FGFR4_RAT
ID FGFR4_RAT Reviewed; 800 AA.
AC Q498D6;
DT 21-MAR-2006, integrated into UniProtKB/Swiss-Prot.
DT 13-SEP-2005, sequence version 1.
DT 03-AUG-2022, entry version 137.
DE RecName: Full=Fibroblast growth factor receptor 4;
DE Short=FGFR-4;
DE EC=2.7.10.1;
DE AltName: CD_antigen=CD334;
DE Flags: Precursor;
GN Name=Fgfr4;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lung;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [2]
RP FUNCTION AS FGF19 RECEPTOR.
RX PubMed=17623664; DOI=10.1074/jbc.m704165200;
RA Kurosu H., Choi M., Ogawa Y., Dickson A.S., Goetz R., Eliseenkova A.V.,
RA Mohammadi M., Rosenblatt K.P., Kliewer S.A., Kuro-o M.;
RT "Tissue-specific expression of betaKlotho and fibroblast growth factor
RT (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21.";
RL J. Biol. Chem. 282:26687-26695(2007).
CC -!- FUNCTION: Tyrosine-protein kinase that acts as cell-surface receptor
CC for fibroblast growth factors and plays a role in the regulation of
CC cell proliferation, differentiation and migration, and in regulation of
CC lipid metabolism, bile acid biosynthesis, glucose uptake, vitamin D
CC metabolism and phosphate homeostasis. Required for normal down-
CC regulation of the expression of CYP7A1, the rate-limiting enzyme in
CC bile acid synthesis, in response to FGF19. Phosphorylates PLCG1 and
CC FRS2. Ligand binding leads to the activation of several signaling
CC cascades. Activation of PLCG1 leads to the production of the cellular
CC signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate.
CC Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and
CC SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the
CC MAP kinase signaling pathway, as well as of the AKT1 signaling pathway.
CC Promotes SRC-dependent phosphorylation of the matrix protease MMP14 and
CC its lysosomal degradation. FGFR4 signaling is down-regulated by
CC receptor internalization and degradation; MMP14 promotes
CC internalization and degradation of FGFR4 (By similarity). {ECO:0000250,
CC ECO:0000269|PubMed:17623664}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-
CC [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA-
CC COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858,
CC ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.1;
CC Evidence={ECO:0000255|PROSITE-ProRule:PRU10028};
CC -!- ACTIVITY REGULATION: Present in an inactive conformation in the absence
CC of bound ligand. Ligand binding leads to dimerization and activation by
CC autophosphorylation on tyrosine residues (By similarity).
CC {ECO:0000250}.
CC -!- SUBUNIT: Monomer. Homodimer after ligand binding. Interacts with FGF1,
CC FGF2, FGF4, FGF6, FGF8, FGF9, FGF16, FGF17, FGF18, FGF19, FGF21 and
CC FGF23 (in vitro). Binding affinity for FGF family members is enhanced
CC by interactions between FGFs and heparan sulfate proteoglycans.
CC Interacts with KLB; this strongly increases the affinity for FGF19 and
CC FGF23. Affinity for FGF19 is strongly increased by KLB and sulfated
CC glycosaminoglycans. KLB and KL both interact with the core-glycosylated
CC FGFR4 in the endoplasmic reticulum and promote its degradation, so that
CC only FGFR4 with fully mature N-glycans is expressed at the cell
CC surface. Identified in a complex with NCAM1, CDH2, PLCG1, FRS2, SRC,
CC SHC1, GAP43 and CTTN. Interacts with MMP14 and HIP1. Interacts with
CC STAT3 (By similarity). {ECO:0000250|UniProtKB:P22455}.
CC -!- SUBCELLULAR LOCATION: Cell membrane; Single-pass type I membrane
CC protein. Endosome {ECO:0000250}. Endoplasmic reticulum {ECO:0000250}.
CC Note=Internalized from the cell membrane to recycling endosomes, and
CC from there back to the cell membrane. {ECO:0000250}.
CC -!- PTM: N-glycosylated. Full maturation of the glycan chains in the Golgi
CC is essential for high affinity interaction with FGF19 (By similarity).
CC {ECO:0000250}.
CC -!- PTM: Ubiquitinated. Subject to proteasomal degradation when not fully
CC glycosylated (By similarity). {ECO:0000250}.
CC -!- PTM: Autophosphorylated. Binding of FGF family members together with
CC heparan sulfate proteoglycan or heparin promotes receptor dimerization
CC and autophosphorylation on tyrosine residues. Autophosphorylation
CC occurs in trans between the two FGFR molecules present in the dimer (By
CC similarity). {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein
CC kinase family. Fibroblast growth factor receptor subfamily.
CC {ECO:0000255|PROSITE-ProRule:PRU00159}.
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DR EMBL; BC100260; AAI00261.1; -; mRNA.
DR RefSeq; NP_001103374.1; NM_001109904.1.
DR AlphaFoldDB; Q498D6; -.
DR SMR; Q498D6; -.
DR STRING; 10116.ENSRNOP00000050988; -.
DR BindingDB; Q498D6; -.
DR ChEMBL; CHEMBL4802008; -.
DR GlyGen; Q498D6; 4 sites.
DR iPTMnet; Q498D6; -.
DR PhosphoSitePlus; Q498D6; -.
DR jPOST; Q498D6; -.
DR PaxDb; Q498D6; -.
DR PRIDE; Q498D6; -.
DR ABCD; Q498D6; 1 sequenced antibody.
DR GeneID; 25114; -.
DR KEGG; rno:25114; -.
DR UCSC; RGD:2612; rat.
DR CTD; 2264; -.
DR RGD; 2612; Fgfr4.
DR VEuPathDB; HostDB:ENSRNOG00000016763; -.
DR eggNOG; KOG0200; Eukaryota.
DR HOGENOM; CLU_000288_74_3_1; -.
DR InParanoid; Q498D6; -.
DR OMA; NRPFGRD; -.
DR OrthoDB; 220433at2759; -.
DR PhylomeDB; Q498D6; -.
DR TreeFam; TF316307; -.
DR Reactome; R-RNO-109704; PI3K Cascade.
DR Reactome; R-RNO-1257604; PIP3 activates AKT signaling.
DR Reactome; R-RNO-190322; FGFR4 ligand binding and activation.
DR Reactome; R-RNO-5654228; Phospholipase C-mediated cascade, FGFR4.
DR Reactome; R-RNO-5654712; FRS-mediated FGFR4 signaling.
DR Reactome; R-RNO-5654719; SHC-mediated cascade:FGFR4.
DR Reactome; R-RNO-5654720; PI-3K cascade:FGFR4.
DR Reactome; R-RNO-5654733; Negative regulation of FGFR4 signaling.
DR Reactome; R-RNO-5673001; RAF/MAP kinase cascade.
DR Reactome; R-RNO-6811558; PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling.
DR PRO; PR:Q498D6; -.
DR Proteomes; UP000002494; Chromosome 17.
DR Bgee; ENSRNOG00000016763; Expressed in lung and 15 other tissues.
DR Genevisible; Q498D6; RN.
DR GO; GO:0005911; C:cell-cell junction; IEA:Ensembl.
DR GO; GO:0005783; C:endoplasmic reticulum; ISS:UniProtKB.
DR GO; GO:0005768; C:endosome; IEA:UniProtKB-SubCell.
DR GO; GO:0005794; C:Golgi apparatus; ISO:RGD.
DR GO; GO:0005887; C:integral component of plasma membrane; ISS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; ISO:RGD.
DR GO; GO:0043235; C:receptor complex; IBA:GO_Central.
DR GO; GO:0030133; C:transport vesicle; ISO:RGD.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0017134; F:fibroblast growth factor binding; ISS:UniProtKB.
DR GO; GO:0005007; F:fibroblast growth factor receptor activity; IPI:MGI.
DR GO; GO:0008201; F:heparin binding; ISS:UniProtKB.
DR GO; GO:0004714; F:transmembrane receptor protein tyrosine kinase activity; IBA:GO_Central.
DR GO; GO:0061144; P:alveolar secondary septum development; ISO:RGD.
DR GO; GO:0016477; P:cell migration; ISS:UniProtKB.
DR GO; GO:0042632; P:cholesterol homeostasis; ISS:UniProtKB.
DR GO; GO:0008543; P:fibroblast growth factor receptor signaling pathway; IPI:MGI.
DR GO; GO:0042593; P:glucose homeostasis; ISS:UniProtKB.
DR GO; GO:0030324; P:lung development; ISO:RGD.
DR GO; GO:0090272; P:negative regulation of fibroblast growth factor production; ISO:RGD.
DR GO; GO:0010629; P:negative regulation of gene expression; ISO:RGD.
DR GO; GO:0001759; P:organ induction; ISO:RGD.
DR GO; GO:0018108; P:peptidyl-tyrosine phosphorylation; ISS:UniProtKB.
DR GO; GO:0055062; P:phosphate ion homeostasis; ISS:UniProtKB.
DR GO; GO:0043085; P:positive regulation of catalytic activity; ISS:UniProtKB.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; ISS:UniProtKB.
DR GO; GO:2000573; P:positive regulation of DNA biosynthetic process; ISS:UniProtKB.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; ISS:UniProtKB.
DR GO; GO:0010628; P:positive regulation of gene expression; ISO:RGD.
DR GO; GO:0033674; P:positive regulation of kinase activity; IBA:GO_Central.
DR GO; GO:2000830; P:positive regulation of parathyroid hormone secretion; ISO:RGD.
DR GO; GO:0045862; P:positive regulation of proteolysis; ISS:UniProtKB.
DR GO; GO:0046777; P:protein autophosphorylation; ISS:UniProtKB.
DR GO; GO:0070857; P:regulation of bile acid biosynthetic process; ISS:UniProtKB.
DR GO; GO:0010715; P:regulation of extracellular matrix disassembly; ISS:UniProtKB.
