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FGFR4 (fibroblast growth factor receptor 4)

Identity

Other namesCD334
JTK2
TKF
HGNC (Hugo) FGFR4
LocusID (NCBI) 2264
Location 5q35.2
Location_base_pair Starts at 176513873 and ends at 176525143 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

 
  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).
Description The DNA was cloned in 1991 (Partanen et al., 1991).
18.9 Kb; 18 exons.
Transcription 3.1 Kb mRNA; alternative splicing gives rise to 18 transcripts with evidence of 11 transcripts at protein level.

Protein

 
  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.
Description 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.
Expression 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).
Localisation 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.
Function 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).
 
  FGFR4 related pathways are mostly related to an enhanced proliferation, cell survival and cell migration in cancer.
Homology Other fibroblast growth factor receptors (FGFR1, FGFR2 and FGFR3).
Homology with other tyrosin-protein kinase family members through its tyrosin-protein kinase domain.

Mutations

 
  Mutational spectrum of the human FGFR4 gene. Red labels represent somatic mutations occurring in different cancers. Black labels represent germinal mutations.
Germinal 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.
Somatic 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 Various cancers
Note Gly388Arg polymorphism
Disease 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).
Prognosis 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 Prostate cancer
Disease 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 Melanoma
Disease 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 Hepatocellular carcinoma
Note FGF19 and its receptor FGFR4 are co-expressed in human liver, lung and colon tumors and in several colon cancer cell lines.
Prognosis 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).
Oncogenesis 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 Breast cancer
Disease 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 Gastric cancer
Note FGFR4 expression abundance by immunohistochemistry was intermediate or high in 41% and 38% of gastric cancer tissue samples.
Disease 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).
Oncogenesis 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 Rhabdomyosarcomas
Note Rhabdomyosarcoma is a cancer that takes place in the childhood and is originated from skeletal muscle.
Oncogenesis 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 Colorectal cancer
Note 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 Pancreatic cancer
Oncogenesis 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.
  

