UniProtKB - Q03142 (FGFR4_MOUSE)
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Protein
Fibroblast growth factor receptor 4
Gene
Fgfr4
Organism
Mus musculus (Mouse)
Status
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 key | Position(s) | DescriptionActions | Graphical view | Length |
|---|---|---|---|---|
| Binding sitei | 500 | ATPPROSITE-ProRule annotation | 1 | |
| Active sitei | 609 | Proton acceptorPROSITE-ProRule annotation | 1 |
Regions
| Feature key | Position(s) | DescriptionActions | Graphical view | Length |
|---|---|---|---|---|
| Nucleotide bindingi | 470 – 478 | ATPPROSITE-ProRule annotation | 9 |
GO - Molecular functioni
- ATP binding Source: UniProtKB-KW
- fibroblast growth factor-activated receptor activity Source: UniProtKB
- fibroblast growth factor binding Source: UniProtKB
- heparin binding Source: UniProtKB
GO - Biological processi
- alveolar secondary septum development Source: MGI
- cell migration Source: UniProtKB
- fibroblast growth factor receptor signaling pathway Source: MGI
- 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: MGI
- 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
Keywordsi
| Molecular function | Kinase, Receptor, Transferase, Tyrosine-protein kinase |
| Ligand | ATP-binding, Nucleotide-binding |
Enzyme and pathway databases
| BRENDAi | 2.7.10.1. 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 |
| Organismi | Mus musculus (Mouse) |
| Taxonomic identifieri | 10090 [NCBI] |
| Taxonomic lineagei | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Myomorpha › Muroidea › Muridae › Murinae › Mus › Mus |
| Proteomesi |
|
Organism-specific databases
| MGIi | MGI:95525. Fgfr4. |
Subcellular locationi
- Cell membrane 1 Publication; Single-pass type I membrane protein 1 Publication
- Endosome By similarity
- Endoplasmic reticulum By similarity
Note: Internalized from the cell membrane to recycling endosomes, and from there back to the cell membrane.By similarity
Topology
| Feature key | Position(s) | DescriptionActions | Graphical view | Length |
|---|---|---|---|---|
| Topological domaini | 17 – 366 | ExtracellularSequence analysisAdd BLAST | 350 | |
| Transmembranei | 367 – 387 | HelicalSequence analysisAdd BLAST | 21 | |
| Topological domaini | 388 – 799 | CytoplasmicSequence analysisAdd BLAST | 412 |
GO - Cellular componenti
- endoplasmic reticulum Source: UniProtKB
- endosome Source: UniProtKB-SubCell
- Golgi apparatus Source: MGI
- integral component of plasma membrane Source: UniProtKB
- plasma membrane Source: MGI
- transport vesicle Source: MGI
Keywords - Cellular componenti
Cell membrane, Endoplasmic reticulum, Endosome, MembranePathology & 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 key | Position(s) | DescriptionActions | Graphical view | Length |
|---|---|---|---|---|
| Mutagenesisi | 385 | G → R: Results in increased cell proliferation. Results in STAT3 phosphorylation and signaling activation. 1 Publication | 1 |
Chemistry databases
| ChEMBLi | CHEMBL3839. |
PTM / Processingi
Molecule processing
| Feature key | Position(s) | DescriptionActions | Graphical view | Length |
|---|---|---|---|---|
| Signal peptidei | 1 – 16 | Sequence analysisAdd BLAST | 16 | |
| ChainiPRO_0000016788 | 17 – 799 | Fibroblast growth factor receptor 4Add BLAST | 783 |
Amino acid modifications
| Feature key | Position(s) | DescriptionActions | Graphical view | Length |
|---|---|---|---|---|
| Disulfide bondi | 54 ↔ 98 | PROSITE-ProRule annotation | ||
| Glycosylationi | 109 | N-linked (GlcNAc...) asparagineSequence analysis | 1 | |
| Disulfide bondi | 169 ↔ 221 | PROSITE-ProRule annotation | ||
| Glycosylationi | 255 | N-linked (GlcNAc...) asparagineSequence analysis | 1 | |
| Disulfide bondi | 268 ↔ 330 | PROSITE-ProRule annotation | ||
| Glycosylationi | 287 | N-linked (GlcNAc...) asparagineSequence analysis | 1 | |
| Glycosylationi | 308 | N-linked (GlcNAc...) asparagine1 Publication | 1 | |
| Glycosylationi | 319 | N-linked (GlcNAc...) asparagineSequence analysis | 1 | |
| Modified residuei | 570 | PhosphoserineBy similarity | 1 | |
| Modified residuei | 639 | Phosphotyrosine; by autocatalysisBy similarity | 1 | |
| Modified residuei | 640 | Phosphotyrosine; by autocatalysisBy similarity | 1 | |
| Modified residuei | 751 | Phosphotyrosine; by autocatalysisBy similarity | 1 |
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 conjugationProteomic databases
| MaxQBi | Q03142. |
| PaxDbi | Q03142. |
| PRIDEi | Q03142. |
PTM databases
| iPTMneti | Q03142. |
