FGFR4 (fibroblast growth factor receptor 4)

2012-05-01   Alberto Peláez-García , Rodrigo Barderas , J Ignacio Casal 

Functional Proteomics Laboratory, Centro de Investigaciones Biologicas (CIB-CSIC), 28040 Madrid, Spain (APG, JIC); Departamento Bioquimica y Biologia Molecular I, Universidad Complutense de Madrid, 28040 Madrid, Spain (RB)




Atlas Image
FGFR4 comprises an extracellular domain, a transmembrane domain, and an intracellular domain. FGFR4 alternative splicing has been described, with up to 18 different transcripts ranging from 552 to 3559 bp, (evidence of 11 transcripts at protein level ranging from 87 to 1030 aminoacids).


The DNA was cloned in 1991 (Partanen et al., 1991).
18.9 Kb; 18 exons.


3.1 Kb mRNA; alternative splicing gives rise to 18 transcripts with evidence of 11 transcripts at protein level.


Atlas Image
Analysis of the expression of FGFR4 in SW480 colorectal cancer cells by Confocal Microscopy. FGFR4 was detected in plasma membrane, cytoplasm and nucleus. The 4,6-diamidino-2-phenylindole (DAPI) was used to detect the nucleus of the cells in blue. Representative micrographs show FGFR4 in green and F-actin (TRITC-phalloidin) in red.


The canonical sequence possesses 802 amino acids, 120 kDa, contains a signal peptide 1-17 amino acids, an extracellular domain with 3 Ig-like loops, a transmembrane domain with 26 amino acids and an intracellular domain with tyrosine kinase activity.
Transcripts lacking the intracellular domain and transmembrane domain are secreted.


FGFR4 is expressed in a tissue-specific manner during embryogenesis and displays unique affinity for certain FGF ligands (FGF1, FGF2, FGF4, FGF6, FGF8, FGF9, FGF16, FGF17, FGF18 and FGF19). FGFR4 function is not essential during embryogenesis and adult life (Weinstein et al., 1998), though it may be involved in several metabolic pathways (Gutierrez et al., 2006; Yu et al., 2000).
Evidence of FGFR4 expression has been described at: adrenal cortex, adrenal gland, bile duct, cervix, cornea, corneal endothelial cell, corneal epithelial cell, heart, hepatocyte, intestine, islets of langerhans, kidney, lamina propria, liver, lung, lymph node, mammary gland, muscle, muscularis mucosa, ovary, pituitary gland, renal tubular epithelium, retina, skin, spleen, stomach, sublingual gland, ureter, urothelium and uterus (www.hprd.org).


Plasma membrane, but also some FGF-FGFR complexed are endocytosed and develop its function directly in the cytosol or nucleus.
FGFR4 isoform 2 may be secreted.


FGF receptor with tyrosine-protein kinase activity acts as cell-surface receptor for fibroblast growth factors and plays a role in the regulation of cell proliferation, differentiation and migration.
Binding of fibroblast growth factors produces receptor dimerization, autophosphorilation and signal transduction. FGFR4 binds mainly FGF19.
There are evidences that FGFR4 function may not necessarily require FGF ligand: i) heparin in the absence of FGF produced the activation of FGFR4 (Gao and Goldfarb, 1995), ii) FGFR4 was found to function in a complex with N-CAM independently of FGF (Cavallaro et al., 2001), and iii) the detection of N-linked glycosylation on an overexpressed extracellular domain of human FGFR4 suggested that the function of this receptor might also be regulated by glycosylation, similar to what occurs with other FGFRs (Tuominen et al., 2001).
A key regulator of the FGFR4 pathway is its co-receptor klotho-beta (KLB), a 130 kDa transmembrane protein that exhibits a more restricted expression profile in adipose, liver and pancreas tissues. KLB and FGFR4 are both expressed at high levels in mature hepatocytes, where KLB stabilizes FGF19-FGFR4 binding to regulate production of cholesterol 7a-hydroxylase (CYP7A1) and hepatocyte proliferation (Kurosu et al., 2007; Lin et al., 2007; Wu et al., 2010).
It has also been identified that FGFR4 is part of a complex with MT1-MMP, where MT1-MMP and FGFR4 are regulated in an opposite direction depending on the tumor progression and the presence of FGFR4 SNP Gly388Arg (Hotary et al., 2000; Lehti et al., 2000; Okada et al., 1995; Sugiyama et al., 2010). This SNP changes Gly388Arg in the predicted FGFR4 transmembrane domain, resulting in enhanced stability of the activated receptor (Ingvarsen et al., 2008). Both FGFR4-R388 and FGFR4-G388 form a complex with MT1-MMP and induced MT1-MMP tyrosil phosphorylation, but they had opposite effects on MT1-MMP levels. FGFR4-R388 stabilizes MT1-MMP, whereas FGFR4-G388 down-regulates MT1-MMP. The Y573F point mutation blocks MT1-MMP tyrosyl phosphorylation increasing cell-membrane MT1-MMP (Ingvarsen et al., 2008).
Atlas Image
FGFR4 related pathways are mostly related to an enhanced proliferation, cell survival and cell migration in cancer.


