P22455 (FGFR4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Fibroblast growth factor receptor 4
Short name=FGFR-4
EC=2.7.10.1

Alternative name(s):
CD_antigen=CD334

Gene names

Name:	FGFR4
Synonyms:	JTK2, TKF

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	802 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays a role in the regulation of cell proliferation, differentiation and migration, and in regulation of lipid metabolism, bile acid biosynthesis, glucose uptake, vitamin D metabolism and phosphate homeostasis. Required for normal down-regulation of the expression of CYP7A1, the rate-limiting enzyme in bile acid synthesis, in response to FGF19. Phosphorylates PLCG1 and FRS2. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Promotes SRC-dependent phosphorylation of the matrix protease MMP14 and its lysosomal degradation. FGFR4 signaling is down-regulated by receptor internalization and degradation; MMP14 promotes internalization and degradation of FGFR4. Mutations that lead to constitutive kinase activation or impair normal FGFR4 inactivation lead to aberrant signaling. Ref.2 Ref.12 Ref.13 Ref.14 Ref.15 Ref.16 Ref.17 Ref.18 Ref.20 Ref.21 Ref.22 Ref.23 Ref.24 Ref.28
Catalytic activity	ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate. Ref.14 Ref.17 Ref.18 Ref.20
Enzyme regulation	Present in an inactive conformation in the absence of bound ligand. Ligand binding leads to dimerization and activation by autophosphorylation on tyrosine residues. Ref.18
Subunit structure	Monomer. Homodimer after ligand binding. Interacts with FGF1, FGF2, FGF4, FGF6, FGF8, FGF9, FGF16, FGF17, FGF18, FGF19, FGF21 and FGF23 (in vitro). Binding affinity for FGF family members is enhanced by interactions between FGFs and heparan sulfate proteoglycans. Interacts with KLB; this strongly increases the affinity for FGF19 and FGF23. Affinity for FGF19 is strongly increased by KLB and sulfated glycosaminoglycans. KLB and KL both interact with the core-glycosylated FGFR4 in the endoplasmic reticulum and promote its degradation, so that only FGFR4 with fully mature N-glycans is expressed at the cell surface. Identified in a complex with NCAM1, CDH2, PLCG1, FRS2, SRC, SHC1, GAP43 and CTTN. Interacts with MMP14 and HIP1. Ref.12 Ref.13 Ref.14 Ref.15 Ref.16 Ref.20 Ref.21 Ref.23 Ref.24
Subcellular location	Cell membrane; Single-pass type I membrane protein. Endosome. Endoplasmic reticulum. Note: Internalized from the cell membrane to recycling endosomes, and from there back to the cell membrane. Ref.3 Ref.18 Ref.20 Ref.21 Isoform 2: Secreted Ref.3 Ref.18 Ref.20 Ref.21.
Tissue specificity	Expressed in gastrointestinal epithelial cells, pancreas, and gastric and pancreatic cancer cell lines. Ref.3
Post-translational modification	N-glycosylated. Full maturation of the glycan chains in the Golgi is essential for high affinity interaction with FGF19. Ref.17 Ref.21 Ubiquitinated. Subject to proteasomal degradation when not fully glycosylated. Ref.17 Ref.21 Autophosphorylated. Binding of FGF family members together with heparan sulfate proteoglycan or heparin promotes receptor dimerization and autophosphorylation on tyrosine residues. Autophosphorylation occurs in trans between the two FGFR molecules present in the dimer. Ref.12 Ref.17 Ref.20 Ref.21 Ref.23
Sequence similarities	Belongs to the protein kinase superfamily. Tyr protein kinase family. Fibroblast growth factor receptor subfamily. Contains 3 Ig-like C2-type (immunoglobulin-like) domains. Contains 1 protein kinase domain.

