
CC -!- SUBCELLULAR LOCATION: [Isoform 2]: Secreted.
CC -!- SUBCELLULAR LOCATION: [Isoform 3]: Cytoplasm
CC {ECO:0000269|PubMed:11781352}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=P22455-1; Sequence=Displayed;
CC Name=2; Synonyms=Soluble-form;
CC IsoId=P22455-2; Sequence=VSP_035108;
CC Name=3;
CC IsoId=P22455-3; Sequence=VSP_053542;
CC -!- TISSUE SPECIFICITY: Expressed in gastrointestinal epithelial cells,
CC pancreas, and gastric and pancreatic cancer cell lines.
CC {ECO:0000269|PubMed:10631118}.
CC -!- PTM: N-glycosylated. Full maturation of the glycan chains in the Golgi
CC is essential for high affinity interaction with FGF19.
CC -!- PTM: Ubiquitinated. Subject to proteasomal degradation when not fully
CC glycosylated. {ECO:0000269|PubMed:18480409}.
CC -!- PTM: Autophosphorylated. Binding of FGF family members together with
CC heparan sulfate proteoglycan or heparin promotes receptor dimerization
CC and autophosphorylation on tyrosine residues. Autophosphorylation
CC occurs in trans between the two FGFR molecules present in the dimer.
CC {ECO:0000269|PubMed:17311277, ECO:0000269|PubMed:18670643,
CC ECO:0000269|PubMed:7518429}.
CC -!- DISEASE: Note=FGFR4 variants may be involved in the pathogenesis of
CC various cancers. Variant Arg-388 predisposes cancer patients to
CC accelerated disease progression and may be associated with poor
CC prognosis. It has been found in prostate cancer as well as cancers of
CC the breast, colon, head and neck, larynx, lung, skin.
CC {ECO:0000269|PubMed:11781352, ECO:0000269|PubMed:11830541,
CC ECO:0000269|PubMed:18670643, ECO:0000269|PubMed:18756523,
CC ECO:0000269|PubMed:20638838, ECO:0000269|PubMed:20876804,
CC ECO:0000269|PubMed:21349172, ECO:0000269|PubMed:21412156,
CC ECO:0000269|PubMed:21882254, ECO:0000269|PubMed:26675719}.
CC -!- MISCELLANEOUS: [Isoform 3]: Lacks a signal peptide. Constitutively
CC phosphorylated. {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein
CC kinase family. Fibroblast growth factor receptor subfamily.
CC {ECO:0000255|PROSITE-ProRule:PRU00159}.
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/fgfr4/";
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/FGFR4ID512ch5q35.html";
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DR EMBL; X57205; CAA40490.1; -; mRNA.
DR EMBL; L03840; AAB59389.1; -; mRNA.
DR EMBL; AF202063; AAF27432.1; -; mRNA.
DR EMBL; Y13901; CAA74200.1; -; Genomic_DNA.
DR EMBL; AF359246; AAK51435.1; -; mRNA.
DR EMBL; JN007471; AEO19712.1; -; mRNA.
DR EMBL; JN007472; AEO19713.1; -; mRNA.
DR EMBL; JN007473; AEO19714.1; -; mRNA.
DR EMBL; JN007474; AEO19715.1; -; mRNA.
DR EMBL; JN007475; AEO19716.1; -; mRNA.
DR EMBL; JN007476; AEO19717.1; -; mRNA.
DR EMBL; JN007477; AEO19718.1; -; mRNA.
DR EMBL; JN007478; AEO19719.1; -; mRNA.
DR EMBL; JN007479; AEO19720.1; -; mRNA.
DR EMBL; JN007480; AEO19721.1; -; mRNA.
DR EMBL; JN007481; AEO19722.1; -; mRNA.
DR EMBL; JN007482; AEO19723.1; -; mRNA.
DR EMBL; AF487555; AAM13666.1; -; Genomic_DNA.
DR EMBL; EF571596; ABQ01235.1; -; Genomic_DNA.
DR EMBL; AC027314; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471195; EAW85036.1; -; Genomic_DNA.
