| IED ID | IndEnz0002014625 |
| Enzyme Type ID | protease014625 |
| Protein Name |
Fibroblast growth factor receptor 4 FGFR-4 EC 2.7.10.1 CD antigen CD334 |
| Gene Name | FGFR4 JTK2 TKF |
| Organism | Homo sapiens (Human) |
| Taxonomic Lineage | cellular organisms Eukaryota Opisthokonta Metazoa Eumetazoa Bilateria Deuterostomia Chordata Craniata Vertebrata Gnathostomata (jawed vertebrates) Teleostomi Euteleostomi Sarcopterygii Dipnotetrapodomorpha Tetrapoda Amniota Mammalia Theria Eutheria Boreoeutheria Euarchontoglires Primates Haplorrhini Simiiformes Catarrhini Hominoidea (apes) Hominidae (great apes) Homininae Homo Homo sapiens (Human) |
| Enzyme Sequence | MRLLLALLGVLLSVPGPPVLSLEASEEVELEPCLAPSLEQQEQELTVALGQPVRLCCGRAERGGHWYKEGSRLAPAGRVRGWRGRLEIASFLPEDAGRYLCLARGSMIVLQNLTLITGDSLTSSNDDEDPKSHRDPSNRHSYPQQAPYWTHPQRMEKKLHAVPAGNTVKFRCPAAGNPTPTIRWLKDGQAFHGENRIGGIRLRHQHWSLVMESVVPSDRGTYTCLVENAVGSIRYNYLLDVLERSPHRPILQAGLPANTTAVVGSDVELLCKVYSDAQPHIQWLKHIVINGSSFGADGFPYVQVLKTADINSSEVEVLYLRNVSAEDAGEYTCLAGNSIGLSYQSAWLTVLPEEDPTWTAAAPEARYTDIILYASGSLALAVLLLLAGLYRGQALHGRHPRPPATVQKLSRFPLARQFSLESGSSGKSSSSLVRGVRLSSSGPALLAGLVSLDLPLDPLWEFPRDRLVLGKPLGEGCFGQVVRAEAFGMDPARPDQASTVAVKMLKDNASDKDLADLVSEMEVMKLIGRHKNIINLLGVCTQEGPLYVIVECAAKGNLREFLRARRPPGPDLSPDGPRSSEGPLSFPVLVSCAYQVARGMQYLESRKCIHRDLAARNVLVTEDNVMKIADFGLARGVHHIDYYKKTSNGRLPVKWMAPEALFDRVYTHQSDVWSFGILLWEIFTLGGSPYPGIPVEELFSLLREGHRMDRPPHCPPELYGLMRECWHAAPSQRPTFKQLVEALDKVLLAVSEEYLDLRLTFGPYSPSGGDASSTCSSSDSVFSHDPLPLGSSSFPFGSGVQT |
| Enzyme Length | 802 |
| Uniprot Accession Number | P22455 |
| Absorption | |
| Active Site | ACT_SITE 612; /note="Proton acceptor"; /evidence="ECO:0000255|PROSITE-ProRule:PRU00159, ECO:0000255|PROSITE-ProRule:PRU10028" |
| Activity Regulation | 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. {ECO:0000269|PubMed:18480409}. |
| Binding Site | BINDING 503; /note=ATP; /evidence=ECO:0000255|PROSITE-ProRule:PRU00159 |
| Calcium Binding | |
| catalytic Activity | CATALYTIC ACTIVITY: Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-[protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA-COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858, ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.1; Evidence={ECO:0000255|PROSITE-ProRule:PRU10028, ECO:0000269|PubMed:11433297, ECO:0000269|PubMed:17311277, ECO:0000269|PubMed:18480409, ECO:0000269|PubMed:18670643}; |
| DNA Binding | |
| EC Number | 2.7.10.1 |
| Enzyme Function | 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. {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}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | NP_BIND 473..481; /note=ATP; /evidence=ECO:0000255|PROSITE-ProRule:PRU00159 |
| Features | Active site (1); Alternative sequence (2); Beta strand (22); Binding site (1); Chain (1); Compositional bias (1); Disulfide bond (3); Domain (4); Glycosylation (5); Helix (16); Modified residue (5); Mutagenesis (2); Natural variant (10); Nucleotide binding (1); Region (1); Sequence conflict (3); Signal peptide (1); Topological domain (2); Transmembrane (1); Turn (4) |
| Keywords | 3D-structure;ATP-binding;Alternative splicing;Cell membrane;Cytoplasm;Direct protein sequencing;Disulfide bond;Endoplasmic reticulum;Endosome;Glycoprotein;Immunoglobulin domain;Kinase;Membrane;Nucleotide-binding;Phosphoprotein;Receptor;Reference proteome;Repeat;Secreted;Signal;Transferase;Transmembrane;Transmembrane helix;Tyrosine-protein kinase;Ubl conjugation |
| Interact With | P50281 |
| Induction | |
| Subcellular Location | SUBCELLULAR LOCATION: Cell 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 LOCATION: [Isoform 2]: Secreted.; SUBCELLULAR LOCATION: [Isoform 3]: Cytoplasm {ECO:0000269|PubMed:11781352}. |