External links

Nomenclature
HGNC (Hugo)FGFR4   3691
Cards
AtlasFGFR4ID512ch5q35
Entrez_Gene (NCBI)FGFR4  2264  fibroblast growth factor receptor 4
GeneCards (Weizmann)FGFR4
Ensembl hg19 (Hinxton)ENSG00000160867 [Gene_View]  chr5:176513873-176525143 [Contig_View]  FGFR4 [Vega]
Ensembl hg38 (Hinxton)ENSG00000160867 [Gene_View]  chr5:176513873-176525143 [Contig_View]  FGFR4 [Vega]
ICGC DataPortalENSG00000160867
cBioPortalFGFR4
AceView (NCBI)FGFR4
Genatlas (Paris)FGFR4
WikiGenes2264
SOURCE (Princeton)FGFR4
Genomic and cartography
GoldenPath hg19 (UCSC)FGFR4  -     chr5:176513873-176525143 +  5q33-qter   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)FGFR4  -     5q33-qter   [Description]    (hg38-Dec_2013)
EnsemblFGFR4 - 5q33-qter [CytoView hg19]  FGFR4 - 5q33-qter [CytoView hg38]
Mapping of homologs : NCBIFGFR4 [Mapview hg19]  FGFR4 [Mapview hg38]
OMIM134935   
Gene and transcription
Genbank (Entrez)AB209631 AF202063 AF359241 AF359246 AK225280
RefSeq transcript (Entrez)NM_001291980 NM_002011 NM_022963 NM_213647
RefSeq genomic (Entrez)AC_000137 NC_000005 NC_018916 NG_012067 NT_023133 NW_001838960 NW_004929325
Consensus coding sequences : CCDS (NCBI)FGFR4
Cluster EST : UnigeneHs.165950 [ NCBI ]
CGAP (NCI)Hs.165950
Alternative Splicing : Fast-db (Paris)GSHG0024509
Alternative Splicing GalleryENSG00000160867
Gene ExpressionFGFR4 [ NCBI-GEO ]     FGFR4 [ SEEK ]   FGFR4 [ MEM ]
SOURCE (Princeton)Expression in : [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP22455 (Uniprot)
NextProtP22455  [Medical]
With graphics : InterProP22455
Splice isoforms : SwissVarP22455 (Swissvar)
Catalytic activity : Enzyme2.7.10.1 [ Enzyme-Expasy ]   2.7.10.12.7.10.1 [ IntEnz-EBI ]   2.7.10.1 [ BRENDA ]   2.7.10.1 [ KEGG ]   
Domaine pattern : Prosite (Expaxy)IG_LIKE (PS50835)    PROTEIN_KINASE_ATP (PS00107)    PROTEIN_KINASE_DOM (PS50011)    PROTEIN_KINASE_TYR (PS00109)   
Domains : Interpro (EBI)FGF_rcpt_fam    Ig-like_dom    Ig-like_fold    Ig_I-set    Ig_sub2    Kinase-like_dom    Prot_kinase_dom    Protein_kinase_ATP_BS    Ser-Thr/Tyr_kinase_cat_dom    Tyr_kinase_AS    Tyr_kinase_cat_dom   
Related proteins : CluSTrP22455
Domain families : Pfam (Sanger)I-set (PF07679)    Pkinase_Tyr (PF07714)   
Domain families : Pfam (NCBI)pfam07679    pfam07714   
Domain families : Smart (EMBL)IGc2 (SM00408)  TyrKc (SM00219)  
DMDM Disease mutations2264
Blocks (Seattle)P22455
PDB (SRS)1QCT   
PDB (PDBSum)1QCT   
PDB (IMB)1QCT   
PDB (RSDB)1QCT   
Human Protein AtlasENSG00000160867
Peptide AtlasP22455
HPRD00625
IPIIPI00304578   IPI00420109   IPI00908504   IPI00556393   IPI00966576   IPI00964579   IPI01019020   IPI00964478   IPI00910457   IPI00964816   
Protein Interaction databases
DIP (DOE-UCLA)P22455
IntAct (EBI)P22455
FunCoupENSG00000160867
BioGRIDFGFR4
IntegromeDBFGFR4
STRING (EMBL)FGFR4
Ontologies - Pathways
QuickGOP22455
Ontology : AmiGOorgan induction  protein tyrosine kinase activity  fibroblast growth factor-activated receptor activity  fibroblast growth factor-activated receptor activity  ATP binding  extracellular region  nucleus  nucleolus  cytoplasm  endosome  endoplasmic reticulum  plasma membrane  integral component of plasma membrane  cell-cell junction  epidermal growth factor receptor signaling pathway  heparin binding  positive regulation of cell proliferation  positive regulation of cell proliferation  insulin receptor signaling pathway  fibroblast growth factor receptor signaling pathway  fibroblast growth factor receptor signaling pathway  fibroblast growth factor receptor signaling pathway  fibroblast growth factor receptor signaling pathway  regulation of extracellular matrix disassembly  cell migration  fibroblast growth factor binding  fibroblast growth factor binding  peptidyl-tyrosine phosphorylation  regulation of lipid metabolic process  Fc-epsilon receptor signaling pathway  glucose homeostasis  innate immune response  positive regulation of proteolysis  protein autophosphorylation  neurotrophin TRK receptor signaling pathway  phosphatidylinositol-mediated signaling  positive regulation of metalloenzyme activity  phosphate ion homeostasis  alveolar secondary septum development  positive regulation of ERK1 and ERK2 cascade  regulation of bile acid biosynthetic process  regulation of cholesterol homeostasis  positive regulation of DNA biosynthetic process  
Ontology : EGO-EBIorgan induction  protein tyrosine kinase activity  fibroblast growth factor-activated receptor activity  fibroblast growth factor-activated receptor activity  ATP binding  extracellular region  nucleus  nucleolus  cytoplasm  endosome  endoplasmic reticulum  plasma membrane  integral component of plasma membrane  cell-cell junction  epidermal growth factor receptor signaling pathway  heparin binding  positive regulation of cell proliferation  positive regulation of cell proliferation  insulin receptor signaling pathway  fibroblast growth factor receptor signaling pathway  fibroblast growth factor receptor signaling pathway  fibroblast growth factor receptor signaling pathway  fibroblast growth factor receptor signaling pathway  regulation of extracellular matrix disassembly  cell migration  fibroblast growth factor binding  fibroblast growth factor binding  peptidyl-tyrosine phosphorylation  regulation of lipid metabolic process  Fc-epsilon receptor signaling pathway  glucose homeostasis  innate immune response  positive regulation of proteolysis  protein autophosphorylation  neurotrophin TRK receptor signaling pathway  phosphatidylinositol-mediated signaling  positive regulation of metalloenzyme activity  phosphate ion homeostasis  alveolar secondary septum development  positive regulation of ERK1 and ERK2 cascade  regulation of bile acid biosynthetic process  regulation of cholesterol homeostasis  positive regulation of DNA biosynthetic process  
Pathways : KEGGMAPK signaling pathway    Ras signaling pathway    Rap1 signaling pathway    Endocytosis    PI3K-Akt signaling pathway    Regulation of actin cytoskeleton   
REACTOMEP22455 [protein]
REACTOME PathwaysREACT_116125 Disease [pathway]
REACTOME PathwaysREACT_6900 Immune System [pathway]
REACTOME PathwaysREACT_111102 Signal Transduction [pathway]
Protein Interaction DatabaseFGFR4
DoCM (Curated mutations)FGFR4
Wikipedia pathwaysFGFR4
Gene fusion - rearrangements
Polymorphisms : SNP, variants
NCBI Variation ViewerFGFR4 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)FGFR4
dbVarFGFR4
ClinVarFGFR4
1000_GenomesFGFR4 
Exome Variant ServerFGFR4
SNP (GeneSNP Utah)FGFR4
SNP : HGBaseFGFR4
Genetic variants : HAPMAPFGFR4
Genomic VariantsFGFR4  FGFR4 [DGVbeta]
Mutations
ICGC Data PortalENSG00000160867 
Somatic Mutations in Cancer : COSMICFGFR4 
CONAN: Copy Number AnalysisFGFR4 
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] 
Diseases
DECIPHER (Syndromes)5:176513873-176525143
Mutations and Diseases : HGMDFGFR4
OMIM134935   
MedgenFGFR4
NextProtP22455 [Medical]
GENETestsFGFR4
Disease Genetic AssociationFGFR4
Huge Navigator FGFR4 [HugePedia]  FGFR4 [HugeCancerGEM]
snp3D : Map Gene to Disease2264
DGIdb (Drug Gene Interaction db)FGFR4
General knowledge
Homologs : HomoloGeneFGFR4
Homology/Alignments : Family Browser (UCSC)FGFR4
Phylogenetic Trees/Animal Genes : TreeFamFGFR4
Chemical/Protein Interactions : CTD2264
Chemical/Pharm GKB GenePA28130
Clinical trialFGFR4
Cancer Resource (Charite)ENSG00000160867
Other databases
Probes
Litterature
PubMed161 Pubmed reference(s) in Entrez
CoreMineFGFR4
GoPubMedFGFR4
iHOPFGFR4

Bibliography

FGFR-4, a novel acidic fibroblast growth factor receptor with a distinct expression pattern.
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Heparin can activate a receptor tyrosine kinase.
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FGFR-3 and FGFR-4 function cooperatively to direct alveogenesis in the murine lung.
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Elevated cholesterol metabolism and bile acid synthesis in mice lacking membrane tyrosine kinase receptor FGFR4.
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N-CAM modulates tumour-cell adhesion to matrix by inducing FGF-receptor signalling.
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Cancer progression and tumor cell motility are associated with the FGFR4 Arg(388) allele.
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FGFR4 overexpression in pancreatic cancer is mediated by an intronic enhancer activated by HNF1alpha.
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PMID 12447688
 
G388R mutation of the FGFR4 gene is not relevant to breast cancer prognosis.
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Bile acids decrease hepatic paraoxonase 1 expression and plasma high-density lipoprotein levels via FXR-mediated signaling of FGFR4.
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PMID 16284190
 
FGFR4 Arg388 allele correlates with tumour thickness and FGFR4 protein expression with survival of melanoma patients.
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FGFR4 Arg388 allele is associated with resistance to adjuvant therapy in primary breast cancer.
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Tissue-specific expression of betaKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21.
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Liver-specific activities of FGF19 require Klotho beta.
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Genetic alterations in the tyrosine kinase transcriptome of human cancer cell lines.
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Altered fibroblast growth factor receptor 4 stability promotes prostate cancer progression.
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Identification of tumor-associated autoantigens for the diagnosis of colorectal cancer in serum using high density protein microarrays.
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Fibroblast growth factor receptor 4 regulates proliferation, anti-apoptosis and alpha-fetoprotein secretion during hepatocellular carcinoma progression and represents a potential target for therapeutic intervention.
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PMID 19008009
 
Identification of FGFR4-activating mutations in human rhabdomyosarcomas that promote metastasis in xenotransplanted models.
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The FGFR4 Y367C mutant is a dominant oncogene in MDA-MB453 breast cancer cells.
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Contributor(s)

Written05-2012Alberto 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)

Citation

This paper should be referenced as such :
Pelaez-Garcia, A ; Barderas, R ; Casal, JI
FGFR4 (fibroblast growth factor receptor 4)
Atlas Genet Cytogenet Oncol Haematol. 2012;16(11):802-808.
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URL : http://AtlasGeneticsOncology.org/Genes/FGFR4ID512ch5q35.html

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