FGFR4_COTCO
ID FGFR4_COTCO Reviewed; 713 AA.
AC Q90330;
DT 05-SEP-2006, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 112.
DE RecName: Full=Fibroblast growth factor receptor 4;
DE Short=FGFR-4;
DE EC=2.7.10.1;
DE AltName: Full=Fibroblast growth factor receptor-like embryonic kinase;
DE Flags: Precursor;
GN Name=FGFR4; Synonyms=FREK;
OS Coturnix coturnix (Common quail) (Tetrao coturnix).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Archelosauria; Archosauria; Dinosauria; Saurischia; Theropoda;
OC Coelurosauria; Aves; Neognathae; Galloanserae; Galliformes; Phasianidae;
OC Perdicinae; Coturnix.
OX NCBI_TaxID=9091;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND DEVELOPMENTAL STAGE.
RX PubMed=8162862; DOI=10.1242/dev.120.3.683;
RA Marcelle C., Eichmann A., Halevy O., Breant C., Le Douarin N.M.;
RT "Distinct developmental expression of a new avian fibroblast growth factor
RT receptor.";
RL Development 120:683-694(1994).
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).
CC {ECO:0000250}.
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 {ECO:0000250}; Single-pass type I
CC membrane protein {ECO:0000250}. Endosome {ECO:0000250}. Endoplasmic
CC reticulum {ECO:0000250}. Note=Internalized from the cell membrane to
CC recycling endosomes, and from there back to the cell membrane.
CC {ECO:0000250}.
CC -!- DEVELOPMENTAL STAGE: During elongating primitive streak stages, it is
CC expressed in the rostral and lateral epiblast and in the Hensen's node.
CC From 2.5 days of development (E 2.5) on, it is expressed in various
CC ectoderm- and mesoderm-derived structures. In the skeletal muscle
CC lineage, it is highly expressed in the early myotome and, at later
CC stages, in all skeletal muscles of the embryo. From E9 to hatching,
CC expression in the muscles decreases dramatically but is maintained in
CC satellite cells of adult muscles. {ECO:0000269|PubMed:8162862}.
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; X76885; CAA54213.1; -; mRNA.
DR PIR; I50128; I50128.
DR AlphaFoldDB; Q90330; -.
DR SMR; Q90330; -.
DR PRIDE; Q90330; -.
DR GO; GO:0005783; C:endoplasmic reticulum; IEA:UniProtKB-SubCell.
DR GO; GO:0005768; C:endosome; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0005007; F:fibroblast growth factor receptor activity; IEA:InterPro.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; IEA:InterPro.
DR Gene3D; 2.60.40.10; -; 2.
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; 2.
DR Pfam; PF07714; PK_Tyr_Ser-Thr; 1.
DR PIRSF; PIRSF000628; FGFR; 1.
DR PRINTS; PR00109; TYRKINASE.
DR SMART; SM00409; IG; 2.
DR SMART; SM00408; IGc2; 2.
DR SMART; SM00219; TyrKc; 1.
DR SUPFAM; SSF48726; SSF48726; 2.
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 2: Evidence at transcript level;
KW ATP-binding; Cell membrane; Disulfide bond; Endoplasmic reticulum;
KW Endosome; Glycoprotein; Immunoglobulin domain; Kinase; Membrane;
KW Nucleotide-binding; Phosphoprotein; Receptor; Repeat; Signal; Transferase;
KW Transmembrane; Transmembrane helix; Tyrosine-protein kinase;
KW Ubl conjugation.
FT SIGNAL 1..20
FT /evidence="ECO:0000255"
FT CHAIN 21..713
FT /note="Fibroblast growth factor receptor 4"
FT /id="PRO_0000249207"
FT TOPO_DOM 21..281
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 282..302
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 303..713
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 59..152
FT /note="Ig-like C2-type 1"
FT DOMAIN 161..261
FT /note="Ig-like C2-type 2"
FT DOMAIN 379..667
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 21..54
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 524
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10028"
FT BINDING 385..393
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 415
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 554
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250"
FT MOD_RES 555
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250"
FT MOD_RES 666
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250"
FT CARBOHYD 133
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 170
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 202
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 223
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 234
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 84..136
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114"
FT DISULFID 183..245
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114"
SQ SEQUENCE 713 AA; 80170 MW; B7DE1BF422A85F66 CRC64;
MLPLWLVLAG LLLAVGPAAS HRGEMEPDSL ASGDDDEDSD GDGPHGDRSE EPVYMHRAPY
WTHPHRMDKK LYAVPAGNTV KFRCPASGSP SPSIRWFKNG REFRGEHRIG GIRLRHQHWS
LVMESVVPSD RGNYTCLVEN RFGRIRYSYL LDVLERSPHR PILQAGLPAN TTALVGSDVE
FFCKVYSDAQ PHLQWLKHIE VNGSSYGPDG VPYVQVLKTA DINSSEVEVL YLRNVTMEDA
GEYTCLAGNS IGLSYQSAWL TVLPEEELVH EAETSEAKYT DIIIYTSGSL AVAMALIIVV
LCRMQTQSSK QPLEPMAVHK LSKFPLIRQF SLDSSSSGKS STSLMRVTRL SSSCAPMLAG
VVEMDLPLDS KWEFPREKLV LGKPLGEGCF GQVVRAEAYG IDRQWPDRAV TVAVKMLKDN
ATDKDLADLI SEMEMMKLMD KHKNIINLLG VCTQDGPLYV IVEFAAKGNL REYLRARRPP
TPDYTFDITE LHEEQLCFKD LVSCVYQVAR GMEYLESRRC IHRDLAARNV LVTAENVMKI
ADFGLARDVH DIDYYKKTSN GRLPVKWMAP EALFDRVYTH QSDVWSFGIL MWEIFTLGGS
PYPGIPVEEL FKLLKEGHRM DCPSNCTHEL YMLMRECWHA VPLQRPTFKQ LVEGLDKILA
AISEEYLDLS MPFEQYSPSC EDTTSTCSSD DSVFTHDPMP LAPCLFSCPS GRT