DR EMBL; BC011847; AAH11847.1; -; mRNA.
DR EMBL; M59373; AAA63208.1; -; mRNA.
DR CCDS; CCDS4410.1; -. [P22455-1]
DR CCDS; CCDS4411.1; -. [P22455-2]
DR PIR; S15345; TVHUF4.
DR RefSeq; NP_001278909.1; NM_001291980.1.
DR RefSeq; NP_002002.3; NM_002011.4. [P22455-1]
DR RefSeq; NP_075252.2; NM_022963.3. [P22455-2]
DR RefSeq; NP_998812.1; NM_213647.2. [P22455-1]
DR RefSeq; XP_005265895.1; XM_005265838.3.
DR PDB; 4QQ5; X-ray; 2.20 A; A=445-753.
DR PDB; 4QQC; X-ray; 2.40 A; A=445-753.
DR PDB; 4QQJ; X-ray; 1.68 A; A=445-753.
DR PDB; 4QQT; X-ray; 1.50 A; A=445-753.
DR PDB; 4QRC; X-ray; 1.90 A; A=445-753.
DR PDB; 4R6V; X-ray; 2.35 A; A=445-753.
DR PDB; 4TYE; X-ray; 2.80 A; A=447-753.
DR PDB; 4TYG; X-ray; 2.40 A; A=447-753.
DR PDB; 4TYI; X-ray; 3.40 A; A=447-753.
DR PDB; 4TYJ; X-ray; 2.45 A; A=447-753.
DR PDB; 4UXQ; X-ray; 1.85 A; A=447-753.
DR PDB; 4XCU; X-ray; 1.71 A; A=449-751.
DR PDB; 5JKG; X-ray; 2.35 A; A=445-753.
DR PDB; 5NUD; X-ray; 2.50 A; A/B=449-753.
DR PDB; 5NWZ; X-ray; 2.37 A; A/B=449-753.
DR PDB; 5XFF; X-ray; 2.70 A; A=445-753.
DR PDB; 5XFJ; X-ray; 3.25 A; A=445-753.
DR PDB; 6IUO; X-ray; 2.30 A; A=445-753.
DR PDB; 6IUP; X-ray; 2.00 A; A=445-753.
DR PDB; 6J6Y; X-ray; 2.15 A; A/D=141-244.
DR PDB; 6JPE; X-ray; 1.60 A; A=445-753.
DR PDB; 6JPJ; X-ray; 2.64 A; A=445-753.
DR PDB; 6NVG; X-ray; 1.99 A; A=450-751.
DR PDB; 6NVH; X-ray; 1.90 A; A=450-751.
DR PDB; 6NVI; X-ray; 2.12 A; A=450-751.
DR PDB; 6NVJ; X-ray; 2.30 A; A=450-751.
DR PDB; 6NVK; X-ray; 2.30 A; A=450-751.
DR PDB; 6V9C; X-ray; 1.90 A; A=449-751.
DR PDB; 6YI8; X-ray; 2.13 A; A/B=447-753.
DR PDB; 7DTZ; X-ray; 2.01 A; A=445-753.
DR PDB; 7F3M; X-ray; 2.29 A; A=445-753.
DR PDB; 7N1J; X-ray; 2.99 A; A/C=245-355.
DR PDB; 7V29; X-ray; 1.98 A; A/B=445-753.
DR PDB; 7VJL; X-ray; 2.90 A; A/B=453-753.
DR PDB; 7WCT; X-ray; 2.11 A; A=445-753.
DR PDB; 7WCW; X-ray; 2.32 A; A=445-753.
DR PDB; 7WCX; X-ray; 2.17 A; A=445-753.
DR PDBsum; 4QQ5; -.
DR PDBsum; 4QQC; -.
DR PDBsum; 4QQJ; -.
DR PDBsum; 4QQT; -.
DR PDBsum; 4QRC; -.
DR PDBsum; 4R6V; -.
DR PDBsum; 4TYE; -.
DR PDBsum; 4TYG; -.
