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Protein

Fibroblast growth factor receptor 4

Gene

Fgfr4

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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. Plays a role in postnatal lung development. May be involved in the development of skeletal muscle cell lineages.5 Publications

Catalytic activityi

ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.PROSITE-ProRule annotation

Enzyme regulationi

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

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei500ATPPROSITE-ProRule annotation1
Active sitei609Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi470 – 478ATPPROSITE-ProRule annotation9

GO - Molecular functioni

GO - Biological processi

  • alveolar secondary septum development Source: MGI
  • cell migration Source: UniProtKB
  • fibroblast growth factor receptor signaling pathway Source: UniProtKB
  • glucose homeostasis Source: UniProtKB
  • lung development Source: MGI
  • negative regulation of fibroblast growth factor production Source: MGI
  • negative regulation of gene expression Source: MGI
  • organ induction Source: MGI
  • peptidyl-tyrosine phosphorylation Source: UniProtKB
  • phosphate ion homeostasis Source: UniProtKB
  • positive regulation of catalytic activity Source: UniProtKB
  • positive regulation of cell proliferation Source: UniProtKB
  • positive regulation of DNA biosynthetic process Source: UniProtKB
  • positive regulation of ERK1 and ERK2 cascade Source: UniProtKB
  • positive regulation of gene expression Source: MGI
  • positive regulation of parathyroid hormone secretion Source: MGI
  • positive regulation of proteolysis Source: UniProtKB
  • protein autophosphorylation Source: UniProtKB
  • regulation of bile acid biosynthetic process Source: UniProtKB
  • regulation of cholesterol homeostasis Source: UniProtKB
  • regulation of extracellular matrix disassembly Source: UniProtKB
  • regulation of lipid metabolic process Source: UniProtKB
  • regulation of phosphorus metabolic process Source: MGI
  • vacuolar phosphate transport Source: MGI
  • vitamin D3 metabolic process Source: MGI
Complete GO annotation...

Keywords - Molecular functioni

Kinase, Receptor, Transferase, Tyrosine-protein kinase

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.10.1. 3474.

Names & Taxonomyi

Protein namesi
Recommended name:
Fibroblast growth factor receptor 4 (EC:2.7.10.1)
Short name:
FGFR-4
Alternative name(s):
Protein-tyrosine kinase receptor MPK-11
CD_antigen: CD334
Gene namesi
Name:Fgfr4
Synonyms:Fgfr-4, Mpk-11
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Unplaced

Organism-specific databases

MGIiMGI:95525. Fgfr4.

Subcellular locationi

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini17 – 366ExtracellularSequence analysisAdd BLAST350
Transmembranei367 – 387HelicalSequence analysisAdd BLAST21
Topological domaini388 – 799CytoplasmicSequence analysisAdd BLAST412

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Endoplasmic reticulum, Endosome, Membrane

Pathology & Biotechi

Disruption phenotypei

No visible phenotype. Mice display an elevated bile acid pool and elevated excretion of bile acids, due to loss of normal regulation of CYP7A1, the rate-limiting enzyme in bile acid synthesis. When on a normal diet, mice are prone to develop increased levels of white adipose tissue, hyperlipidemia, hypercholesterolemia, glucose intolerance and insulin resistance. Mice lacking both FGFR3 and FGFR4 display pronounced dwarfism, and while their lungs appear normal at birth, they are completely blocked in alveogenesis and do not form secondary septae to delimit alveoli. These mice also show elevated serum levels of 1,25-dihydroxyvitamin D3 and reduced serum phosphorus levels.5 Publications

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi385G → R: Results in increased cell proliferation. Results in STAT3 phosphorylation and signaling activation. 1 Publication1

Chemistry databases

ChEMBLiCHEMBL3839.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 16Sequence analysisAdd BLAST16
ChainiPRO_000001678817 – 799Fibroblast growth factor receptor 4Add BLAST783

