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P22455 · FGFR4_HUMAN

  • Protein
    Fibroblast growth factor receptor 4
  • Gene
    FGFR4
  • Status
    UniProtKB reviewed (Swiss-Prot)
  • Amino acids
  • Protein existence
    Evidence at protein level
  • Annotation score
    5/5

Function

function

Tyrosine-protein kinase that acts as a 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.

Caution

An additional N-terminally truncated cytoplasmic isoform was previously reported to exist. However, the paper was subsequently retracted due to concerns regarding duplication of panels in some figures.

Catalytic activity

Activity regulation

Present in an inactive conformation in the absence of bound ligand. Ligand binding leads to dimerization and activation by autophosphorylation on tyrosine residues.

Features

Showing features for binding site, active site.

Type
IDPosition(s)Description
Binding site473-481ATP (UniProtKB | ChEBI)
Binding site503ATP (UniProtKB | ChEBI)
Active site612Proton acceptor

GO annotations

AspectTerm
Cellular Componentendoplasmic reticulum
Cellular Componentendosome
Cellular Componentextracellular region
Cellular ComponentGolgi apparatus
Cellular Componentplasma membrane
Cellular Componentreceptor complex
Cellular Componenttransport vesicle
Molecular FunctionATP binding
Molecular Functionfibroblast growth factor binding
Molecular Functionfibroblast growth factor receptor activity
Molecular Functionheparin binding
Biological Processcell migration
Biological Processcholesterol homeostasis
Biological Processfibroblast growth factor receptor signaling pathway
Biological Processglucose homeostasis
Biological Processpeptidyl-tyrosine phosphorylation
Biological Processphosphate ion homeostasis
Biological Processpositive regulation of catalytic activity
Biological Processpositive regulation of cell population proliferation
Biological Processpositive regulation of DNA biosynthetic process
Biological Processpositive regulation of ERK1 and ERK2 cascade
Biological Processpositive regulation of gene expression
Biological Processpositive regulation of proteolysis
Biological Processprotein autophosphorylation
Biological Processregulation of bile acid biosynthetic process
Biological Processregulation of extracellular matrix disassembly
Biological Processregulation of lipid metabolic process

Keywords

Enzyme and pathway databases

Protein family/group databases

Community curation (1)

Community annotation

FGFR4 p.G388R variant increases phosphorylation of STAT3 (at Tyr-705) and thereby enhances STAT3 signaling in CD4(+)CD25(+)FOXP3(+) regulatory T cells in rs351855-A allele SNP knock-in mice; thereby suppresses the expansion of CD8 T cells in the lymph nodes and tumor milieu.

SourceSubmission dateContributor
PubMed:294381080000-0002-4717-6228

Names & Taxonomy

Protein names

  • Recommended name
    Fibroblast growth factor receptor 4
  • EC number
  • Short names
    FGFR-4
  • CD Antigen Name
    • CD334

Gene names

    • Name
      FGFR4
    • Synonyms
      JTK2, TKF
Community curation (1)

Community suggested name: Fibroblast growth factor receptor 4; FGFR4; CD334.

SourceSubmission dateContributor
PubMed:294381080000-0002-4717-6228

Organism names

  • Taxonomic identifier
  • Taxonomic lineage
    Eukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo

Accessions

  • Primary accession
    P22455
  • Secondary accessions
    • G3JVM2
    • G3JVM5
    • G3JVM7
    • G3JVM9
    • O43785

Proteomes

Organism-specific databases

Subcellular Location

Cell membrane ; Single-pass type I membrane protein
Note: Internalized from the cell membrane to recycling endosomes, and from there back to the cell membrane.

Isoform 2

Features

Showing features for topological domain, transmembrane.

Type
IDPosition(s)Description
Topological domain22-369Extracellular
Transmembrane370-390Helical
Topological domain391-802Cytoplasmic

Keywords

Disease & Variants

Involvement in disease

  • FGFR4 variants may be involved in the pathogenesis of various cancers. Variant Arg-388 predisposes cancer patients to accelerated disease progression and may be associated with poor prognosis. It has been found in prostate cancer as well as cancers of the breast, colon, head and neck, larynx, lung, skin

Features

Showing features for natural variant, mutagenesis.

Type
IDPosition(s)Description
Natural variantVAR_02918510in dbSNP:rs1966265
Natural variantVAR_042211136in dbSNP:rs376618
Natural variantVAR_042212179in dbSNP:rs55675160
Natural variantVAR_014797388in cancer cells, may be associated with accelerated disease progression and increased tumor cell motility, possibly due to increased stability of the protease MMP14; leads to phosphorylation at residue Y-390, resulting in prolonged FGFR4 activity; increases interaction with STAT3, resulting in STAT3 phosphorylation and signaling activation.; dbSNP:rs351855
Natural variantVAR_046102426in dbSNP:rs55879131
Mutagenesis503Loss of kinase activity.
Natural variantVAR_042213516in dbSNP:rs34158682
Natural variantVAR_049720529in dbSNP:rs34284947
Natural variantVAR_046103550in breast pleomorphic lobular sample; somatic mutation; dbSNP:rs774571806
Natural variantVAR_046104712in a lung adenocarcinoma sample; somatic mutation
Mutagenesis754Loss of interaction with PLCG1.
Natural variantVAR_046105772in a lung neuroendocrine carcinoma sample; somatic mutation

Variants

We now provide the "Disease & Variants" viewer in its own tab.