DR PDBsum; 4TYI; -.
DR PDBsum; 4TYJ; -.
DR PDBsum; 4UXQ; -.
DR PDBsum; 4XCU; -.
DR PDBsum; 5JKG; -.
DR PDBsum; 5NUD; -.
DR PDBsum; 5NWZ; -.
DR PDBsum; 5XFF; -.
DR PDBsum; 5XFJ; -.
DR PDBsum; 6IUO; -.
DR PDBsum; 6IUP; -.
DR PDBsum; 6J6Y; -.
DR PDBsum; 6JPE; -.
DR PDBsum; 6JPJ; -.
DR PDBsum; 6NVG; -.
DR PDBsum; 6NVH; -.
DR PDBsum; 6NVI; -.
DR PDBsum; 6NVJ; -.
DR PDBsum; 6NVK; -.
DR PDBsum; 6V9C; -.
DR PDBsum; 6YI8; -.
DR PDBsum; 7DTZ; -.
DR PDBsum; 7F3M; -.
DR PDBsum; 7N1J; -.
DR PDBsum; 7V29; -.
DR PDBsum; 7VJL; -.
DR PDBsum; 7WCT; -.
DR PDBsum; 7WCW; -.
DR PDBsum; 7WCX; -.
DR AlphaFoldDB; P22455; -.
DR SMR; P22455; -.
DR BioGRID; 108555; 226.
DR CORUM; P22455; -.
DR DIP; DIP-5149N; -.
DR IntAct; P22455; 46.
DR MINT; P22455; -.
DR STRING; 9606.ENSP00000292408; -.
DR BindingDB; P22455; -.
DR ChEMBL; CHEMBL3973; -.
DR DrugBank; DB12147; Erdafitinib.
DR DrugBank; DB01109; Heparin.
DR DrugBank; DB11886; Infigratinib.
DR DrugBank; DB09078; Lenvatinib.
DR DrugBank; DB15102; Pemigatinib.
DR DrugBank; DB08901; Ponatinib.
DR DrugCentral; P22455; -.
DR GuidetoPHARMACOLOGY; 1811; -.
DR TCDB; 8.A.23.1.9; the basigin (basigin) family.
DR GlyConnect; 1938; 7 N-Linked glycans (4 sites).
DR GlyGen; P22455; 8 sites, 7 N-linked glycans (4 sites), 1 O-linked glycan (1 site).
DR iPTMnet; P22455; -.
DR PhosphoSitePlus; P22455; -.
DR BioMuta; FGFR4; -.
DR DMDM; 13432140; -.
DR CPTAC; CPTAC-1768; -.
DR EPD; P22455; -.
DR jPOST; P22455; -.
DR MassIVE; P22455; -.
DR MaxQB; P22455; -.
DR PaxDb; P22455; -.
DR PeptideAtlas; P22455; -.
DR PRIDE; P22455; -.
DR ProteomicsDB; 53990; -. [P22455-1]
DR ProteomicsDB; 53991; -. [P22455-2]
DR ABCD; P22455; 1 sequenced antibody.
DR Antibodypedia; 3922; 833 antibodies from 45 providers.
DR DNASU; 2264; -.
DR Ensembl; ENST00000292408.9; ENSP00000292408.4; ENSG00000160867.15. [P22455-1]
DR Ensembl; ENST00000393637.5; ENSP00000377254.1; ENSG00000160867.15. [P22455-2]
DR Ensembl; ENST00000502906.5; ENSP00000424960.1; ENSG00000160867.15. [P22455-1]
DR GeneID; 2264; -.
DR KEGG; hsa:2264; -.
DR MANE-Select; ENST00000292408.9; ENSP00000292408.4; NM_213647.3; NP_998812.1.
DR UCSC; uc003mfl.4; human. [P22455-1]
DR CTD; 2264; -.
DR DisGeNET; 2264; -.
DR GeneCards; FGFR4; -.
DR HGNC; HGNC:3691; FGFR4.
DR HPA; ENSG00000160867; Tissue enhanced (liver, lung).
