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MGP001077

UniProt Annotations

Entry Information
Gene Namefibroblast growth factor receptor 4
Protein EntryFGFR4_HUMAN
UniProt IDP22455
SpeciesHuman
Comments
Comment typeDescription
Alternative ProductsEvent=Alternative splicing; Named isoforms=3; Name=1; IsoId=P22455-1; Sequence=Displayed; Name=2; Synonyms=Soluble-form; IsoId=P22455-2; Sequence=VSP_035108; Name=3; IsoId=P22455-3; Sequence=VSP_053542; Note=Lacks a signal peptide. Constitutively phosphorylated.;
Catalytic ActivityATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate. {ECO:0000255|PROSITE- ProRule:PRU10028, ECO:0000269|PubMed:11433297, ECO:0000269|PubMed:17311277, ECO:0000269|PubMed:18480409, ECO:0000269|PubMed:18670643}.
Enzyme RegulationPresent in an inactive conformation in the absence of bound ligand. Ligand binding leads to dimerization and activation by autophosphorylation on tyrosine residues. {ECO:0000269|PubMed:18480409}.
FunctionTyrosine-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. {ECO:0000269|PubMed:11433297, ECO:0000269|PubMed:16597617, ECO:0000269|PubMed:17311277, ECO:0000269|PubMed:17623664, ECO:0000269|PubMed:18480409, ECO:0000269|PubMed:18670643, ECO:0000269|PubMed:20018895, ECO:0000269|PubMed:20683963, ECO:0000269|PubMed:20798051, ECO:0000269|PubMed:20876804, ECO:0000269|PubMed:21653700, ECO:0000269|PubMed:7518429, ECO:0000269|PubMed:7680645, ECO:0000269|PubMed:8663044}.
PtmAutophosphorylated. 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. {ECO:0000269|PubMed:17311277, ECO:0000269|PubMed:18670643, ECO:0000269|PubMed:7518429}.
PtmN-glycosylated. Full maturation of the glycan chains in the Golgi is essential for high affinity interaction with FGF19.
PtmUbiquitinated. Subject to proteasomal degradation when not fully glycosylated. {ECO:0000269|PubMed:18480409}.
SimilarityBelongs to the protein kinase superfamily. Tyr protein kinase family. Fibroblast growth factor receptor subfamily. {ECO:0000255|PROSITE-ProRule:PRU00159}.
SimilarityContains 1 protein kinase domain. {ECO:0000255|PROSITE-ProRule:PRU00159}.
SimilarityContains 3 Ig-like C2-type (immunoglobulin-like) domains. {ECO:0000305}.
Subcellular LocationCell 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.
Subcellular LocationIsoform 2: Secreted.
Subcellular LocationIsoform 3: Cytoplasm {ECO:0000269|PubMed:11781352}.
SubunitMonomer. 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. {ECO:0000269|PubMed:11433297, ECO:0000269|PubMed:16597617, ECO:0000269|PubMed:17623664, ECO:0000269|PubMed:18670643, ECO:0000269|PubMed:20683963, ECO:0000269|PubMed:20798051, ECO:0000269|PubMed:21653700, ECO:0000269|PubMed:7518429, ECO:0000269|PubMed:8663044}.
Tissue SpecificityExpressed in gastrointestinal epithelial cells, pancreas, and gastric and pancreatic cancer cell lines. {ECO:0000269|PubMed:10631118}.
Web ResourceName=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/FGFR4ID512ch5q35.html";
Web ResourceName=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/fgfr4/";
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