The viewer provides 1,816 variants from UniProt as well as other sources including ClinVar and dbSNP.

Go to variant viewer

Organism-specific databases

Miscellaneous

Chemistry

Genetic variation databases

PTM/Processing

Features

Showing features for signal, chain, disulfide bond, glycosylation, modified residue, modified residue (large scale data).

Type
IDPosition(s)Source
Description
Signal1-21UniProt
ChainPRO_000001678722-802UniProtFibroblast growth factor receptor 4
Disulfide bond57↔101UniProt
Glycosylation112UniProtN-linked (GlcNAc...) asparagine
Disulfide bond172↔224UniProt
Glycosylation258UniProtN-linked (GlcNAc...) asparagine
Disulfide bond271↔333UniProt
Glycosylation290UniProtN-linked (GlcNAc...) asparagine
Glycosylation311UniProtN-linked (GlcNAc...) asparagine
Glycosylation322UniProtN-linked (GlcNAc...) asparagine
Modified residue390UniProtPhosphotyrosine; in variant R-388
Modified residue (large scale data)419PRIDEPhosphoserine
Modified residue573UniProtPhosphoserine
Modified residue (large scale data)573PRIDEPhosphoserine
Modified residue642UniProtPhosphotyrosine; by autocatalysis
Modified residue (large scale data)642PRIDEPhosphotyrosine
Modified residue643UniProtPhosphotyrosine; by autocatalysis
Modified residue754UniProtPhosphotyrosine; by autocatalysis

Post-translational modification

N-glycosylated. Full maturation of the glycan chains in the Golgi is essential for high affinity interaction with FGF19.
Ubiquitinated. Subject to proteasomal degradation when not fully glycosylated.
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.

Keywords

Proteomic databases

PTM databases

Expression

Tissue specificity

Expressed in gastrointestinal epithelial cells, pancreas, and gastric and pancreatic cancer cell lines.

Gene expression databases

Organism-specific databases

Interaction

Subunit

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 (PubMed:11433297, PubMed:16597617, PubMed:17623664, PubMed:18670643, PubMed:20683963, PubMed:20798051, PubMed:21653700, PubMed:7518429, PubMed:8663044).
Interacts with STAT3 (PubMed:26675719).

Binary interactions

TypeEntry 1Entry 2Number of experimentsIntAct
BINARY P22455FGFR1 P113623EBI-6256193, EBI-1028277
BINARY P22455MMP14 P502816EBI-6256193, EBI-992788
BINARY P22455RET P079492EBI-6256193, EBI-2480756

Protein-protein interaction databases

Chemistry

Miscellaneous

Family & Domains

Features

Showing features for domain, region, compositional bias.

Type
IDPosition(s)Description
Domain22-118Ig-like C2-type 1
Region119-148Disordered
Compositional bias124-138Basic and acidic residues
Domain152-240Ig-like C2-type 2
Domain249-349Ig-like C2-type 3
Domain467-755Protein kinase

Sequence similarities

Keywords

Phylogenomic databases

Family and domain databases

Sequence & Isoform

Align isoforms (2)
  • Sequence status
    Complete
  • Sequence processing
    The displayed sequence is further processed into a mature form.

This entry describes 2 isoforms produced by Alternative splicing.

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.

  • Length
    802
  • Mass (Da)
    87,954
  • Last updated
    2001-04-27 v2
  • MD5 Checksum
    0C799CD8EB4A963B013291894BF69E69
MRLLLALLGVLLSVPGPPVLSLEASEEVELEPCLAPSLEQQEQELTVALGQPVRLCCGRAERGGHWYKEGSRLAPAGRVRGWRGRLEIASFLPEDAGRYLCLARGSMIVLQNLTLITGDSLTSSNDDEDPKSHRDPSNRHSYPQQAPYWTHPQRMEKKLHAVPAGNTVKFRCPAAGNPTPTIRWLKDGQAFHGENRIGGIRLRHQHWSLVMESVVPSDRGTYTCLVENAVGSIRYNYLLDVLERSPHRPILQAGLPANTTAVVGSDVELLCKVYSDAQPHIQWLKHIVINGSSFGADGFPYVQVLKTADINSSEVEVLYLRNVSAEDAGEYTCLAGNSIGLSYQSAWLTVLPEEDPTWTAAAPEARYTDIILYASGSLALAVLLLLAGLYRGQALHGRHPRPPATVQKLSRFPLARQFSLESGSSGKSSSSLVRGVRLSSSGPALLAGLVSLDLPLDPLWEFPRDRLVLGKPLGEGCFGQVVRAEAFGMDPARPDQASTVAVKMLKDNASDKDLADLVSEMEVMKLIGRHKNIINLLGVCTQEGPLYVIVECAAKGNLREFLRARRPPGPDLSPDGPRSSEGPLSFPVLVSCAYQVARGMQYLESRKCIHRDLAARNVLVTEDNVMKIADFGLARGVHHIDYYKKTSNGRLPVKWMAPEALFDRVYTHQSDVWSFGILLWEIFTLGGSPYPGIPVEELFSLLREGHRMDRPPHCPPELYGLMRECWHAAPSQRPTFKQLVEALDKVLLAVSEEYLDLRLTFGPYSPSGGDASSTCSSSDSVFSHDPLPLGSSSFPFGSGVQT