DR MalaCards; FGFR4; -.
DR MIM; 134935; gene.
DR neXtProt; NX_P22455; -.
DR OpenTargets; ENSG00000160867; -.
DR PharmGKB; PA28130; -.
DR VEuPathDB; HostDB:ENSG00000160867; -.
DR eggNOG; KOG0200; Eukaryota.
DR GeneTree; ENSGT00940000161469; -.
DR HOGENOM; CLU_000288_74_3_1; -.
DR InParanoid; P22455; -.
DR OMA; NRPFGRD; -.
DR OrthoDB; 220433at2759; -.
DR PhylomeDB; P22455; -.
DR TreeFam; TF316307; -.
DR BRENDA; 2.7.10.1; 2681.
DR PathwayCommons; P22455; -.
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-1839128; FGFR4 mutant receptor activation.
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-5655291; Signaling by FGFR4 in disease.
DR Reactome; R-HSA-5673001; RAF/MAP kinase cascade.
DR Reactome; R-HSA-6811558; PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling.
DR SignaLink; P22455; -.
DR SIGNOR; P22455; -.
DR BioGRID-ORCS; 2264; 21 hits in 1111 CRISPR screens.
DR ChiTaRS; FGFR4; human.
DR GeneWiki; Fibroblast_growth_factor_receptor_4; -.
DR GenomeRNAi; 2264; -.
DR Pharos; P22455; Tclin.
DR PRO; PR:P22455; -.
DR Proteomes; UP000005640; Chromosome 5.
DR RNAct; P22455; protein.
DR Bgee; ENSG00000160867; Expressed in right lobe of liver and 110 other tissues.
DR ExpressionAtlas; P22455; baseline and differential.
DR Genevisible; P22455; HS.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB.
DR GO; GO:0005768; C:endosome; IEA:UniProtKB-SubCell.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB.
DR GO; GO:0005887; C:integral component of plasma membrane; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0043235; C:receptor complex; IBA:GO_Central.
DR GO; GO:0030133; C:transport vesicle; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0017134; F:fibroblast growth factor binding; IDA:UniProtKB.
DR GO; GO:0005007; F:fibroblast growth factor receptor activity; IDA:UniProtKB.
DR GO; GO:0008201; F:heparin binding; IDA:UniProtKB.
DR GO; GO:0004714; F:transmembrane receptor protein tyrosine kinase activity; IBA:GO_Central.
DR GO; GO:0016477; P:cell migration; IMP:UniProtKB.
DR GO; GO:0042632; P:cholesterol homeostasis; ISS:UniProtKB.
DR GO; GO:0008543; P:fibroblast growth factor receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0042593; P:glucose homeostasis; ISS:UniProtKB.
DR GO; GO:0018108; P:peptidyl-tyrosine phosphorylation; IDA:UniProtKB.
DR GO; GO:0055062; P:phosphate ion homeostasis; ISS:UniProtKB.
DR GO; GO:0043085; P:positive regulation of catalytic activity; IMP:UniProtKB.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; IDA:UniProtKB.
DR GO; GO:2000573; P:positive regulation of DNA biosynthetic process; IMP:UniProtKB.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IMP:UniProtKB.
DR GO; GO:0010628; P:positive regulation of gene expression; IMP:UniProtKB.
DR GO; GO:0033674; P:positive regulation of kinase activity; IBA:GO_Central.
DR GO; GO:0045862; P:positive regulation of proteolysis; IMP:UniProtKB.
DR GO; GO:0046777; P:protein autophosphorylation; IDA:UniProtKB.
DR GO; GO:0070857; P:regulation of bile acid biosynthetic process; IMP:UniProtKB.
DR GO; GO:0010715; P:regulation of extracellular matrix disassembly; IMP:UniProtKB.
DR GO; GO:0019216; P:regulation of lipid metabolic process; ISS:UniProtKB.
DR GO; GO:0007169; P:transmembrane receptor protein tyrosine kinase signaling pathway; IBA:GO_Central.
DR Gene3D; 2.60.40.10; -; 3.
