Molecular Target Synopsis
Overview
Domains and Structures
Drugs and Clinical Candidates
Druggability
Chemistry
Ligand Efficiency Plot
Pathways
Family Cladogram
Interaction Network
Gene Expression
Gene Copy Number Variation
RNAi
Mutations
Germline Genetics

FGFR4 (P22455) - Overview - Molecular Target Synopsis

Protein


FGFR4, Fibroblast growth factor receptor 4
Enzyme Classification 2.7.10.1
UniProt P22455

Also Known as FGFR4_HUMAN, FGFR4, JTK2, TKF

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. 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 (PubMed:11433297, PubMed:16597617, PubMed:17623664, PubMed:18670643, PubMed:20683963, PubMed:20798051, PubMed:21653700, PubMed:7518429, PubMed:8663044). Interacts with STAT3 (PubMed:26675719).

6J6Y
FGFR4 D2 - FAB COMPLEX
RCSB/PDB
Inspect Structure
See all 3D Structures for FGFR4

Isoforms / Transcripts (Protein Coding)


Drugs


FGFR4 is targeted by Approved Drugs Erdafitinib, Nintedanib. (see details)
Erdafitinib
Nintedanib

Sub-cellular localization


UniProt: FGFR4 is active in the following subcellular-locations: cell membrane, cytoplasm, endoplasmic reticulum, endosome, secreted.
GO terms: FGFR4 is active in the following subcellular-locations: endoplasmic reticulum, endosome, extracellular region, Golgi apparatus, integral component of plasma membrane, plasma membrane, receptor complex, transport vesicle.



UniProt
GO terms

Gene Copy Number Variation


In COSMIC - Cell Lines Project FGFR4 has gain in 2 cell-lines, loss in 3 cell-lines and no signal in 1000 cell-lines. (see details)

Gene Expression


In NCI60, the highest expressing cell lines are: COLO205, KM12, HCC_2998

In Array Express (RNA-seq of 675 commonly used human cancer cell lines), the highest expressing cell lines are: MDA-MB-453, SJCRH30, MDA-MB-134-VI

In Array Express (RNA-seq of long poly adenylated RNA and long non poly adenylated RNA from ENCODE cell lines), the highest expressing cell lines are: A549, K562, HSMM

(see details)

RNA Interference


FGFR4 was reported in the following RNAI studies:

Cell - Large Scale Profiling of Kinase Dependencies in Cancer Cell Lines, the highest RNAi cell lines are: HCH1, LM7. (see details)

3D Structures


For FGFR4 there are:
24 structures (27 chains) solved
19 are solved in complex with at least one small molecule ligand
3 are solved with an approved drug

FGFR4 is solved in complex with the approved drug(s):

0LI/PONATINIB (4QRC_A, 4TYJ_A, 4UXQ_A).

(see details)
Molecular Target 3D Synopsis

Screening and Chemistry


FGFR4 has been screened with 2218 compounds (2962 bioactivities), 1178 compounds have bioactivities that show binding affinity of <= 500nM (1259 bioactivities). (see details)