DR GO; GO:0019216; P:regulation of lipid metabolic process; ISS:UniProtKB.
DR GO; GO:0010966; P:regulation of phosphate transport; ISO:RGD.
DR GO; GO:0051174; P:regulation of phosphorus metabolic process; ISO:RGD.
DR GO; GO:0007169; P:transmembrane receptor protein tyrosine kinase signaling pathway; IBA:GO_Central.
DR GO; GO:0070640; P:vitamin D3 metabolic process; ISO:RGD.
DR Gene3D; 2.60.40.10; -; 3.
DR InterPro; IPR016248; FGF_rcpt_fam.
DR InterPro; IPR007110; Ig-like_dom.
DR InterPro; IPR036179; Ig-like_dom_sf.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR013098; Ig_I-set.
DR InterPro; IPR003599; Ig_sub.
DR InterPro; IPR003598; Ig_sub2.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
DR InterPro; IPR008266; Tyr_kinase_AS.
DR InterPro; IPR020635; Tyr_kinase_cat_dom.
DR Pfam; PF07679; I-set; 1.
DR Pfam; PF07714; PK_Tyr_Ser-Thr; 1.
DR PIRSF; PIRSF000628; FGFR; 1.
DR PRINTS; PR00109; TYRKINASE.
DR SMART; SM00409; IG; 3.
DR SMART; SM00408; IGc2; 3.
DR SMART; SM00219; TyrKc; 1.
DR SUPFAM; SSF48726; SSF48726; 3.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS50835; IG_LIKE; 2.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00109; PROTEIN_KINASE_TYR; 1.
PE 1: Evidence at protein level;
KW ATP-binding; Cell membrane; Disulfide bond; Endoplasmic reticulum;
KW Endosome; Glycoprotein; Immunoglobulin domain; Kinase; Membrane;
KW Nucleotide-binding; Phosphoprotein; Receptor; Reference proteome; Repeat;
KW Signal; Transferase; Transmembrane; Transmembrane helix;
KW Tyrosine-protein kinase; Ubl conjugation.
FT SIGNAL 1..16
FT /evidence="ECO:0000255"
FT CHAIN 17..800
FT /note="Fibroblast growth factor receptor 4"
FT /id="PRO_0000227548"
FT TOPO_DOM 17..367
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 368..388
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 389..800
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 17..115
FT /note="Ig-like C2-type 1"
FT DOMAIN 148..236
FT /note="Ig-like C2-type 2"
FT DOMAIN 245..345
FT /note="Ig-like C2-type 3"
FT DOMAIN 465..753
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 768..800
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 610
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10028"
FT BINDING 471..479
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 501
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 571
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P22455"
FT MOD_RES 640
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P22455"
FT MOD_RES 641
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P22455"
FT MOD_RES 752
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P22455"
FT CARBOHYD 109
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 254
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 286
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 307
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 54..98
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114"
FT DISULFID 168..220
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114"
FT DISULFID 267..329
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114"
SQ SEQUENCE 800 AA; 88708 MW; 4D3CF9C152C9A4EE CRC64;
MWLLLALLSI FQETPAFSLE ASEEMEQEPC PAPISEQQEQ VLTVALGQPV RLCCGRTERG
RHWYKEGSRL ASAGRVRGWR GRLEIASFLP EDAGRYLCLA RGSMTVVHNL TLIMDDSLPS
INNEDPKTLS SSSSGHSYLQ QAPYWTHPQR MEKKLHAVPA GNTVKFRCPA AGNPMPTIHW
LKNGQAFHGE NRIGGIRLRH QHWSLVMESV VPSDRGTYTC LVENSLGSIR YSYLLDVLER
SPHRPILQAG LPANTTAVVG SNVELLCKVY SDAQPHIQWL KHIVINGSSF GADGFPYVQV
LKTTDINSSE VEVLYLRNVS AEDAGEYTCL AGNSIGLSYQ SAWLTVLPAE EEDLAWTTAT
SEARYTDIIL YVSGSLALVL LLLLAGVYHR QAIHGHHSRQ PVTVQKLSRF PLARQFSLES
RSSGKSSLSL VRGVRLSSSG PPLLTGLVSL DLPLDPLWEF PRDRLVLGKP LGEGCFGQVV
RAEALGMDSS RPDQTSTVAV KMLKDNASDK DLADLISEME MMKLIGRHKN IINLLGVCTQ
EGPLYVIVEY AAKGNLREFL RARRPPGPDL SPDGPRSSEG PLSFPALVSC AYQVARGMQY
LESRKCIHRD LAARNVLVTE DDVMKIADFG LARGVHHIDY YKKTSNGRLP VKWMAPEALF
DRVYTHQSDV WSFGILLWEI FTLGGSPYPG IPVEELFSLL REGHRMERPP NCPSELYGLM
RECWHAAPSQ RPTFKQLVEA LDKVLLAVSE EYLDLRLTFG PYSPNNGDAS STCSSSDSVF
SHDPLPLEPS PFPFPEAQTT