| PhosphoSitePlusi | Q03142. |
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
| Bgeei | ENSMUSG00000005320. |
| CleanExi | MM_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
- fibroblast growth factor binding Source: UniProtKB
Protein-protein interaction databases
| BioGridi | 199660. 2 interactors. |
| DIPi | DIP-58508N. |
| STRINGi | 10090.ENSMUSP00000005452. |
Chemistry databases
| BindingDBi | Q03142. |
Structurei
3D structure databases
| ProteinModelPortali | Q03142. |
| SMRi | Q03142. |
| ModBasei | Search... |
| MobiDBi | Search... |
Family & Domainsi
Domains and Repeats
| Feature key | Position(s) | DescriptionActions | Graphical view | Length |
|---|---|---|---|---|
| Domaini | 17 – 115 | Ig-like C2-type 1Add BLAST | 99 | |
| Domaini | 149 – 237 | Ig-like C2-type 2Add BLAST | 89 | |
| Domaini | 246 – 346 | Ig-like C2-type 3Add BLAST | 101 | |
| Domaini | 464 – 752 | Protein kinasePROSITE-ProRule annotationAdd BLAST | 289 |
Sequence similaritiesi
Belongs to the protein kinase superfamily. Tyr protein kinase family. Fibroblast growth factor receptor subfamily.PROSITE-ProRule annotation
Keywords - Domaini
Immunoglobulin domain, Repeat, Signal, Transmembrane, Transmembrane helixPhylogenomic databases
| eggNOGi | KOG0200. Eukaryota. COG0515. LUCA. |
| HOGENOMi | HOG000263410. |
| HOVERGENi | HBG000345. |
| InParanoidi | Q03142. |
| KOi | K05095. |
| PhylomeDBi | Q03142. |
| TreeFami | TF316307. |
Family and domain databases
| Gene3Di | 2.60.40.10. 3 hits. |
| InterProi | View protein in InterPro IPR016248. 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. |
| Pfami | View protein in Pfam PF07679. I-set. 1 hit. PF07714. Pkinase_Tyr. 1 hit. |
| PIRSFi | PIRSF000628. FGFR. 1 hit. |
| PRINTSi | PR00109. TYRKINASE. |
| SMARTi | View protein in SMART SM00409. IG. 3 hits. SM00408. IGc2. 3 hits. SM00219. TyrKc. 1 hit. |
| SUPFAMi | SSF48726. SSF48726. 3 hits. SSF56112. SSF56112. 1 hit. |
| PROSITEi | View protein in PROSITE PS50835. IG_LIKE. 2 hits. PS00107. PROTEIN_KINASE_ATP. 1 hit. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00109. PROTEIN_KINASE_TYR. 1 hit. |
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.
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
Experimental Info
| Feature key | Position(s) | DescriptionActions | Graphical view | Length |
|---|---|---|---|---|
| Sequence conflicti | 172 – 173 | AG → CR in CAA42551 (PubMed:1723680).Curated | 2 | |
| Sequence conflicti | 309 | S → I in CAA42551 (PubMed:1723680).Curated | 1 | |
| Sequence conflicti | 313 | E → Q in CAA42551 (PubMed:1723680).Curated | 1 | |
| Sequence conflicti | 474 | C → CFGQVVRAEA in CAA42551 (PubMed:1723680).Curated | 1 | |
| Sequence conflicti | 673 | E → G in ABD43187 (PubMed:18186042).Curated | 1 | |
| Sequence conflicti | 673 | E → G in BAC39292 (PubMed:16141072).Curated | 1 | |
| Sequence conflicti | 673 | E → G in AAH33313 (PubMed:15489334).Curated | 1 | |
| Sequence conflicti | 726 | A → V in AAH33313 (PubMed:15489334).Curated | 1 |
Alternative sequence
| Feature key | Position(s) | DescriptionActions | Graphical view | Length |
|---|---|---|---|---|
| Alternative sequenceiVSP_017545 | 670 – 715 | Missing in isoform 2. 1 PublicationAdd BLAST | 46 |
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. |
| CCDSi | CCDS26540.1. [Q03142-1] |
| PIRi | S18209. |
| RefSeqi | NP_032037.2. NM_008011.2. |
| UniGenei | Mm.276715. |
Genome annotation databases
| GeneIDi | 14186. |
| KEGGi | mmu:14186. |
| UCSCi | uc007qqb.1. mouse. [Q03142-1] uc011yzq.1. mouse. [Q03142-2] |
Keywords - Coding sequence diversityi
Alternative splicingSimilar 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. |
Entry informationi
| Entry namei | FGFR4_MOUSE | |
| Accessioni | Q03142Primary (citable) accession number: Q03142 Secondary accession number(s): Q27Q87 Q8CIB8 | |
| Entry historyi | Integrated into UniProtKB/Swiss-Prot: | October 1, 1994 |
| Last sequence update: | March 21, 2006 | |
| Last modified: | May 10, 2017 | |
| This is version 173 of the entry and version 3 of the sequence. See complete history. | ||
| Entry statusi | Reviewed (UniProtKB/Swiss-Prot) | |
| Annotation program | Chordata Protein Annotation Program | |
Miscellaneousi
Keywords - Technical termi
Complete proteome, Reference proteomeDocuments
- MGD cross-references
Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot - Human and mouse protein kinases
Human and mouse protein kinases: classification and index - SIMILARITY comments
Index of protein domains and families