Other fibroblast growth factor receptors (FGFR1, FGFR2 and FGFR3).
Homology with other tyrosin-protein kinase family members through its tyrosin-protein kinase domain.


Atlas Image
Mutational spectrum of the human FGFR4 gene. Red labels represent somatic mutations occurring in different cancers. Black labels represent germinal mutations.


In the FGFR4 gene transcript from a mammary carcinoma cell line, a G-to-A transition was discovered that resulted in the substitution of glycine by arginine at position 388 in the transmembrane domain of the receptor (Bange et al., 2002). The arg388 allele was also found in cell lines derived from a variety of other tumor types as well as in the germline of cancer patients and healthy individuals. Analysis of 3 geographically separated groups indicated that it occurs in approximately 50% of humans. Moreover, the FGFR4 arg388 allele was associated with early metastasis and advanced tumor-node metastasis stage in 82 colon cancer patients.
The results support that FGFR4 arg388 allele represents an innocuous determinant in healthy individuals but predisposes cancer patients for significantly accelerated disease progression.


FGFR4 was significantly overexpressed in rhabdomyosarcoma tumors of high metastatic potential. Higher FGFR4 expression was associated to a lower rate of survival (Taylor et al., 2009).
Six missense mutations were observed in the FGFR4 tyrosine kinase domain among 7 of 94 (7.5%) primary rhabdomyosarcomas, and none of these substitutions were found in normal controls. Comparison with the available genomic data suggested that the mutations were somatic. Four of the mutations affected residues Asn535 and Val550 and were predicted to be activating mutations that would alter conformational dynamics during phosphorylation in the case of Asn535 substitutions and ATP binding in the case of Val550 substitutions.
Using human and mouse rhabdomyosarcoma cell lines, it was found that two of these mutations, Asn535Lys (N535K) and Val550Glu (V550E), increased autophosphorylation, Stat3 signaling, cell growth, tumor proliferation and metastatic potential when injected into nude mice (Taylor et al., 2009). These mutants differentiated mouse NIH3T3 cells to an enhanced metastatic phenotype.
Ruhe et al. discovered the Y367C mutation in the FGFR4 gene by a comprehensive analysis of the tyrosine kinase gene family in cancer cell lines (Ruhe et al., 2007). This mutation occurred in the MDA-MB453 breast cancer cell line.
Cloning and ectopic expression of the FGFR4 Y367C mutant in HEK293 cells revealed high pERK levels and enhanced cell proliferation (Roidl et al., 2010).
Based on these findings, it has been proposed that FGFR4 may be a driver gene of tumour growth.

