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Atlas of Genetics and Cytogenetics in Oncology and Haematology INIST-CNRS OPEN ACCESS JOURNAL Gene Section Review FGFR4 (fibroblast growth factor receptor 4) 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) Published in Atlas Database: May 2012 Online updated version : http://AtlasGeneticsOncology.org/Genes/FGFR4ID512ch5q35.html DOI: 10.4267/2042/48227 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity DNA/RNA Other names: CD334, JTK2, TKF HGNC (Hugo): FGFR4 Location: 5q35.2 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. 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). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(11) 802 FGFR4 (fibroblast growth factor receptor 4) Peláez-García A, et al. 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. 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). Protein 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. 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. Expression Function 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, 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 NCAM independently of FGF (Cavallaro et al., 2001), and iii) the detection of N-linked glycosylation on an Atlas Genet Cytogenet Oncol Haematol. 2012; 16(11) 803 FGFR4 (fibroblast growth factor receptor 4) Peláez-García A, et al. 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 coreceptor 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 7ahydroxylase (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 MT1MMP 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). 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 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. FGFR4 related pathways are mostly related to an enhanced proliferation, cell survival and cell migration in cancer. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(11) 804 FGFR4 (fibroblast growth factor receptor 4) Peláez-García A, et al. Mutational spectrum of the human FGFR4 gene. Red labels represent somatic mutations occurring in different cancers. Black labels represent germinal mutations. 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). 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. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(11) 805 FGFR4 (fibroblast growth factor receptor 4) Peláez-García A, et al. association between the presence of the SNP and predisposition to develop skin cancer. 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. 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 coexpress FGF19 and FGFR4 (Desnoyers et al., 2008). Implicated in 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). 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). 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). Gastric cancer Melanoma 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 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 Atlas Genet Cytogenet Oncol Haematol. 2012; 16(11) 806 FGFR4 (fibroblast growth factor receptor 4) Peláez-García A, et al. I collagen matrix by membrane-type matrix metalloproteinases 1, 2, and 3. J Cell Biol. 2000 Jun 12;149(6):1309-23 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). Lehti K, Valtanen H, Wickström SA, Lohi J, Keski-Oja J. Regulation of membrane-type-1 matrix metalloproteinase activity by its cytoplasmic domain. J Biol Chem. 2000 May 19;275(20):15006-13 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). Yu C, Wang F, Kan M, Jin C, Jones RB, Weinstein M, Deng CX, McKeehan WL. Elevated cholesterol metabolism and bile acid synthesis in mice lacking membrane tyrosine kinase receptor FGFR4. J Biol Chem. 2000 May 19;275(20):15482-9 Cavallaro U, Niedermeyer J, Fuxa M, Christofori G. N-CAM modulates tumour-cell adhesion to matrix by inducing FGFreceptor signalling. Nat Cell Biol. 2001 Jul;3(7):650-7 Tuominen H, Heikinheimo P, Loo BM, Kataja K, Oker-Blom C, Uutela M, Jalkanen M, Goldman A. Expression and glycosylation studies of human FGF receptor 4. Protein Expr Purif. 2001 Mar;21(2):275-85 Bange J, Prechtl D, Cheburkin Y, Specht K, Harbeck N, Schmitt M, Knyazeva T, Müller S, Gärtner S, Sures I, Wang H, Imyanitov E, Häring HU, Knayzev P, Iacobelli S, Höfler H, Ullrich A. Cancer progression and tumor cell motility are associated with the FGFR4 Arg(388) allele. Cancer Res. 2002 Feb 1;62(3):840-7 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). Shah RN, Ibbitt JC, Alitalo K, Hurst HC. FGFR4 overexpression in pancreatic cancer is mediated by an intronic enhancer activated by HNF1alpha. Oncogene. 2002 Nov 28;21(54):8251-61 Jézéquel P, Campion L, Joalland MP, Millour M, Dravet F, Classe JM, Delecroix V, Deporte R, Fumoleau P, Ricolleau G. G388R mutation of the FGFR4 gene is not relevant to breast cancer prognosis. Br J Cancer. 2004 Jan 12;90(1):189-93 Baird K, Davis S, Antonescu CR, Harper UL, Walker RL, Chen Y, Glatfelter AA, Duray PH, Meltzer PS. Gene expression profiling of human sarcomas: insights into sarcoma biology. Cancer Res. 2005 Oct 15;65(20):9226-35 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. Gutierrez A, Ratliff EP, Andres AM, Huang X, McKeehan WL, Davis RA. Bile acids decrease hepatic paraoxonase 1 expression and plasma high-density lipoprotein levels via FXRmediated signaling of FGFR4. Arterioscler Thromb Vasc Biol. 2006 Feb;26(2):301-6 Streit S, Mestel DS, Schmidt M, Ullrich A, Berking C. FGFR4 Arg388 allele correlates with tumour thickness and FGFR4 protein expression with survival of melanoma patients. Br J Cancer. 2006 Jun 19;94(12):1879-86 Thussbas C, Nahrig J, Streit S, Bange J, Kriner M, Kates R, Ulm K, Kiechle M, Hoefler H, Ullrich A, Harbeck N. FGFR4 Arg388 allele is associated with resistance to adjuvant therapy in primary breast cancer. J Clin Oncol. 2006 Aug 10;24(23):3747-55 References Partanen J, Mäkelä TP, Eerola E, Korhonen J, Hirvonen H, Claesson-Welsh L, Alitalo K. FGFR-4, a novel acidic fibroblast growth factor receptor with a distinct expression pattern. EMBO J. 1991 Jun;10(6):1347-54 Kurosu H, Choi M, Ogawa Y, Dickson AS, Goetz R, Eliseenkova AV, Mohammadi M, Rosenblatt KP, Kliewer SA, Kuro-o M. Tissue-specific expression of betaKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21. J Biol Chem. 2007 Sep 14;282(37):26687-95 Gao G, Goldfarb M. Heparin can activate a receptor tyrosine kinase. EMBO J. 1995 May 15;14(10):2183-90 Okada A, Bellocq JP, Rouyer N, Chenard MP, Rio MC, Chambon P, Basset P. Membrane-type matrix metalloproteinase (MT-MMP) gene is expressed in stromal cells of human colon, breast, and head and neck carcinomas. Proc Natl Acad Sci U S A. 1995 Mar 28;92(7):2730-4 Lin BC, Wang M, Blackmore C, Desnoyers LR. Liver-specific activities of FGF19 require Klotho beta. J Biol Chem. 2007 Sep 14;282(37):27277-84 Ruhe JE, Streit S, Hart S, Wong CH, Specht K, Knyazev P, Knyazeva T, Tay LS, Loo HL, Foo P, Wong W, Pok S, Lim SJ, Ong H, Luo M, Ho HK, Peng K, Lee TC, Bezler M, Mann C, Gaertner S, Hoefler H, Iacobelli S, Peter S, Tay A, Brenner S, Venkatesh B, Ullrich A. Genetic alterations in the tyrosine Weinstein M, Xu X, Ohyama K, Deng CX. FGFR-3 and FGFR4 function cooperatively to direct alveogenesis in the murine lung. Development. 1998 Sep;125(18):3615-23 Hotary K, Allen E, Punturieri A, Yana I, Weiss SJ. Regulation of cell invasion and morphogenesis in a three-dimensional type Atlas Genet Cytogenet Oncol Haematol. 2012; 16(11) 807 FGFR4 (fibroblast growth factor receptor 4) Peláez-García A, et al. kinase transcriptome of human cancer cell lines. Cancer Res. 2007 Dec 1;67(23):11368-76 receptor 4 regulates tumor invasion by coupling fibroblast growth factor signaling to extracellular matrix degradation. Cancer Res. 2010 Oct 15;70(20):7851-61 Desnoyers LR, Pai R, Ferrando RE, Hötzel K, Le T, Ross J, Carano R, D'Souza A, Qing J, Mohtashemi I, Ashkenazi A, French DM. Targeting FGF19 inhibits tumor growth in colon cancer xenograft and FGF19 transgenic hepatocellular carcinoma models. Oncogene. 2008 Jan 3;27(1):85-97 Wu X, Ge H, Lemon B, Vonderfecht S, Weiszmann J, Hecht R, Gupte J, Hager T, Wang Z, Lindberg R, Li Y. FGF19-induced hepatocyte proliferation is mediated through FGFR4 activation. J Biol Chem. 2010 Feb 19;285(8):5165-70 Ingvarsen S, Madsen DH, Hillig T, Lund LR, Holmbeck K, Behrendt N, Engelholm LH. Dimerization of endogenous MT1MMP is a regulatory step in the activation of the 72-kDa gelatinase MMP-2 on fibroblasts and fibrosarcoma cells. Biol Chem. 2008 Jul;389(7):943-53 Xu W, Li Y, Wang X, Chen B, Wang Y, Liu S, Xu J, Zhao W, Wu J. FGFR4 transmembrane domain polymorphism and cancer risk: a meta-analysis including 8555 subjects. Eur J Cancer. 2010 Dec;46(18):3332-8 Ye Y, Shi Y, Zhou Y, Du C, Wang C, Zhan H, Zheng B, Cao X, Sun MH, Fu H. The fibroblast growth factor receptor-4 Arg388 allele is associated with gastric cancer progression. