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FLASH GENE

Symbol

FGFR4

contributors: mct - updated : 10-11-2010

HGNC name	fibroblast growth factor receptor 4
HGNC id	3691

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

EXPRESSION

Type

widely

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive intestine       highly   liver       predominantly Homo sapiens Lymphoid/Immune spleen       highly Visual eye lens

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Muscular striatum skeletal   highly

cells

System Cell Pubmed Species Stage Rna symbol Digestive hepatocyte Homo sapiens

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

embryo

Text	strongly, in early development in the CNS (habenular nucleus)

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	a signal peptide
	three Ig-like domains, an acidic region between the first and second Ig loops
	a single membrane-spanning segment
	an intracellular split tyrosine-kinase domain
	a FGFR4-extracellular domain that might potentially neutralize FGF19, containing three immunoglobulin-like domains (D1-D3)(D2 and D3 are involved in ligand binding, and the C-terminus of D3 profoundly determines ligand specificity )

HOMOLOGY

interspecies

homolog to murine Fgfr4 (highly)

Homologene

FAMILY	protein kinase superfamily
	Tyr protein kinase family
	fibroblast growth factor receptor subfamily

CATEGORY

signaling growth factor , receptor

SUBCELLULAR LOCALIZATION

plasma membrane

basic FUNCTION	involved in the development of endoderm derivatives and in skeletal muscle formation
	playing a role in the cascade of molecular events leading to terminal muscle differentiation
	functions in a distinctly different manner than the prototype FGFR during myogenic differentiation
	required for effective muscle regeneration through a MYOD1-TEAD2-FGFR4 transcriptional pathway
	regulates bile acid synthesis by repression of CYP7A1 expression
	may contribute to the repression of bile acid synthesis through JNK signaling but is not required for activation of JNK signaling by bile acids
	contributes significantly to hepatocellular carcinoma progression by modulating AFP secretion, proliferation and anti-apoptosis
	plays important roles in negatively regulating hepatic bile acid synthesis and positively regulating hepatic steatosis induced by high fat diet
	KLB/FGFR4 partnership that mediates endocrine control of hepatic metabolism plays a role in cellular homeostasis and hepatoma suppression through negative control of cell population growth mediated by pro-apoptotic signaling
	plays a crucial role in the regulation of hepatic bile acid and lipid metabolism

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

a component

MMP14/FGFR4 membrane complex that either stimulates or suppresses MMP14 and FGFR4 activities, depending on a tumor progression-associated polymorphism in FGFR4

INTERACTION

DNA

RNA

small molecule

protein	interacting with CYP7A1
	KLB is a novel FGFR4 coreceptor required for FGF19 liver specific functions
	interacts with cell-adhesion receptors such as N-cadherin
	interacting with FGF19 (FGFR4 activation is the mechanism whereby FGF19 can increase hepatocyte proliferation and induce hepatocellular carcinoma formation)
	KLB-FGFR4 partnership caused a depression of activated AKT1 and mammalian target of rapamycin while activating ERK1/2 that may underlie the pro-apoptotic effect

cell & other

REGULATION

activated by

FGF19

Other

expression in liver is decreased by fasting and increased by insulin

ASSOCIATED DISORDERS

corresponding disease(s)

DUP5QD

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --over   in pancreatic cancer (mediated by an intronic enhancer activated by HNF1alpha) tumoral     --over   in lung carcinoma tumoral     --over   in all epithelial carcinomas

Susceptibility

to cancer invasion

Variant & Polymorphism other	Gly388Arg polymorphism most likely contributes to susceptibility to cancer
	-R388 risk variant is a unique inducer of MMP14 and collagen invasion

Candidate gene	for limb malformation in terminal del5q patients
Marker
Therapy target
	System Type Disorder Pubmed digestive liver   inhibition of FGFR4 activation may be an effective way to prevent or treat nonalcoholic fatty liver disease (NAFLD) cancer digestive liver frequent overexpression in patients renders its inhibition a novel and much needed pharmacological approach against hepatocellular carcinoma

ANIMAL & CELL MODELS

Fgfr4-deficient mice exhibit an elevated bile acid synthesis due to the upregulation of CYP7A1 in the liver, indicating that activation of hepatocyte FGFR4 negatively regulates bile acid synthesis