Reviewed, UniProtKB/Swiss-Prot P22455 (FGFR4_HUMAN)

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) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › 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	Receptor for acidic fibroblast growth factor. Does not bind to basic fibroblast growth factor. Binds FGF19.
Catalytic activity	ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
Subunit structure	Interacts with KLB By similarity.
Subcellular location	Membrane; Single-pass type I membrane protein. Note: Isoform 2 may be secreted. Ref.3
Tissue specificity	Expressed in gastrointestinal epithelial cells, pancreas, and gastric and pancreatic cancer cell lines. Ref.3
Post-translational modification	Glycosylated By similarity. Phosphorylated on tyrosine residue By similarity. Phosphorylation requires the presence of a functional (phosphorylated) FGFR1 and not necessarily by means of FGFR heterodimerization By similarity.
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	Membrane
Coding sequence diversity	Alternative splicing Polymorphism
Domain	Immunoglobulin domain Repeat Signal Transmembrane
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Receptor Transferase Tyrosine-protein kinase
PTM	Disulfide bond Glycoprotein Phosphoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing
Gene Ontology (GO)
Biological process	fibroblast growth factor receptor signaling pathway Inferred from genetic interaction. Source: MGI positive regulation of cell proliferation Inferred from genetic interaction. Source: MGI protein amino acid phosphorylation Inferred from electronic annotation. Source: InterPro
Cellular component	integral to plasma membrane Traceable author statement. Source: ProtInc
Molecular function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW fibroblast growth factor binding Inferred from physical interaction. Source: UniProtKB fibroblast growth factor receptor activity Inferred from physical interaction. Source: MGI
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.10

Chain

22 – 802

781

Fibroblast growth factor receptor 4

PRO_0000016787

Regions

Topological domain

22 – 369

348

Extracellular Potential

Transmembrane

370 – 390

21

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.11

Modified residue

643

1

Phosphotyrosine; by autocatalysis By similarity

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

Potential

Disulfide bond

172 ↔ 224

Potential

Disulfide bond

271 ↔ 333

Potential

Natural variations

Alternative sequence

353 – 416

64

EEDPT…FPLAR → GTGRIPHLTCDSLTPAGRTK SPTL in isoform 2.

VSP_035108

Natural variant

10

1

V → I: dbSNP rs1966265. Ref.6 Ref.12

VAR_029185

Natural variant

136

1

P → L: dbSNP rs376618. Ref.3 Ref.6 Ref.12 Ref.5 Ref.7

VAR_042211

Natural variant

179

1

T → A: dbSNP rs55675160. Ref.12

VAR_042212

Natural variant

388

1

G → R: dbSNP rs351855. Ref.6

VAR_014797

Natural variant

426

1

G → S: dbSNP rs55879131. Ref.12

VAR_046102

Natural variant

516

1

D → N: dbSNP rs34158682. Ref.12

VAR_042213

Natural variant

529

1

R → Q: dbSNP rs34284947.

VAR_049720

Natural variant

550

1

V → M in breast pleomorphic lobular sample; somatic mutation. Ref.12

VAR_046103

Natural variant

712

1

P → T in a lung adenocarcinoma sample; somatic mutation. Ref.12

VAR_046104

Natural variant

772

1

S → N in a lung neuroendocrine carcinoma sample; somatic mutation. Ref.12

VAR_046105

Experimental info

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). 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: 1709094] [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: 7680645] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). 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: 10631118] [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: 9457674] [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]	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.
[8]	"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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Tissue: Muscle.
[9]	"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: 2247464] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 609-676. Tissue: Blood.
[10]	"Signal peptide prediction based on analysis of experimentally verified cleavage sites." Zhang Z., Henzel W.J. Protein Sci. 13:2819-2824(2004) [PubMed: 15340161] [Abstract] Cited for: PROTEIN SEQUENCE OF 22-38.
[11]	"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: 18691976] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-573, MASS SPECTROMETRY.
[12]	"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: 17344846] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] ILE-10; LEU-136; ALA-179; SER-426; ASN-516; MET-550; THR-712 AND ASN-772.
+	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.
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.
NP_075252.2.
NP_998812.1.

UniGene

Hs.165950

3D structure databases

PDBe
RCSB PDB
PDBj

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

SMR

P22455. Positions 146-355, 454-747, 464-773.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-5149N.

STRING

P22455.

PTM databases

PhosphoSite

P22455.

Proteomic databases

PRIDE

P22455.

Genome annotation databases

Ensembl

ENST00000292408; ENSP00000292408; ENSG00000160867; Homo sapiens. [Genome view]
ENST00000393648; ENSP00000377259; ENSG00000160867; Homo sapiens. [Genome view]

GeneID

2264.

KEGG

hsa:2264.

UCSC

uc003mfl.1. human.

Organism-specific databases

CTD

2264.

GeneCards

GC05P176446.

H-InvDB

HIX0005452.

HGNC

HGNC:3691. FGFR4.

HPA

CAB005196.

MIM

134935. gene.

PharmGKB

PA28130.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG11483.

HOVERGEN

P22455.

OrthoDB

EOG93JFPX.

PhylomeDB

P22455.

Enzyme and pathway databases

BRENDA

2.7.10.1. 247.

Pathway_Interaction_DB

fgf_pathway. FGF signaling pathway.

Reactome

REACT_9470. Signaling by FGFR.

Gene expression databases

ArrayExpress

P22455.

Bgee

P22455.

CleanEx

HS_FGFR4.

Genevestigator

P22455.

GermOnline

ENSG00000160867. Homo sapiens.

Family and domain databases

InterPro

IPR007110. Ig-like.
IPR013783. Ig-like_fold.
IPR003598. Ig_sub2.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_cat_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR020933. Tyr_kin_fibroblast_GF_rcpt_reg.
IPR016248. Tyr_kinase_fibroblast_GF_rcpt.
IPR020635. Tyr_Pkinase_cat_dom.
IPR020685. Tyr_prot_kinase.
IPR008266. Tyr_prot_kinase_AS.
[Graphical view]

Gene3D

G3DSA:2.60.40.10. Ig-like_fold. 3 hits.

PANTHER

PTHR23256:SF276. Tyr_kinase_fibroblast_GF_rcpt. 1 hit.
PTHR23256. Tyr_prot_kinase. 1 hit.

PIRSF

PIRSF000628. FGFR. 1 hit.

SMART

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

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 Resources

DrugBank

DB00039. Palifermin.

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:	February 9, 2010
This is version 117 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

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.