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi54 ↔ 98PROSITE-ProRule annotation
Glycosylationi109N-linked (GlcNAc...)Sequence analysis1
Disulfide bondi169 ↔ 221PROSITE-ProRule annotation
Glycosylationi255N-linked (GlcNAc...)Sequence analysis1
Disulfide bondi268 ↔ 330PROSITE-ProRule annotation
Glycosylationi287N-linked (GlcNAc...)Sequence analysis1
Glycosylationi308N-linked (GlcNAc...)1 Publication1
Glycosylationi319N-linked (GlcNAc...)Sequence analysis1
Modified residuei570PhosphoserineBy similarity1
Modified residuei639Phosphotyrosine; by autocatalysisBy similarity1
Modified residuei640Phosphotyrosine; by autocatalysisBy similarity1
Modified residuei751Phosphotyrosine; by autocatalysisBy similarity1

Post-translational modificationi

N-glycosylated. Isoform 1 and isoform 2 are glycosylated. Full maturation of the glycan chains in the Golgi is essential for high affinity interaction with FGF19 (By similarity).By similarity
Ubiquitinated. Subject to proteasomal degradation when not fully glycosylated (By similarity).By similarity
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. Isoform 1 and isoform 2 are phosphorylated on tyrosine residues (By similarity).By similarity

Keywords - PTMi

Disulfide bond, Glycoprotein, Phosphoprotein, Ubl conjugation

Proteomic databases

MaxQBiQ03142.
PaxDbiQ03142.
PRIDEiQ03142.

PTM databases

iPTMnetiQ03142.
PhosphoSitePlusiQ03142.

Expressioni

Tissue specificityi

Isoform 1 and isoform 2 are expressed in lung and proliferating myoblasts and myotubes of primary myogenic cells (at protein level). Isoform 1 and isoform 2 are expressed in liver, muscle, spleen, heart, lung, kidney and in primary myogenic cells.2 Publications

Developmental stagei

Expressed in the developing gut endoderm, in myotomally derived skeletal muscle, the adrenal cortex, kidney and condensing cartilage.1 Publication

Inductioni

Isoform 1 and isoform 2 are up-regulated by estradiol during myogenic differentiation and down-regulated in fully developed myotubes.1 Publication

Gene expression databases

BgeeiENSMUSG00000005320.
CleanExiMM_FGFR4.

Interactioni

Subunit structurei

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. Interacts with STAT3 (By similarity).By similarity

GO - Molecular functioni

Protein-protein interaction databases

BioGridi199660. 2 interactors.
DIPiDIP-58508N.
STRINGi10090.ENSMUSP00000005452.

Chemistry databases

BindingDBiQ03142.

Structurei

3D structure databases

ProteinModelPortaliQ03142.
SMRiQ03142.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini17 – 115Ig-like C2-type 1Add BLAST99
Domaini149 – 237Ig-like C2-type 2Add BLAST89
Domaini246 – 346Ig-like C2-type 3Add BLAST101
Domaini464 – 752Protein kinasePROSITE-ProRule annotationAdd BLAST289

Sequence similaritiesi

Belongs to the protein kinase superfamily. Tyr protein kinase family. Fibroblast growth factor receptor subfamily.PROSITE-ProRule annotation
Contains 1 protein kinase domain.PROSITE-ProRule annotation

Keywords - Domaini

Immunoglobulin domain, Repeat, Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG0200. Eukaryota.
COG0515. LUCA.
HOGENOMiHOG000263410.
HOVERGENiHBG000345.
InParanoidiQ03142.
KOiK05095.
PhylomeDBiQ03142.
TreeFamiTF316307.

Family and domain databases

Gene3Di2.60.40.10. 3 hits.
InterProiIPR016248. FGF_rcpt_fam.
IPR007110. Ig-like_dom.
IPR013783. Ig-like_fold.
IPR013098. Ig_I-set.
IPR003599. Ig_sub.
IPR003598. Ig_sub2.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
IPR008266. Tyr_kinase_AS.
IPR020635. Tyr_kinase_cat_dom.
[Graphical view]
PfamiPF07679. I-set. 1 hit.
PF07714. Pkinase_Tyr. 1 hit.
[Graphical view]
PIRSFiPIRSF000628. FGFR. 1 hit.
PRINTSiPR00109. TYRKINASE.
SMARTiSM00409. IG. 3 hits.
SM00408. IGc2. 3 hits.
SM00219. TyrKc. 1 hit.
[Graphical view]
SUPFAMiSSF48726. SSF48726. 3 hits.
SSF56112. SSF56112. 1 hit.
PROSITEiPS50835. IG_LIKE. 2 hits.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00109. PROTEIN_KINASE_TYR. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q03142-1) [UniParc]FASTAAdd to basket

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.

« Hide

        10         20         30         40         50
MWLLLALLSI FQGTPALSLE ASEEMEQEPC LAPILEQQEQ VLTVALGQPV
60 70 80 90 100
RLCCGRTERG RHWYKEGSRL ASAGRVRGWR GRLEIASFLP EDAGRYLCLA
110 120 130 140 150
RGSMTVVHNL TLLMDDSLTS ISNDEDPKTL SSSSSGHVYP QQAPYWTHPQ
160 170 180 190 200
RMEKKLHAVP AGNTVKFRCP AAGNPMPTIH WLKDGQAFHG ENRIGGIRLR
210 220 230 240 250
HQHWSLVMES VVPSDRGTYT CLVENSLGSI RYSYLLDVLE RSPHRPILQA
260 270 280 290 300
GLPANTTAVV GSDVELLCKV YSDAQPHIQW LKHVVINGSS FGADGFPYVQ
310 320 330 340 350
VLKTTDINSS EVEVLYLRNV SAEDAGEYTC LAGNSIGLSY QSAWLTVLPE
360 370 380 390 400
EDLTWTTATP EARYTDIILY VSGSLVLLVL LLLAGVYHRQ VIRGHYSRQP
410 420 430 440 450
VTIQKLSRFP LARQFSLESR SSGKSSLSLV RGVRLSSSGP PLLTGLVNLD
460 470 480 490 500
LPLDPLWEFP RDRLVLGKPL GEGCFGQVVR AEAFGMDPSR PDQTSTVAVK
510 520 530 540 550
MLKDNASDKD LADLVSEMEV MKLIGRHKNI INLLGVCTQE GPLYVIVECA
560 570 580 590 600
AKGNLREFLR ARRPPGPDLS PDGPRSSEGP LSFPALVSCA YQVARGMQYL
610 620 630 640 650
ESRKCIHRDL AARNVLVTED DVMKIADFGL ARGVHHIDYY KKTSNGRLPV
660 670 680 690 700
KWMAPEALFD RVYTHQSDVW SFEILLWEIF TLGGSPYPGI PVEELFSLLR
710 720 730 740 750
EGHRMERPPN CPSELYGLMR ECWHAAPSQR PTFKQLVEAL DKVLLAVSEE
760 770 780 790
YLDLRLTFGP FSPSNGDASS TCSSSDSVFS HDPLPLEPSP FPFSDSQTT
Length:799
Mass (Da):88,661
Last modified:March 21, 2006 - v3
Checksum:i799E17845CD4021E
GO
Isoform 2 (identifier: Q03142-2) [UniParc]FASTAAdd to basket
Also known as: Fgfr4 lacking exon 16, Fgfr4(-16)

The sequence of this isoform differs from the canonical sequence as follows:
     670-715: Missing.

Show »
Length:753
Mass (Da):83,335
Checksum:i511687E06090ED01
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti172 – 173AG → CR in CAA42551 (PubMed:1723680).Curated2
Sequence conflicti309S → I in CAA42551 (PubMed:1723680).Curated1
Sequence conflicti313E → Q in CAA42551 (PubMed:1723680).Curated1
Sequence conflicti474C → CFGQVVRAEA in CAA42551 (PubMed:1723680).Curated1
Sequence conflicti673E → G in ABD43187 (PubMed:18186042).Curated1
Sequence conflicti673E → G in BAC39292 (PubMed:16141072).Curated1
Sequence conflicti673E → G in AAH33313 (PubMed:15489334).Curated1
Sequence conflicti726A → V in AAH33313 (PubMed:15489334).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_017545670 – 715Missing in isoform 2. 1 PublicationAdd BLAST46

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X59927 mRNA. Translation: CAA42551.1.
DQ388428 mRNA. Translation: ABD43187.1.
AY493377 mRNA. Translation: AAS72387.2.
AK084850 mRNA. Translation: BAC39292.1.
BC033313 mRNA. Translation: AAH33313.1.
X57236 mRNA. Translation: CAA40512.1.
CCDSiCCDS26540.1. [Q03142-1]
PIRiS18209.
RefSeqiNP_032037.2. NM_008011.2.
UniGeneiMm.276715.

Genome annotation databases

GeneIDi14186.
KEGGimmu:14186.
UCSCiuc007qqb.1. mouse. [Q03142-1]
uc011yzq.1. mouse. [Q03142-2]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X59927 mRNA. Translation: CAA42551.1.
DQ388428 mRNA. Translation: ABD43187.1.
AY493377 mRNA. Translation: AAS72387.2.
AK084850 mRNA. Translation: BAC39292.1.
BC033313 mRNA. Translation: AAH33313.1.
X57236 mRNA. Translation: CAA40512.1.
CCDSiCCDS26540.1. [Q03142-1]
PIRiS18209.
RefSeqiNP_032037.2. NM_008011.2.
UniGeneiMm.276715.

3D structure databases

ProteinModelPortaliQ03142.
SMRiQ03142.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi199660. 2 interactors.
DIPiDIP-58508N.
STRINGi10090.ENSMUSP00000005452.

Chemistry databases

BindingDBiQ03142.
ChEMBLiCHEMBL3839.

PTM databases

iPTMnetiQ03142.
PhosphoSitePlusiQ03142.

Proteomic databases

MaxQBiQ03142.
PaxDbiQ03142.
PRIDEiQ03142.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

GeneIDi14186.
KEGGimmu:14186.
UCSCiuc007qqb.1. mouse. [Q03142-1]
uc011yzq.1. mouse. [Q03142-2]

Organism-specific databases

CTDi2264.
MGIiMGI:95525. Fgfr4.

Phylogenomic databases

eggNOGiKOG0200. Eukaryota.
COG0515. LUCA.
HOGENOMiHOG000263410.
HOVERGENiHBG000345.
InParanoidiQ03142.
KOiK05095.
PhylomeDBiQ03142.
TreeFamiTF316307.

Enzyme and pathway databases

BRENDAi2.7.10.1. 3474.

Miscellaneous databases

PROiQ03142.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000005320.
CleanExiMM_FGFR4.

Family and domain databases

Gene3Di2.60.40.10. 3 hits.
InterProiIPR016248. FGF_rcpt_fam.
IPR007110. Ig-like_dom.
IPR013783. Ig-like_fold.
IPR013098. Ig_I-set.
IPR003599. Ig_sub.
IPR003598. Ig_sub2.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
IPR008266. Tyr_kinase_AS.
IPR020635. Tyr_kinase_cat_dom.
[Graphical view]
PfamiPF07679. I-set. 1 hit.
PF07714. Pkinase_Tyr. 1 hit.
[Graphical view]
PIRSFiPIRSF000628. FGFR. 1 hit.
PRINTSiPR00109. TYRKINASE.
SMARTiSM00409. IG. 3 hits.
SM00408. IGc2. 3 hits.
SM00219. TyrKc. 1 hit.
[Graphical view]
SUPFAMiSSF48726. SSF48726. 3 hits.
SSF56112. SSF56112. 1 hit.
PROSITEiPS50835. IG_LIKE. 2 hits.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00109. PROTEIN_KINASE_TYR. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiFGFR4_MOUSE
AccessioniPrimary (citable) accession number: Q03142
Secondary accession number(s): Q27Q87
, Q5J7D9, Q8C3V5, Q8CIB8
Entry historyi
Integrated into UniProtKB/Swiss-Prot: October 1, 1994
Last sequence update: March 21, 2006
Last modified: November 2, 2016
This is version 170 of the entry and version 3 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  3. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.