| Modified Residue | MOD_RES 390; /note="Phosphotyrosine; in variant R-388"; /evidence="ECO:0000269|PubMed:26675719"; MOD_RES 573; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:23186163, ECO:0007744|PubMed:24275569"; MOD_RES 642; /note="Phosphotyrosine; by autocatalysis"; /evidence="ECO:0000269|PubMed:18670643"; MOD_RES 643; /note="Phosphotyrosine; by autocatalysis"; /evidence="ECO:0000269|PubMed:18670643"; MOD_RES 754; /note="Phosphotyrosine; by autocatalysis"; /evidence="ECO:0000269|PubMed:7518429" |
| Post Translational Modification | 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. {ECO:0000269|PubMed:18480409}.; 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. {ECO:0000269|PubMed:17311277, ECO:0000269|PubMed:18670643, ECO:0000269|PubMed:7518429}. |
| Signal Peptide | SIGNAL 1..21; /evidence=ECO:0000269|PubMed:15340161 |
| Structure 3D | X-ray crystallography (30) |
| Cross Reference PDB | 4QQ5; 4QQC; 4QQJ; 4QQT; 4QRC; 4R6V; 4TYE; 4TYG; 4TYI; 4TYJ; 4UXQ; 4XCU; 5JKG; 5NUD; 5NWZ; 5XFF; 5XFJ; 6IUO; 6IUP; 6J6Y; 6JPE; 6JPJ; 6NVG; 6NVH; 6NVI; 6NVJ; 6NVK; 6V9C; 6YI8; 7DTZ; |
| Mapped Pubmed ID | 10579907; 10629055; 10652257; 10918587; 11157491; 11294897; 11353842; 11429702; 11447289; 11689702; 11739186; 11759058; 11958417; 11981041; 11997436; 12373339; 12419216; 12642581; 12660731; 12815007; 12815057; 12974390; 1379698; 1381348; 14534538; 14601095; 14710228; 15070963; 15094036; 15231874; 15448004; 15448205; 15564323; 15750181; 15834429; 15863029; 16012724; 16061909; 16091423; 16091734; 16109476; 16210019; 1656221; 16647110; 16721364; 16822847; 16844695; 16847462; 17084840; 17088904; 17227708; 17339340; 17487277; 17505008; 17519899; 17599042; 17664243; 18056464; 18070145; 18310279; 18315732; 18337450; 18349267; 18373495; 18381441; 18452557; 18487077; 18552176; 18593907; 18606717; 18754654; 18757403; 18762813; 18829560; 18840094; 18949411; 19008009; 19063940; 19103595; 19147536; 19187780; 19237543; 19240166; 19296538; 19381019; 19407855; 19411071; 19500394; 19644473; 19652666; 19730683; 19749790; 19805105; 19809159; 19918264; 19946327; 20066896; 20080590; 20127014; 20147743; 20179196; 20453000; 20522708; 20565774; 20634891; 20644561; 20657013; 20660043; 20691689; 20709759; 20713702; 20844967; 21102635; 21109934; 21160078; 21203561; 21317208; 21368164; 21372320; 21616061; 21622724; 21625954; 21656577; 21666749; 21668414; 21711248; 21827571; 21827948; 21976531; 22034009; 22174695; 22188813; 22241720; 22271411; 22419713; 22439738; 22442730; 22535390; 22573348; 22588880; 22648271; 22802530; 22888118; 22971346; 22986737; 23226373; 23303910; 23344261; 23393200; 23455922; 23481570; 23524567; 23597563; 23901234; 23943801; 23944363; 24126887; 24200957; 24239227; 24248544; 24288432; 24324363; 24410190; 24416997; 24503538; 24550147; 24565842; 24606918; 24625004; 24937142; 25031272; 25070056; 25219510; 25241761; 25317566; 25349422; 25465127; 25640309; 25684949; 25776529; 25860955; 26152288; 26323668; 26431494; 26432329; 26498355; 26551585; 26681731; 26840079; 26856750; 27154171; 27192118; 27447573; 27615514; 27618313; 27640814; 27650548; 27857023; 27966451; 28056982; 28069043; 28445152; 28445975; 28583379; 28650667; 28919046; 28951455; 29048661; 29402970; 29438108; 29438906; 29569792; 29603419; 29763898; 29884889; 29982249; 30074276; 30108871; 30298149; 30518874; 30541128; 30903103; 31041948; 31074061; 31184820; 31335138; 31350344; 31385026; 31413803; 31527546; 31529503; 31575540; 31601997; 32111983; 32114392; 32236572; 32573490; 32599983; 32677805; 32781755; 32930584; 33017009; 33030342; 33051476; 33062171; 33099480; 33151453; 33446698; 33859803; 34163030; 34400727; 7543144; 7559490; 8264585; 8493579; 8576110; 8622701; 8657148; 8696350; 8780727; 8845844; 9045692; 9182757; 9299490; 9438390; 9480847; 9632781; 9660748; 9857065; |
| Motif | |
| Gene Encoded By | |
| Mass | 87,954 |
| Kinetics | |
| Metal Binding | |
| Rhea ID | RHEA:10596 |
| Cross Reference Brenda | 2.7.10.1; |