DR InterPro; IPR016248; FGF_rcpt_fam.
DR InterPro; IPR007110; Ig-like_dom.
DR InterPro; IPR036179; Ig-like_dom_sf.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR013098; Ig_I-set.
DR InterPro; IPR003599; Ig_sub.
DR InterPro; IPR003598; Ig_sub2.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
DR InterPro; IPR008266; Tyr_kinase_AS.
DR InterPro; IPR020635; Tyr_kinase_cat_dom.
DR Pfam; PF07679; I-set; 1.
DR Pfam; PF07714; PK_Tyr_Ser-Thr; 1.
DR PIRSF; PIRSF000628; FGFR; 1.
DR PRINTS; PR00109; TYRKINASE.
DR SMART; SM00409; IG; 3.
DR SMART; SM00408; IGc2; 3.
DR SMART; SM00219; TyrKc; 1.
DR SUPFAM; SSF48726; SSF48726; 3.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS50835; IG_LIKE; 2.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00109; PROTEIN_KINASE_TYR; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; ATP-binding; Cell membrane; Cytoplasm;
KW Direct protein sequencing; Disulfide bond; Endoplasmic reticulum; Endosome;
KW Glycoprotein; Immunoglobulin domain; Kinase; Membrane; Nucleotide-binding;
KW Phosphoprotein; Receptor; Reference proteome; Repeat; Secreted; Signal;
KW Transferase; Transmembrane; Transmembrane helix; Tyrosine-protein kinase;
KW Ubl conjugation.
FT SIGNAL 1..21
FT /evidence="ECO:0000269|PubMed:15340161"
FT CHAIN 22..802
FT /note="Fibroblast growth factor receptor 4"
FT /id="PRO_0000016787"
FT TOPO_DOM 22..369
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 370..390
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 391..802
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 22..118
FT /note="Ig-like C2-type 1"
FT DOMAIN 152..240
FT /note="Ig-like C2-type 2"
FT DOMAIN 249..349
FT /note="Ig-like C2-type 3"
FT DOMAIN 467..755
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 119..148
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 124..138
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 612
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10028"
FT BINDING 473..481
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 503
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 390
FT /note="Phosphotyrosine; in variant R-388"
FT /evidence="ECO:0000269|PubMed:26675719"
FT MOD_RES 573
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163,
FT ECO:0007744|PubMed:24275569"
FT MOD_RES 642
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:18670643"
FT MOD_RES 643
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:18670643"
FT MOD_RES 754
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:7518429"
FT CARBOHYD 112
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 258
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 290
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 311
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 322
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 57..101
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114"
FT DISULFID 172..224
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114"
FT DISULFID 271..333
