ID:FGFR4_HUMAN DESCRIPTION: RecName: Full=Fibroblast growth factor receptor 4; Short=FGFR-4; EC=2.7.10.1; AltName: CD_antigen=CD334; Flags: Precursor; FUNCTION: 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. Mutations that lead to constitutive kinase activation or impair normal FGFR4 inactivation lead to aberrant signaling. CATALYTIC ACTIVITY: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate. ENZYME REGULATION: Present in an inactive conformation in the absence of bound ligand. Ligand binding leads to dimerization and activation by autophosphorylation on tyrosine residues. 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. SUBCELLULAR LOCATION: Cell membrane; Single-pass type I membrane protein. Endosome. Endoplasmic reticulum. Note=Internalized from the cell mebrane to recycling endosomes, and from there back to the cell membrane. SUBCELLULAR LOCATION: Isoform 2: Secreted. TISSUE SPECIFICITY: Expressed in gastrointestinal epithelial cells, pancreas, and gastric and pancreatic cancer cell lines. PTM: N-glycosylated. Full maturation of the glycan chains in the Golgi is essential for high affinity interaction with FGF19. PTM: Ubiquitinated. Subject to proteasomal degradation when not fully glycosylated. PTM: 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. SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein kinase family. Fibroblast growth factor receptor subfamily. SIMILARITY: Contains 3 Ig-like C2-type (immunoglobulin-like) domains. SIMILARITY: Contains 1 protein kinase domain. WEB RESOURCE: Name=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/fgfr4/";
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on P22455
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Biological Process: GO:0000165 MAPK cascade GO:0006468 protein phosphorylation GO:0008284 positive regulation of cell proliferation GO:0008543 fibroblast growth factor receptor signaling pathway GO:0010628 positive regulation of gene expression GO:0010715 regulation of extracellular matrix disassembly GO:0016310 phosphorylation GO:0016477 cell migration GO:0018108 peptidyl-tyrosine phosphorylation GO:0019216 regulation of lipid metabolic process GO:0036092 phosphatidylinositol-3-phosphate biosynthetic process GO:0042593 glucose homeostasis GO:0042632 cholesterol homeostasis GO:0043085 positive regulation of catalytic activity GO:0045862 positive regulation of proteolysis GO:0046777 protein autophosphorylation GO:0046854 phosphatidylinositol phosphorylation GO:0051897 positive regulation of protein kinase B signaling GO:0055062 phosphate ion homeostasis GO:0070374 positive regulation of ERK1 and ERK2 cascade GO:0070857 regulation of bile acid biosynthetic process GO:2000573 positive regulation of DNA biosynthetic process GO:1903412 response to bile acid
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Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