Ontologies

Keywords
Cellular component	Cell membrane Endoplasmic reticulum Endosome Membrane Secreted
Coding sequence diversity	Alternative splicing Polymorphism
Domain	Immunoglobulin domain Repeat Signal Transmembrane Transmembrane helix
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Receptor Transferase Tyrosine-protein kinase
PTM	Disulfide bond Glycoprotein Phosphoprotein Ubl conjugation
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	alveolar secondary septum development Inferred from electronic annotation. Source: Compara cell migration Inferred from mutant phenotype Ref.28. Source: UniProtKB glucose homeostasis Inferred from sequence or structural similarity. Source: UniProtKB insulin receptor signaling pathway Traceable author statement. Source: Reactome organ induction Inferred from electronic annotation. Source: Compara peptidyl-tyrosine phosphorylation Inferred from direct assay Ref.18Ref.21. Source: UniProtKB phosphate ion homeostasis Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of DNA biosynthetic process Inferred from mutant phenotype Ref.24. Source: UniProtKB positive regulation of ERK1 and ERK2 cascade Inferred from mutant phenotype Ref.24. Source: UniProtKB positive regulation of cell proliferation Inferred from direct assay Ref.13. Source: UniProtKB positive regulation of metalloenzyme activity Inferred from mutant phenotype Ref.23. Source: UniProtKB positive regulation of proteolysis Inferred from mutant phenotype Ref.23. Source: UniProtKB protein autophosphorylation Inferred from direct assay Ref.23. Source: UniProtKB regulation of bile acid biosynthetic process Inferred from mutant phenotype Ref.16Ref.21. Source: UniProtKB regulation of cholesterol homeostasis Inferred from sequence or structural similarity. Source: UniProtKB regulation of extracellular matrix disassembly Inferred from mutant phenotype Ref.28. Source: UniProtKB
Cellular_component	endoplasmic reticulum Inferred from direct assay Ref.21. Source: UniProtKB endosome Inferred from electronic annotation. Source: UniProtKB-SubCell extracellular region Inferred from electronic annotation. Source: UniProtKB-SubCell integral to plasma membrane Inferred from direct assay Ref.21. Source: UniProtKB nucleus Inferred from direct assay. Source: HPA
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW fibroblast growth factor binding Inferred from direct assay Ref.18Ref.13. Source: UniProtKB fibroblast growth factor-activated receptor activity Inferred from direct assay Ref.18Ref.24Ref.13. Source: UniProtKB heparin binding Inferred from direct assay Ref.18. Source: UniProtKB
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P22455-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: P22455-2)

Also known as: Soluble-form;

The sequence of this isoform differs from the canonical sequence as follows:
     353-416: EEDPTWTAAA...QKLSRFPLAR → GTGRIPHLTCDSLTPAGRTKSPTL

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 21

21

Ref.11

Chain

22 – 802

781

Fibroblast growth factor receptor 4

PRO_0000016787

Regions

Topological domain

22 – 369

348

Extracellular Potential

Transmembrane

370 – 390

21

Helical; Potential

Topological domain

391 – 802

412

Cytoplasmic Potential

Domain

22 – 118

97

Ig-like C2-type 1

Domain

152 – 240

89

Ig-like C2-type 2

Domain

249 – 349

101

Ig-like C2-type 3

Domain

467 – 755

289

Protein kinase

Nucleotide binding

473 – 481

9

ATP By similarity

Sites

Active site

612

1

Proton acceptor By similarity

Binding site

503

1

ATP By similarity

Amino acid modifications

Modified residue

573

1

Phosphoserine Ref.19

Modified residue

642

1

Phosphotyrosine; by autocatalysis Ref.20

Modified residue

643

1

Phosphotyrosine; by autocatalysis Ref.20

Modified residue

754

1

Phosphotyrosine; by autocatalysis Ref.12

Glycosylation

112

1

N-linked (GlcNAc...) Potential

Glycosylation

258

1

N-linked (GlcNAc...) Potential

Glycosylation

290

1

N-linked (GlcNAc...) Potential

Glycosylation

311

1

N-linked (GlcNAc...) Potential

Glycosylation

322

1

N-linked (GlcNAc...) Potential

Disulfide bond

57 ↔ 101

By similarity

Disulfide bond

172 ↔ 224

By similarity

Disulfide bond

271 ↔ 333

By similarity

Natural variations

Alternative sequence

353 – 416

64

EEDPT…FPLAR → GTGRIPHLTCDSLTPAGRTK SPTL in isoform 2.

VSP_035108

Natural variant

10

1

V → I. Ref.6 Ref.25
Corresponds to variant rs1966265 [ dbSNP | Ensembl ].

VAR_029185

Natural variant

136

1

P → L. Ref.3 Ref.5 Ref.6 Ref.8 Ref.25
Corresponds to variant rs376618 [ dbSNP | Ensembl ].

VAR_042211

Natural variant

179

1

T → A. Ref.25
Corresponds to variant rs55675160 [ dbSNP | Ensembl ].

VAR_042212

Natural variant

388

1

G → R Prolonged FGFR4 activity, increased cell motility and tumor cell invasion, possibly due to increased stability of the protease MMP14. Ref.6 Ref.20 Ref.28
Corresponds to variant rs351855 [ dbSNP | Ensembl ].

VAR_014797

Natural variant

426

1

G → S. Ref.25
Corresponds to variant rs55879131 [ dbSNP | Ensembl ].

VAR_046102

Natural variant

516

1

D → N. Ref.25
Corresponds to variant rs34158682 [ dbSNP | Ensembl ].

VAR_042213

Natural variant

529

1

R → Q.
Corresponds to variant rs34284947 [ dbSNP | Ensembl ].

VAR_049720

Natural variant

550

1

V → M in breast pleomorphic lobular sample; somatic mutation. Ref.25

VAR_046103

Natural variant

712

1

P → T in a lung adenocarcinoma sample; somatic mutation. Ref.25

VAR_046104

Natural variant

772

1

S → N in a lung neuroendocrine carcinoma sample; somatic mutation. Ref.25

VAR_046105

Experimental info

Mutagenesis

503

1

K → R: Loss of kinase activity. Ref.14 Ref.17

Mutagenesis

754

1

Y → F: Loss of interaction with PLCG1. Ref.12

Sequence conflict

121

1

L → S in AAF27432. Ref.3

Sequence conflict

194

1

E → G in AAF27432. Ref.3

Sequence conflict

297

1

D → V in CAA40490. Ref.1

Secondary structure

1

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802

Helix Strand Turn

Details...

Beta strand

45 – 47

3

Beta strand

65 – 67

3

Beta strand

75 – 81

7

Helix

93 – 95

3

Beta strand

100 – 102

3

Beta strand

114 – 116

3

Beta strand

160 – 163

4

Beta strand

168 – 171

4

Turn

176 – 178

3

Turn

180 – 183

4

Beta strand

189 – 191

3

Turn

192 – 194

3

Beta strand

199 – 205

7

Beta strand

208 – 213

6

Helix

216 – 218

3

Beta strand

220 – 227

8

Beta strand

229 – 242

14

Beta strand

256 – 260

5

Beta strand

263 – 265

3

Beta strand

267 – 271

5

Beta strand

273 – 275

3

Beta strand

277 – 285

9

Beta strand

295 – 298

4

Beta strand

301 – 304

4

Beta strand

312 – 322

11

Helix

325 – 327

3

Beta strand

331 – 336

6

Beta strand

342 – 349

8

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified April 27, 2001. Version 2. Checksum: B22B259831BB889F	FASTA	802	87,954
	10 20 30 40 50 60 MRLLLALLGV LLSVPGPPVL SLEASEEVEL EPCLAPSLEQ QEQELTVALG QPVRLCCGRA 70 80 90 100 110 120 ERGGHWYKEG SRLAPAGRVR GWRGRLEIAS FLPEDAGRYL CLARGSMIVL QNLTLITGDS 130 140 150 160 170 180 LTSSNDDEDP KSHRDPSNRH SYPQQAPYWT HPQRMEKKLH AVPAGNTVKF RCPAAGNPTP 190 200 210 220 230 240 TIRWLKDGQA FHGENRIGGI RLRHQHWSLV MESVVPSDRG TYTCLVENAV GSIRYNYLLD 250 260 270 280 290 300 VLERSPHRPI LQAGLPANTT AVVGSDVELL CKVYSDAQPH IQWLKHIVIN GSSFGADGFP 310 320 330 340 350 360 YVQVLKTADI NSSEVEVLYL RNVSAEDAGE YTCLAGNSIG LSYQSAWLTV LPEEDPTWTA 370 380 390 400 410 420 AAPEARYTDI ILYASGSLAL AVLLLLAGLY RGQALHGRHP RPPATVQKLS RFPLARQFSL 430 440 450 460 470 480 ESGSSGKSSS SLVRGVRLSS SGPALLAGLV SLDLPLDPLW EFPRDRLVLG KPLGEGCFGQ 490 500 510 520 530 540 VVRAEAFGMD PARPDQASTV AVKMLKDNAS DKDLADLVSE MEVMKLIGRH KNIINLLGVC 550 560 570 580 590 600 TQEGPLYVIV ECAAKGNLRE FLRARRPPGP DLSPDGPRSS EGPLSFPVLV SCAYQVARGM 610 620 630 640 650 660 QYLESRKCIH RDLAARNVLV TEDNVMKIAD FGLARGVHHI DYYKKTSNGR LPVKWMAPEA 670 680 690 700 710 720 LFDRVYTHQS DVWSFGILLW EIFTLGGSPY PGIPVEELFS LLREGHRMDR PPHCPPELYG 730 740 750 760 770 780 LMRECWHAAP SQRPTFKQLV EALDKVLLAV SEEYLDLRLT FGPYSPSGGD ASSTCSSSDS 790 800 VFSHDPLPLG SSSFPFGSGV QT
	Isoform 2 (Soluble-form) [UniParc]. Checksum: BECABBA4E04A35BC	FASTA	762	83,452
	10 20 30 40 50 60 MRLLLALLGV LLSVPGPPVL SLEASEEVEL EPCLAPSLEQ QEQELTVALG QPVRLCCGRA 70 80 90 100 110 120 ERGGHWYKEG SRLAPAGRVR GWRGRLEIAS FLPEDAGRYL CLARGSMIVL QNLTLITGDS 130 140 150 160 170 180 LTSSNDDEDP KSHRDPSNRH SYPQQAPYWT HPQRMEKKLH AVPAGNTVKF RCPAAGNPTP 190 200 210 220 230 240 TIRWLKDGQA FHGENRIGGI RLRHQHWSLV MESVVPSDRG TYTCLVENAV GSIRYNYLLD 250 260 270 280 290 300 VLERSPHRPI LQAGLPANTT AVVGSDVELL CKVYSDAQPH IQWLKHIVIN GSSFGADGFP 310 320 330 340 350 360 YVQVLKTADI NSSEVEVLYL RNVSAEDAGE YTCLAGNSIG LSYQSAWLTV LPGTGRIPHL 370 380 390 400 410 420 TCDSLTPAGR TKSPTLQFSL ESGSSGKSSS SLVRGVRLSS SGPALLAGLV SLDLPLDPLW 430 440 450 460 470 480 EFPRDRLVLG KPLGEGCFGQ VVRAEAFGMD PARPDQASTV AVKMLKDNAS DKDLADLVSE 490 500 510 520 530 540 MEVMKLIGRH KNIINLLGVC TQEGPLYVIV ECAAKGNLRE FLRARRPPGP DLSPDGPRSS 550 560 570 580 590 600 EGPLSFPVLV SCAYQVARGM QYLESRKCIH RDLAARNVLV TEDNVMKIAD FGLARGVHHI 610 620 630 640 650 660 DYYKKTSNGR LPVKWMAPEA LFDRVYTHQS DVWSFGILLW EIFTLGGSPY PGIPVEELFS 670 680 690 700 710 720 LLREGHRMDR PPHCPPELYG LMRECWHAAP SQRPTFKQLV EALDKVLLAV SEEYLDLRLT 730 740 750 760 FGPYSPSGGD ASSTCSSSDS VFSHDPLPLG SSSFPFGSGV QT

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"FGFR-4, a novel acidic fibroblast growth factor receptor with a distinct expression pattern." Partanen J.M., Maekelae T.P., Eerola E., Korhonen J., Hirvonen H., Claesson-Welsh L., Alitalo K. EMBO J. 10:1347-1354(1991) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[2]	"Fibroblast growth factor receptor 4 is a high affinity receptor for both acidic and basic fibroblast growth factor but not for keratinocyte growth factor." Ron D., Reich R., Chedid M., Lengel C., Cohen O.E., Chan A.M., Neufeld G., Miki T., Tronick S.R. J. Biol. Chem. 268:5388-5394(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION AS RECEPTOR FOR FGF1 AND FGF2. Tissue: Mammary gland.
[3]	"Identification of a novel alternative splicing of human FGF receptor 4: soluble-form splice variant expressed in human gastrointestinal epithelial cells." Takaishi S., Sawada M., Morita Y., Seno H., Fukuzawa H., Chiba T. Biochem. Biophys. Res. Commun. 267:658-662(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), VARIANT LEU-136, TISSUE SPECIFICITY, SUBCELLULAR LOCATION. Tissue: Intestine.
[4]	"Genomic structure and complete sequence of the human FGFR4 gene." Kostrzewa M., Muller U. Mamm. Genome 9:131-135(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[5]	"Sequence variation in fibroblast growth factor receptors 3 and 4." Lind D.L., Cox D.R. Submitted (FEB-2002) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT LEU-136.
[6]	NIEHS SNPs program Submitted (APR-2007) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS ILE-10; LEU-136 AND ARG-388.
[7]	"The DNA sequence and comparative analysis of human chromosome 5." Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S., Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M., She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S. , Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M., Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M., Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R., Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N., Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M. Nature 431:268-274(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[8]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], VARIANT LEU-136.
[9]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Tissue: Muscle.
[10]	"Putative tyrosine kinases expressed in K-562 human leukemia cells." Partanen J., Maekelae T.P., Alitalo R., Lehvaeslaiho H., Alitalo K. Proc. Natl. Acad. Sci. U.S.A. 87:8913-8917(1990) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 609-676. Tissue: Blood.
[11]	"Signal peptide prediction based on analysis of experimentally verified cleavage sites." Zhang Z., Henzel W.J. Protein Sci. 13:2819-2824(2004) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 22-38.
[12]	"Signal transduction by fibroblast growth factor receptor-4 (FGFR-4). Comparison with FGFR-1." Vainikka S., Joukov V., Wennstrom S., Bergman M., Pelicci P.G., Alitalo K. J. Biol. Chem. 269:18320-18326(1994) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION AS FGF1 RECEPTOR AND IN ACTIVATION OF SIGNALING VIA PLCG1 AND PIK3R1, INTERACTION WITH PLCG1, PHOSPHORYLATION AT TYR-754, MUTAGENESIS OF TYR-754.
[13]	"Receptor specificity of the fibroblast growth factor family." Ornitz D.M., Xu J., Colvin J.S., McEwen D.G., MacArthur C.A., Coulier F., Gao G., Goldfarb M. J. Biol. Chem. 271:15292-15297(1996) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH FGF1; FGF2; FGF4; FGF6; FGF8 AND FGF9, FUNCTION IN CELL PROLIFERATION.
[14]	"N-CAM modulates tumour-cell adhesion to matrix by inducing FGF-receptor signalling." Cavallaro U., Niedermeyer J., Fuxa M., Christofori G. Nat. Cell Biol. 3:650-657(2001) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN CELL DIFFERENTIATION, MUTAGENESIS OF LYS-503, CATALYTIC ACTIVITY, IDENTIFICATION IN A COMPLEX WITH NCAM1; CDH2; PLCG1; FRS2; SRC; SHC; GAP43 AND CTTN.
[15]	"Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family." Zhang X., Ibrahimi O.A., Olsen S.K., Umemori H., Mohammadi M., Ornitz D.M. J. Biol. Chem. 281:15694-15700(2006) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH FGF1; FGF17; FGF18; FGF19; FGF21 AND FGF23, FUNCTION IN STIMULATION OF CELL PROLIFERATION.
[16]	"Tissue-specific expression of betaKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21." Kurosu H., Choi M., Ogawa Y., Dickson A.S., Goetz R., Eliseenkova A.V., Mohammadi M., Rosenblatt K.P., Kliewer S.A., Kuro-o M. J. Biol. Chem. 282:26687-26695(2007) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH FGF19; FGF21 AND KLB, FUNCTION IN SIGNALING AND IN REGULATION OF CYP7A1 AND BILE ACID SYNTHESIS.
[17]	"Fibroblast growth factor receptor-induced phosphorylation of STAT1 at the Golgi apparatus without translocation to the nucleus." Citores L., Bai L., Sorensen V., Olsnes S. J. Cell. Physiol. 212:148-156(2007) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN STAT1 PHOSPHORYLATION, CATALYTIC ACTIVITY, MUTAGENESIS OF LYS-503, GLYCOSYLATION, PHOSPHORYLATION.
[18]	"Ubiquitination of fibroblast growth factor receptor 1 is required for its intracellular sorting but not for its endocytosis." Haugsten E.M., Malecki J., Bjorklund S.M., Olsnes S., Wesche J. Mol. Biol. Cell 19:3390-3403(2008) [PubMed] [Europe PMC] [Abstract] Cited for: CATALYTIC ACTIVITY, FUNCTION AS FGF1 RECEPTOR AND IN ACTIVATION OF PLCG1; FRS2; MAPK1/ERK2 AND MAPK3/ERK1, ENZYME REGULATION, UBIQUITINATION, SUBCELLULAR LOCATION.
[19]	"Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle." Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M. Mol. Cell 31:438-448(2008) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-573, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[20]	"Altered fibroblast growth factor receptor 4 stability promotes prostate cancer progression." Wang J., Yu W., Cai Y., Ren C., Ittmann M.M. Neoplasia 10:847-856(2008) [PubMed] [Europe PMC] [Abstract] Cited for: CATALYTIC ACTIVITY, FUNCTION AS FGF2 RECEPTOR AND IN STIMULATION OF CELL PROLIFERATION, SUBCELLULAR LOCATION, INTERACTION WITH FGF2 AND HIP1, PHOSPHORYLATION AT TYR-642 AND TYR-643, CHARACTERIZATION OF VARIANT ARG-388.
[21]	"Glycosylation of fibroblast growth factor receptor 4 is a key regulator of fibroblast growth factor 19-mediated down-regulation of cytochrome P450 7A1." Triantis V., Saeland E., Bijl N., Oude-Elferink R.P., Jansen P.L. Hepatology 52:656-666(2010) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN FGF19 SIGNALING AND IN REGULATION OF BILE ACID SYNTHESIS VIA CYP7A1, INTERACTION WITH FGF19; KL AND KLB, AUTOPHOSPHORYLATION, SUBCELLULAR LOCATION, GLYCOSYLATION.
[22]	"FGF19-induced hepatocyte proliferation is mediated through FGFR4 activation." Wu X., Ge H., Lemon B., Vonderfecht S., Weiszmann J., Hecht R., Gupte J., Hager T., Wang Z., Lindberg R., Li Y. J. Biol. Chem. 285:5165-5170(2010) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN HEPATOCYTE PROLIFERATION AND FGF19 SIGNALING.
[23]	"FGF receptor-4 (FGFR4) polymorphism acts as an activity switch of a membrane type 1 matrix metalloproteinase-FGFR4 complex." Sugiyama N., Varjosalo M., Meller P., Lohi J., Chan K.M., Zhou Z., Alitalo K., Taipale J., Keski-Oja J., Lehti K. Proc. Natl. Acad. Sci. U.S.A. 107:15786-15791(2010) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN DOWN-REGULATION OF MMP14, AUTOPHOSPHORYLATION, INTERACTION WITH MMP14.
[24]	"Sulfated glycosaminoglycans are required for specific and sensitive fibroblast growth factor (FGF) 19 signaling via FGF receptor 4 and betaKlotho." Nakamura M., Uehara Y., Asada M., Honda E., Nagai N., Kimata K., Suzuki M., Imamura T. J. Biol. Chem. 286:26418-26423(2011) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN FGF19 SIGNALING, FUNCTION IN STIMULATION OF CELL PROLIFERATION AND ACTIVATION OF MAPK1/ERK2 AND MAPK3/ERK1, INTERACTION WITH FGF19; KLB AND SULFATED GLYCOSAMINOGLYCANS.
[25]	"Patterns of somatic mutation in human cancer genomes." Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R. Nature 446:153-158(2007) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] ILE-10; LEU-136; ALA-179; SER-426; ASN-516; MET-550; THR-712 AND ASN-772.
[26]	"Cellular signaling by fibroblast growth factor receptors." Eswarakumar V.P., Lax I., Schlessinger J. Cytokine Growth Factor Rev. 16:139-149(2005) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON LIGAND SELECTIVITY AND SIGNALING.
[27]	"Fibroblast growth factor signalling: from development to cancer." Turner N., Grose R. Nat. Rev. Cancer 10:116-129(2010) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON FUNCTION IN FGF SIGNALING.
[28]	"Fibroblast growth factor receptor 4 regulates tumor invasion by coupling fibroblast growth factor signaling to extracellular matrix degradation." Sugiyama N., Varjosalo M., Meller P., Lohi J., Hyytiainen M., Kilpinen S., Kallioniemi O., Ingvarsen S., Engelholm L.H., Taipale J., Alitalo K., Keski-Oja J., Lehti K. Cancer Res. 70:7851-7861(2010) [PubMed] [Europe PMC] [Abstract] Cited for: CHARACTERIZATION OF VARIANT ARG-388, FUNCTION IN TUMOR CELL INVASION.
+	Additional computationally mapped references.

Web resources

NIEHS-SNPs

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

X57205 mRNA. Translation: CAA40490.1.
L03840 mRNA. Translation: AAB59389.1.
AF202063 mRNA. Translation: AAF27432.1.
Y13901 Genomic DNA. Translation: CAA74200.1.
AF487555 Genomic DNA. Translation: AAM13666.1.
EF571596 Genomic DNA. Translation: ABQ01235.1.
AC027314 Genomic DNA. No translation available.
CH471195 Genomic DNA. Translation: EAW85036.1.
BC011847 mRNA. Translation: AAH11847.1.
M59373 mRNA. Translation: AAA63208.1.

IPI

IPI00304578.
IPI00420109.

PIR

TVHUF4. S15345.

RefSeq

NP_002002.3. NM_002011.3.
NP_075252.2. NM_022963.2.
NP_998812.1. NM_213647.1.

UniGene

Hs.165950.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1QCT	model	-	B/E	36-353	[»]

ProteinModelPortal

P22455.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-5149N.

IntAct

P22455. 1 interaction.

STRING

9606.ENSP00000292408.

Protein family/group databases

MEROPS

I43.001.

PTM databases

PhosphoSite

P22455.

Polymorphism databases

DMDM

13432140.

Proteomic databases

PaxDb

P22455.

PRIDE

P22455.

Protocols and materials databases

DNASU

2264.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000292408; ENSP00000292408; ENSG00000160867.
ENST00000292410; ENSP00000292410; ENSG00000160867.
ENST00000393637; ENSP00000377254; ENSG00000160867.
ENST00000502906; ENSP00000424960; ENSG00000160867.

GeneID

2264.

KEGG

hsa:2264.

UCSC

uc003mfl.3. human.
uc003mfo.3. human.

Organism-specific databases

CTD

2264.

GeneCards

GC05P176513.

HGNC

HGNC:3691. FGFR4.

HPA

CAB005196.
HPA027273.
HPA027369.
HPA028251.

MIM

134935. gene.

neXtProt

NX_P22455.

PharmGKB

PA28130.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0515.

HOGENOM

HOG000263410.

HOVERGEN

HBG000345.

KO

K05095.

OrthoDB

EOG490789.

PhylomeDB

P22455.

Enzyme and pathway databases

BRENDA

2.7.10.1. 2681.

Pathway_Interaction_DB

fgf_pathway. FGF signaling pathway.

Reactome

REACT_111102. Signal Transduction.
REACT_116125. Disease.
REACT_6900. Immune System.

Gene expression databases

ArrayExpress

P22455.

Bgee

P22455.

CleanEx

HS_FGFR4.

Genevestigator

P22455.

GermOnline

ENSG00000160867. Homo sapiens.

Family and domain databases

Gene3D

2.60.40.10. 3 hits.

InterPro

IPR007110. Ig-like_dom.
IPR013783. Ig-like_fold.
IPR013098. Ig_I-set.
IPR003598. Ig_sub2.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_cat_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
IPR008266. Tyr_kinase_AS.
IPR020635. Tyr_kinase_cat_dom.
IPR016248. Tyr_kinase_fibroblast_GF_rcpt.
[Graphical view]

Pfam

PF07679. I-set. 2 hits.
PF07714. Pkinase_Tyr. 1 hit.
[Graphical view]

PIRSF

PIRSF000628. FGFR. 1 hit.

PRINTS

PR00109. TYRKINASE.

SMART

SM00408. IGc2. 3 hits.
SM00219. TyrKc. 1 hit.
[Graphical view]

SUPFAM

SSF56112. Kinase_like. 1 hit.

PROSITE

PS50835. IG_LIKE. 2 hits.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00109. PROTEIN_KINASE_TYR. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

P22455.

ChEMBL

CHEMBL3973.

ChiTaRS

FGFR4. human.

DrugBank

DB00039. Palifermin.

GenomeRNAi

2264.

NextBio

9195.

SOURCE

Search...

Entry information

Entry name

FGFR4_HUMAN

Accession

Primary (citable) accession number: P22455
Secondary accession number(s): O43785 , Q14309, Q71TW8, Q8TDA0

Entry history

Integrated into UniProtKB/Swiss-Prot:	August 1, 1991
Last sequence update:	April 27, 2001
Last modified:	May 1, 2013
This is version 151 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.