FGFR4_HUMAN » Fibroblast growth factor receptor 4

FGFR4_HUMAN » Fibroblast growth factor receptor 4
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Topology in Plasma membrane
Topologyextracellular side
cytoplasmic side
FGFR4_HUMAN » Fibroblast growth factor receptor 4 » FGFR-4;
Hydrophobic Thickness 30.8 ± 3.0 Å
Tilt Angle 0 ± 0°
ΔGtransfer -30.5 kcal/mol
ΔGfold -16.0 kcal/mol
Links UniProtKB, Pfam, Interpro, iHOP, STRING, HGNC, HMDB
Topology Out
TM Segments 367-389 (363-393)
Pathways

Endocytosis (KEGG)

Immune System (Reactome)

MAPK signaling pathway (KEGG)

PI3K-Akt signaling pathway (KEGG)

Regulation of actin cytoskeleton (KEGG)

Signal Transduction (Reactome)

PDB 4r6v (445-753), 4qqc (445-753), 4qqj (445-753), 4qqt (445-753), 4qrc (445-753), 4tyj (447-753), 4tyi (447-753), 4tyg (447-753), 4tye (447-753), 4uxq (447-753), 4qq5 (A=445-753)
OPM none
Complexes none
Interactions

CADH2, Complex: CADH2:FGFR4, PubMed

EPHA4, Complex: EPHA4:FGFR4, PubMed

GLCE, Complex: FGFR4:GLCE, PubMed

MMP14, Complex: FGFR4:MMP14, PubMed

Domains

AA: 154-241, PDBID: 1RY7, Subunit B, Seq Identity:70%, Immunoglobulin I-set domain

AA: 248-337, PDBID: 1RY7, Subunit B, Seq Identity:60%, Immunoglobulin domain

AA: 467-743, PDBID: 4QQ5, Subunit A, Seq Identity:100%, Protein tyrosine kinase

UniProt annotation for FGFR4_HUMAN » Fibroblast growth factor receptor 4
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.

TISSUE SPECIFICITY: Expressed in gastrointestinal epithelial cells, pancreas, and gastric and pancreatic cancer cell lines.

UniProt features for FGFR4_HUMAN » Fibroblast growth factor receptor 4
SIGNAL 1 21
CHAIN 22 802 Fibroblast growth factor receptor 4.
DOMAIN 22 118 Ig-like C2-type 1.
DOMAIN 152 240 Ig-like C2-type 2.
DOMAIN 249 349 Ig-like C2-type 3.
DOMAIN 467 755 Protein kinase.
ACT_SITE 612 612 Proton acceptor (By similarity).
DISULFID 57 101 By similarity.
DISULFID 172 224 By similarity.
DISULFID 271 333 By similarity.
Amino Acid Sequence for FGFR4_HUMAN » Fibroblast growth factor receptor 4
MRLLLALLGV LLSVPGPPVL SLEASEEVEL EPCLAPSLEQ QEQELTVALG QPVRLCCGRA ERGGHWYKEG SRLAPAGRVR GWRGRLEIAS FLPEDAGRYL CLARGSMIVL QNLTLITGDS LTSSNDDEDP KSHRDPSNRH SYPQQAPYWT HPQRMEKKLH AVPAGNTVKF RCPAAGNPTP TIRWLKDGQA FHGENRIGGI RLRHQHWSLV MESVVPSDRG TYTCLVENAV GSIRYNYLLD VLERSPHRPI LQAGLPANTT AVVGSDVELL CKVYSDAQPH IQWLKHIVIN GSSFGADGFP YVQVLKTADI NSSEVEVLYL RNVSAEDAGE YTCLAGNSIG LSYQSAWLTV LPEEDPTWTA AAPEARYTDI ILYASGSLAL AVLLLLAGLY RGQALHGRHP RPPATVQKLS RFPLARQFSL ESGSSGKSSS SLVRGVRLSS SGPALLAGLV SLDLPLDPLW EFPRDRLVLG KPLGEGCFGQ VVRAEAFGMD PARPDQASTV AVKMLKDNAS DKDLADLVSE MEVMKLIGRH KNIINLLGVC TQEGPLYVIV ECAAKGNLRE FLRARRPPGP DLSPDGPRSS EGPLSFPVLV SCAYQVARGM QYLESRKCIH RDLAARNVLV TEDNVMKIAD FGLARGVHHI DYYKKTSNGR LPVKWMAPEA LFDRVYTHQS DVWSFGILLW EIFTLGGSPY PGIPVEELFS LLREGHRMDR PPHCPPELYG LMRECWHAAP SQRPTFKQLV EALDKVLLAV SEEYLDLRLT FGPYSPSGGD ASSTCSSSDS VFSHDPLPLG SSSFPFGSGV QT