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114"
FT VAR_SEQ 1..210
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:11781352"
FT /id="VSP_053542"
FT VAR_SEQ 353..416
FT /note="EEDPTWTAAAPEARYTDIILYASGSLALAVLLLLAGLYRGQALHGRHPRPPA
FT TVQKLSRFPLAR -> GTGRIPHLTCDSLTPAGRTKSPTL (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:10631118"
FT /id="VSP_035108"
FT VARIANT 10
FT /note="V -> I (in dbSNP:rs1966265)"
FT /evidence="ECO:0000269|PubMed:17344846,
FT ECO:0000269|PubMed:21882254, ECO:0000269|Ref.8"
FT /id="VAR_029185"
FT VARIANT 136
FT /note="P -> L (in dbSNP:rs376618)"
FT /evidence="ECO:0000269|PubMed:10631118,
FT ECO:0000269|PubMed:17344846, ECO:0000269|PubMed:21882254,
FT ECO:0000269|Ref.10, ECO:0000269|Ref.7, ECO:0000269|Ref.8"
FT /id="VAR_042211"
FT VARIANT 179
FT /note="T -> A (in dbSNP:rs55675160)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_042212"
FT VARIANT 388
FT /note="G -> R (in cancer cells, may be associated with
FT accelerated disease progression and increased tumor cell
FT motility, possibly due to increased stability of the
FT protease MMP14; leads to phosphorylation at residue Y-390,
FT resulting in prolonged FGFR4 activity; increases
FT interaction with STAT3, resulting in STAT3 phosphorylation
FT and signaling activation.; dbSNP:rs351855)"
FT /evidence="ECO:0000269|PubMed:11781352,
FT ECO:0000269|PubMed:18670643, ECO:0000269|PubMed:18756523,
FT ECO:0000269|PubMed:20876804, ECO:0000269|PubMed:21349172,
FT ECO:0000269|PubMed:21882254, ECO:0000269|PubMed:26675719,
FT ECO:0000269|Ref.8"
FT /id="VAR_014797"
FT VARIANT 426
FT /note="G -> S (in dbSNP:rs55879131)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_046102"
FT VARIANT 516
FT /note="D -> N (in dbSNP:rs34158682)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_042213"
FT VARIANT 529
FT /note="R -> Q (in dbSNP:rs34284947)"
FT /id="VAR_049720"
FT VARIANT 550
FT /note="V -> M (in breast pleomorphic lobular sample;
FT somatic mutation; dbSNP:rs774571806)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_046103"
FT VARIANT 712
FT /note="P -> T (in a lung adenocarcinoma sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_046104"
FT VARIANT 772
FT /note="S -> N (in a lung neuroendocrine carcinoma sample;
FT somatic mutation)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_046105"
FT MUTAGEN 503
FT /note="K->R: Loss of kinase activity."
FT /evidence="ECO:0000269|PubMed:11433297,
FT ECO:0000269|PubMed:17311277"
FT MUTAGEN 754
FT /note="Y->F: Loss of interaction with PLCG1."
FT /evidence="ECO:0000269|PubMed:7518429"
FT CONFLICT 121
FT /note="L -> S (in Ref. 3; AAF27432)"
FT /evidence="ECO:0000305"
FT CONFLICT 194
FT /note="E -> G (in Ref. 3; AAF27432)"
FT /evidence="ECO:0000305"
FT CONFLICT 297
FT /note="D -> V (in Ref. 1; CAA40490)"
FT /evidence="ECO:0000305"
FT STRAND 145..150
FT /evidence="ECO:0007829|PDB:6J6Y"
FT HELIX 152..155
FT /evidence="ECO:0007829|PDB:6J6Y"
FT STRAND 159..163
FT /evidence="ECO:0007829|PDB:6J6Y"
FT STRAND 168..171
FT /evidence="ECO:0007829|PDB:6J6Y"
FT STRAND 174..178
FT /evidence="ECO:0007829|PDB:6J6Y"
FT STRAND 181..186
FT /evidence="ECO:0007829|PDB:6J6Y"
FT STRAND 201..203
FT /evidence="ECO:0007829|PDB:6J6Y"
FT TURN 204..207
FT /evidence="ECO:0007829|PDB:6J6Y"
FT STRAND 208..213
FT /evidence="ECO:0007829|PDB:6J6Y"
FT HELIX 216..218
FT /evidence="ECO:0007829|PDB:6J6Y"
FT STRAND 220..227
FT /evidence="ECO:0007829|PDB:6J6Y"
FT STRAND 232..242
FT /evidence="ECO:0007829|PDB:6J6Y"
FT HELIX 445..448
FT /evidence="ECO:0007829|PDB:4QQ5"
FT TURN 458..460
FT /evidence="ECO:0007829|PDB:4QQT"
FT HELIX 464..466
FT /evidence="ECO:0007829|PDB:4QQT"
FT STRAND 467..474
FT /evidence="ECO:0007829|PDB:4QQT"
FT STRAND 480..487
FT /evidence="ECO:0007829|PDB:4QQT"
FT STRAND 489..493
FT /evidence="ECO:0007829|PDB:6NVH"
FT STRAND 497..504
FT /evidence="ECO:0007829|PDB:4QQT"
FT HELIX 511..527
FT /evidence="ECO:0007829|PDB:4QQT"
FT STRAND 531..533
FT /evidence="ECO:0007829|PDB:5XFJ"
FT STRAND 536..540
FT /evidence="ECO:0007829|PDB:4QQT"
FT STRAND 542..544
FT /evidence="ECO:0007829|PDB:4QQT"
FT STRAND 547..551
FT /evidence="ECO:0007829|PDB:4QQT"
FT HELIX 558..563
FT /evidence="ECO:0007829|PDB:4QQT"
FT TURN 570..572
FT /evidence="ECO:0007829|PDB:6YI8"
FT TURN 577..580
FT /evidence="ECO:0007829|PDB:6JPE"
FT HELIX 586..605
FT /evidence="ECO:0007829|PDB:4QQT"
FT HELIX 615..617
FT /evidence="ECO:0007829|PDB:4QQT"
FT STRAND 618..620
FT /evidence="ECO:0007829|PDB:4QQT"
FT STRAND 626..628
FT /evidence="ECO:0007829|PDB:4QQT"
FT TURN 631..635
FT /evidence="ECO:0007829|PDB:4XCU"
FT HELIX 637..639
FT /evidence="ECO:0007829|PDB:4QQT"
FT STRAND 642..644
FT /evidence="ECO:0007829|PDB:4UXQ"
FT HELIX 652..655
FT /evidence="ECO:0007829|PDB:4QQT"
FT HELIX 658..663
FT /evidence="ECO:0007829|PDB:4QQT"
FT HELIX 668..683
FT /evidence="ECO:0007829|PDB:4QQT"
FT STRAND 689..692
FT /evidence="ECO:0007829|PDB:6NVH"
FT HELIX 695..703
FT /evidence="ECO:0007829|PDB:4QQT"
FT HELIX 716..725
FT /evidence="ECO:0007829|PDB:4QQT"
FT HELIX 730..732
FT /evidence="ECO:0007829|PDB:4QQT"
FT HELIX 736..748
FT /evidence="ECO:0007829|PDB:4QQT"
SQ SEQUENCE 802 AA; 87954 MW; B22B259831BB889F CRC64;
MRLLLALLGV LLSVPGPPVL SLEASEEVEL EPCLAPSLEQ QEQELTVALG QPVRLCCGRA
ERGGHWYKEG SRLAPAGRVR GWRGRLEIAS FLPEDAGRYL CLARGSMIVL QNLTLITGDS
LTSSNDDEDP KSHRDPSNRH SYPQQAPYWT HPQRMEKKLH AVPAGNTVKF RCPAAGNPTP
TIRWLKDGQA FHGENRIGGI RLRHQHWSLV MESVVPSDRG TYTCLVENAV GSIRYNYLLD
VLERSPHRPI LQAGLPANTT AVVGSDVELL CKVYSDAQPH IQWLKHIVIN GSSFGADGFP
YVQVLKTADI NSSEVEVLYL RNVSAEDAGE YTCLAGNSIG LSYQSAWLTV LPEEDPTWTA
AAPEARYTDI ILYASGSLAL AVLLLLAGLY RGQALHGRHP RPPATVQKLS RFPLARQFSL
ESGSSGKSSS SLVRGVRLSS SGPALLAGLV SLDLPLDPLW EFPRDRLVLG KPLGEGCFGQ
VVRAEAFGMD PARPDQASTV AVKMLKDNAS DKDLADLVSE MEVMKLIGRH KNIINLLGVC
TQEGPLYVIV ECAAKGNLRE FLRARRPPGP DLSPDGPRSS EGPLSFPVLV SCAYQVARGM
QYLESRKCIH RDLAARNVLV TEDNVMKIAD FGLARGVHHI DYYKKTSNGR LPVKWMAPEA
LFDRVYTHQS DVWSFGILLW EIFTLGGSPY PGIPVEELFS LLREGHRMDR PPHCPPELYG
LMRECWHAAP SQRPTFKQLV EALDKVLLAV SEEYLDLRLT FGPYSPSGGD ASSTCSSSDS
VFSHDPLPLG SSSFPFGSGV QT