Implicated in

Entity name
Various cancers
Gly388Arg polymorphism
Gly388Arg polymorphism seems to be associated to poor prognosis and cancer aggressiveness in different cancers but no with predisposition to any cancer as it has been described prostate, breast, gastric and skin cancer (see in paragraphs below).
Gly388Arg seems to be associated to a worst prognosis and aggressiveness in different cancers. The SNP might be mainly associated with increased risks of breast and prostate cancer, and contributes to susceptibility to cancer, especially in Asians (Xu et al., 2010).
Entity name
Prostate cancer
It has been described a significant association between FGFR4 polymorphism and prostate cancer using a total of 2618 cases and 2305 controls. FGFR4 contributes to susceptibility to prostate cancer (Liwei et al., 2011).
FGFR4 polymorphism results in an increased stability and activation of the receptor, resulting in an association of prostate cancer patients to clinical progression (Wang et al., 2008).
Entity name
FGFR4 Arg388 polymorphism was detected in 83 out of 185 (45%) melanoma patients and was significantly associated to tumour thickness and the nodular melanoma subtype. Moreover, the analysis of 137 melanoma tissues by immunohistochemistry showed that 45% of the specimens expressed FGFR4 at different levels and correlated with pTNM tumour stages, metastases, number of primary tumors and survival (Streit et al., 2006).
In another independent study with 218 samples from melanoma, 285 squamous cell carcinoma, 300 basal cell carcinoma and 870 controls, it was observed no association between the presence of the SNP and predisposition to develop skin cancer.
Entity name
Hepatocellular carcinoma
FGF19 and its receptor FGFR4 are co-expressed in human liver, lung and colon tumors and in several colon cancer cell lines.
The presence of the SNP in cancer patients in a population of 58 cases (29% heterozygous and 24% homozygous) and 88 controls (43% heterozygous and 27% homozygous) was associated with a poor prognosis in hepatocellular carcinoma patients. Moreover, overexpression of FGFR4 was also observed in 33% of cancer patients (Ho et al., 2009).
A specific antibody directed against FGF19 abolished signaling mediated through FGFR4 in vitro, resulting in an inhibition of tumor xenografts in vivo and preventing hepatocellular carcinomas in FGF19 transgenic mice.
The targeting of FGF19 by antibodies that disrupt FGF19-FGFR4 interaction could be beneficial for colon, liver and lung cancer patients whose tumors co-express FGF19 and FGFR4 (Desnoyers et al., 2008).
Entity name
Breast cancer
Approximately 40% and 10% of breast cancer patients present the Gly388Arg polymorphism in heterozygous or homozygous, respectively; without significant differences in the presence of the SNP between control and case specimens. FGFR4 expression levels do not correlate with the presence of the SNP (Thussbas et al., 2006).
Gly388Arg polymorphism is not associated with initiation of breast cancer but has been suggested that could be a marker for increased tumor aggressiveness in advanced breast cancer (Bange et al., 2002; Jezequel et al., 2004; Thussbas et al., 2006).
Entity name
Gastric cancer
FGFR4 expression abundance by immunohistochemistry was intermediate or high in 41% and 38% of gastric cancer tissue samples.
The SNP is present in 50% of gastric cancer patients in either heterozygous or homozygous. It was found a significant association between Gly388Arg and gastric cancer patient survival, suggesting that FGFR4 Arg388 genotype might be a marker of gastric cancer progression (Ye et al., 2010; Ye et al., 2011).
FGFR4 expression was associated to lymph node status and survival decreased with an increased in FGFR4 expression.
Knockdown of FGFR4 expression produced a decrease in proliferation by increasing the apoptosis rate of gastric cancer cell lines in vitro (Ye et al., 2011).
Entity name
Rhabdomyosarcoma is a cancer that takes place in the childhood and is originated from skeletal muscle.
FGFR4 is highly overexpressed in RMS samples at mRNA and protein level in comparison to pediatric tumors and normal tissue (Taylor et al., 2009). FGFR4 overexpression has been linked to advanced-stage cancer and poor survival (Baird et al., 2005; Taylor et al., 2009). FGFR4 silencing in the RH30 alveolar RMS human cell line produced a significant reduction in tumor growth and lung metastases when xenotransplanted in mice (Taylor et al., 2009).
Entity name
Colorectal cancer
FGFR4 is overexpressed in low- and high-metastatic CRC cell lines, with higher expression at late CRC stages (Barderas et al., 2012).
FGFR4 is a tumor-associated antigen of autoantibodies in colorectal cancer patients; it might serve for the diagnosis of colorectal cancer at early stages in combination with other tumor-associated antigens (Babel et al., 2009; Barderas et al., 2012).
Entity name
Pancreatic cancer
FGFR4 is overexpressed in 50-70% of pancreatic cancer cell lines and pancreatic carcinomas (Motoda et al., 2011; Shah et al., 2002).
FGFR4 is significantly increased in high-grade pancreatic intraepithelial neoplasia and pancreatic ductal adenocarcinoma, where FGFR4 stimulation by FGF19 increased cell adhesion to extracellular matrix and decreased cell migration.


Pubmed IDLast YearTitleAuthors
196386182009Identification of tumor-associated autoantigens for the diagnosis of colorectal cancer in serum using high density protein microarrays.Babel I et al
162303832005Gene expression profiling of human sarcomas: insights into sarcoma biology.Baird K et al
118305412002Cancer progression and tumor cell motility are associated with the FGFR4 Arg(388) allele.Bange J et al
224657122012An optimized predictor panel for colorectal cancer diagnosis based on the combination of tumor-associated antigens obtained from protein and phage microarrays.Barderas R et al
114332972001N-CAM modulates tumour-cell adhesion to matrix by inducing FGF-receptor signalling.Cavallaro U et al
175990422008Targeting FGF19 inhibits tumor growth in colon cancer xenograft and FGF19 transgenic hepatocellular carcinoma models.Desnoyers LR et al
77745761995Heparin can activate a receptor tyrosine kinase.Gao G et al
162841902006Bile acids decrease hepatic paraoxonase 1 expression and plasma high-density lipoprotein levels via FXR-mediated signaling of FGFR4.Gutierrez A et al
190080092009Fibroblast growth factor receptor 4 regulates proliferation, anti-apoptosis and alpha-fetoprotein secretion during hepatocellular carcinoma progression and represents a potential target for therapeutic intervention.Ho HK et al
108510272000Regulation of cell invasion and morphogenesis in a three-dimensional type I collagen matrix by membrane-type matrix metalloproteinases 1, 2, and 3.Hotary K et al
186273132008Dimerization of endogenous MT1-MMP is a regulatory step in the activation of the 72-kDa gelatinase MMP-2 on fibroblasts and fibrosarcoma cells.Ingvarsen S et al
147102282004G388R mutation of the FGFR4 gene is not relevant to breast cancer prognosis.Jézéquel P et al
176236642007Tissue-specific expression of betaKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21.Kurosu H et al
107481992000Regulation of membrane-type-1 matrix metalloproteinase activity by its cytoplasmic domain.Lehti K et al
176279372007Liver-specific activities of FGF19 require Klotho beta.Lin BC et al
216250792011Association between fibroblast growth factor receptor-4 gene polymorphism and risk of prostate cancer: a meta-analysis.Liwei L et al
211099342011Overexpression of fibroblast growth factor receptor 4 in high-grade pancreatic intraepithelial neoplasia and pancreatic ductal adenocarcinoma.Motoda N et al
77087151995Membrane-type matrix metalloproteinase (MT-MMP) gene is expressed in stromal cells of human colon, breast, and head and neck carcinomas.Okada A et al
17090941991FGFR-4, a novel acidic fibroblast growth factor receptor with a distinct expression pattern.Partanen J et al
199463272010The FGFR4 Y367C mutant is a dominant oncogene in MDA-MB453 breast cancer cells.Roidl A et al
180564642007Genetic alterations in the tyrosine kinase transcriptome of human cancer cell lines.Ruhe JE et al
124476882002FGFR4 overexpression in pancreatic cancer is mediated by an intronic enhancer activated by HNF1alpha.Shah RN et al
167213642006FGFR4 Arg388 allele correlates with tumour thickness and FGFR4 protein expression with survival of melanoma patients.Streit S et al
208768042010Fibroblast growth factor receptor 4 regulates tumor invasion by coupling fibroblast growth factor signaling to extracellular matrix degradation.Sugiyama N et al
198091592009Identification of FGFR4-activating mutations in human rhabdomyosarcomas that promote metastasis in xenotransplanted models.Taylor JG 6th et al
168228472006FGFR4 Arg388 allele is associated with resistance to adjuvant therapy in primary breast cancer.Thussbas C et al
112376892001Expression and glycosylation studies of human FGF receptor 4.Tuominen H et al
186706432008Altered fibroblast growth factor receptor 4 stability promotes prostate cancer progression.Wang J et al
97165271998FGFR-3 and FGFR-4 function cooperatively to direct alveogenesis in the murine lung.Weinstein M et al
200188952010FGF19-induced hepatocyte proliferation is mediated through FGFR4 activation.Wu X et al
206388382010FGFR4 transmembrane domain polymorphism and cancer risk: a meta-analysis including 8555 subjects.Xu W et al
208449672010The fibroblast growth factor receptor-4 Arg388 allele is associated with gastric cancer progression.Ye Y et al
215673882011Fibroblast growth factor receptor 4 regulates proliferation and antiapoptosis during gastric cancer progression.Ye YW et al
108097802000Elevated cholesterol metabolism and bile acid synthesis in mice lacking membrane tyrosine kinase receptor FGFR4.Yu C et al

Other Information

Locus ID:

NCBI: 2264
MIM: 134935
HGNC: 3691
Ensembl: ENSG00000160867


dbSNP: 2264
ClinVar: 2264
TCGA: ENSG00000160867


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
MAPK signaling pathwayKEGGko04010
Regulation of actin cytoskeletonKEGGko04810
MAPK signaling pathwayKEGGhsa04010
Regulation of actin cytoskeletonKEGGhsa04810
PI3K-Akt signaling pathwayKEGGhsa04151
PI3K-Akt signaling pathwayKEGGko04151
Ras signaling pathwayKEGGhsa04014
Rap1 signaling pathwayKEGGhsa04015
Rap1 signaling pathwayKEGGko04015
Signaling pathways regulating pluripotency of stem cellsKEGGhsa04550
Signaling pathways regulating pluripotency of stem cellsKEGGko04550
Diseases of signal transductionREACTOMER-HSA-5663202
Signaling by FGFR in diseaseREACTOMER-HSA-1226099
Signaling by FGFR4 in diseaseREACTOMER-HSA-5655291
FGFR4 mutant receptor activationREACTOMER-HSA-1839128
PI3K/AKT Signaling in CancerREACTOMER-HSA-2219528
Constitutive Signaling by Aberrant PI3K in CancerREACTOMER-HSA-2219530
Immune SystemREACTOMER-HSA-168256
Adaptive Immune SystemREACTOMER-HSA-1280218
Signaling by the B Cell Receptor (BCR)REACTOMER-HSA-983705
Downstream signaling events of B Cell Receptor (BCR)REACTOMER-HSA-1168372
PIP3 activates AKT signalingREACTOMER-HSA-1257604
Negative regulation of the PI3K/AKT networkREACTOMER-HSA-199418
Innate Immune SystemREACTOMER-HSA-168249
DAP12 interactionsREACTOMER-HSA-2172127
DAP12 signalingREACTOMER-HSA-2424491
RAF/MAP kinase cascadeREACTOMER-HSA-5673001
Fc epsilon receptor (FCERI) signalingREACTOMER-HSA-2454202
FCERI mediated MAPK activationREACTOMER-HSA-2871796
Role of LAT2/NTAL/LAB on calcium mobilizationREACTOMER-HSA-2730905
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Signaling by InterleukinsREACTOMER-HSA-449147
Interleukin-2 signalingREACTOMER-HSA-451927
Interleukin receptor SHC signalingREACTOMER-HSA-912526
Interleukin-3, 5 and GM-CSF signalingREACTOMER-HSA-512988
Signal TransductionREACTOMER-HSA-162582
Signaling by EGFRREACTOMER-HSA-177929
GRB2 events in EGFR signalingREACTOMER-HSA-179812
SHC1 events in EGFR signalingREACTOMER-HSA-180336
GAB1 signalosomeREACTOMER-HSA-180292
Signaling by FGFRREACTOMER-HSA-190236
Signaling by FGFR4REACTOMER-HSA-5654743
FGFR4 ligand binding and activationREACTOMER-HSA-190322
betaKlotho-mediated ligand bindingREACTOMER-HSA-1307965
Downstream signaling of activated FGFR4REACTOMER-HSA-5654716
FRS-mediated FGFR4 signalingREACTOMER-HSA-5654712
Phospholipase C-mediated cascade; FGFR4REACTOMER-HSA-5654228
SHC-mediated cascade:FGFR4REACTOMER-HSA-5654719
PI-3K cascade:FGFR4REACTOMER-HSA-5654720
Negative regulation of FGFR4 signalingREACTOMER-HSA-5654733
Signaling by Insulin receptorREACTOMER-HSA-74752
Insulin receptor signalling cascadeREACTOMER-HSA-74751
IRS-mediated signallingREACTOMER-HSA-112399
PI3K CascadeREACTOMER-HSA-109704
SOS-mediated signallingREACTOMER-HSA-112412
Signalling by NGFREACTOMER-HSA-166520
NGF signalling via TRKA from the plasma membraneREACTOMER-HSA-187037
Signalling to ERKsREACTOMER-HSA-187687
Signalling to RASREACTOMER-HSA-167044
Signalling to p38 via RIT and RINREACTOMER-HSA-187706
Prolonged ERK activation eventsREACTOMER-HSA-169893
Frs2-mediated activationREACTOMER-HSA-170968
ARMS-mediated activationREACTOMER-HSA-170984
PI3K/AKT activationREACTOMER-HSA-198203
Signaling by PDGFREACTOMER-HSA-186797
Downstream signal transductionREACTOMER-HSA-186763
Signaling by VEGFREACTOMER-HSA-194138
VEGFR2 mediated cell proliferationREACTOMER-HSA-5218921
Signaling by SCF-KITREACTOMER-HSA-1433557
MAPK family signaling cascadesREACTOMER-HSA-5683057
MAPK1/MAPK3 signalingREACTOMER-HSA-5684996
Signaling by GPCRREACTOMER-HSA-372790
Gastrin-CREB signalling pathway via PKC and MAPKREACTOMER-HSA-881907
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)REACTOMER-HSA-2404192
IGF1R signaling cascadeREACTOMER-HSA-2428924
IRS-related events triggered by IGF1RREACTOMER-HSA-2428928
Signaling by LeptinREACTOMER-HSA-2586552
Developmental BiologyREACTOMER-HSA-1266738
Axon guidanceREACTOMER-HSA-422475
NCAM signaling for neurite out-growthREACTOMER-HSA-375165
PI5P, PP2A and IER3 Regulate PI3K/AKT SignalingREACTOMER-HSA-6811558
RET signalingREACTOMER-HSA-8853659

Protein levels (Protein atlas)

Not detected


Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA443560Breast NeoplasmsDiseaseClinicalAnnotationassociatedPD16822847


Pubmed IDYearTitleCitations
198091592009Identification of FGFR4-activating mutations in human rhabdomyosarcomas that promote metastasis in xenotransplanted models.103
118305412002Cancer progression and tumor cell motility are associated with the FGFR4 Arg(388) allele.76
118305412002Cancer progression and tumor cell motility are associated with the FGFR4 Arg(388) allele.76
175990422008Targeting FGF19 inhibits tumor growth in colon cancer xenograft and FGF19 transgenic hepatocellular carcinoma models.71
197306832009The variant rs1867277 in FOXE1 gene confers thyroid cancer susceptibility through the recruitment of USF1/USF2 transcription factors.59
154480042004The fibroblast growth factor receptor-4 Arg388 allele is associated with prostate cancer initiation and progression.53
154480042004The fibroblast growth factor receptor-4 Arg388 allele is associated with prostate cancer initiation and progression.53
176642432007FGFR4 prevents hyperlipidemia and insulin resistance but underlies high-fat diet induced fatty liver.53
190080092009Fibroblast growth factor receptor 4 regulates proliferation, anti-apoptosis and alpha-fetoprotein secretion during hepatocellular carcinoma progression and represents a potential target for therapeutic intervention.52
190080092009Fibroblast growth factor receptor 4 regulates proliferation, anti-apoptosis and alpha-fetoprotein secretion during hepatocellular carcinoma progression and represents a potential target for therapeutic intervention.52


Alberto Peláez-García ; Rodrigo Barderas ; J Ignacio Casal

FGFR4 (fibroblast growth factor receptor 4)

Atlas Genet Cytogenet Oncol Haematol. 2012-05-01

Online version: http://atlasgeneticsoncology.org/gene/512/fgfr4-(fibroblast-growth-factor-receptor-4)