P22455-2

  • Name
    2
  • Synonyms
    Soluble-form
  • See also
    sequence in UniParc or sequence clusters in UniRef
  • Differences from canonical
    • 353-416: EEDPTWTAAAPEARYTDIILYASGSLALAVLLLLAGLYRGQALHGRHPRPPATVQKLSRFPLAR → GTGRIPHLTCDSLTPAGRTKSPTL

Computationally mapped potential isoform sequences

There are 7 potential isoforms mapped to this entry

View all
EntryEntry nameGene nameLength
J3KPQ0J3KPQ0_HUMANFGFR4734
E7EWF4E7EWF4_HUMANFGFR4201
D6RJD4D6RJD4_HUMANFGFR487
D6RG06D6RG06_HUMANFGFR4114
D6R9V0D6R9V0_HUMANFGFR4108
H0Y9P2H0Y9P2_HUMANFGFR4280
B5A964B5A964_HUMANFGFR472

Features

Showing features for sequence conflict, compositional bias, alternative sequence.

Type
IDPosition(s)Description
Sequence conflict121in Ref. 3; AAF27432
Compositional bias124-138Basic and acidic residues
Sequence conflict194in Ref. 3; AAF27432
Sequence conflict297in Ref. 1; CAA40490
Alternative sequenceVSP_035108353-416in isoform 2

Keywords

Sequence databases

Nucleotide SequenceProtein SequenceMolecule TypeStatus
X57205
EMBL· GenBank· DDBJ
CAA40490.1
EMBL· GenBank· DDBJ
mRNA
L03840
EMBL· GenBank· DDBJ
AAB59389.1
EMBL· GenBank· DDBJ
mRNA
AF202063
EMBL· GenBank· DDBJ
AAF27432.1
EMBL· GenBank· DDBJ
mRNA
Y13901
EMBL· GenBank· DDBJ
CAA74200.1
EMBL· GenBank· DDBJ
Genomic DNA
AF359246
EMBL· GenBank· DDBJ
AAK51435.1
EMBL· GenBank· DDBJ
mRNA
JN007471
EMBL· GenBank· DDBJ
AEO19712.1
EMBL· GenBank· DDBJ
mRNA
JN007472
EMBL· GenBank· DDBJ
AEO19713.1
EMBL· GenBank· DDBJ
mRNA
JN007473
EMBL· GenBank· DDBJ
AEO19714.1
EMBL· GenBank· DDBJ
mRNA
JN007474
EMBL· GenBank· DDBJ
AEO19715.1
EMBL· GenBank· DDBJ
mRNA
JN007475
EMBL· GenBank· DDBJ
AEO19716.1
EMBL· GenBank· DDBJ
mRNA
JN007476
EMBL· GenBank· DDBJ
AEO19717.1
EMBL· GenBank· DDBJ
mRNA
JN007477
EMBL· GenBank· DDBJ
AEO19718.1
EMBL· GenBank· DDBJ
mRNA
JN007478
EMBL· GenBank· DDBJ
AEO19719.1
EMBL· GenBank· DDBJ
mRNA
JN007479
EMBL· GenBank· DDBJ
AEO19720.1
EMBL· GenBank· DDBJ
mRNA
JN007480
EMBL· GenBank· DDBJ
AEO19721.1
EMBL· GenBank· DDBJ
mRNA
JN007481
EMBL· GenBank· DDBJ
AEO19722.1
EMBL· GenBank· DDBJ
mRNA
JN007482
EMBL· GenBank· DDBJ
AEO19723.1
EMBL· GenBank· DDBJ
mRNA
AF487555
EMBL· GenBank· DDBJ
AAM13666.1
EMBL· GenBank· DDBJ
Genomic DNA
EF571596
EMBL· GenBank· DDBJ
ABQ01235.1
EMBL· GenBank· DDBJ
Genomic DNA
AC027314
EMBL· GenBank· DDBJ
-Genomic DNA No translation available.
CH471195
EMBL· GenBank· DDBJ
EAW85036.1
EMBL· GenBank· DDBJ
Genomic DNA
BC011847
EMBL· GenBank· DDBJ
AAH11847.1
EMBL· GenBank· DDBJ
mRNA
M59373
EMBL· GenBank· DDBJ
AAA63208.1
EMBL· GenBank· DDBJ
mRNA

Genome annotation databases

Similar Proteins

Disclaimer

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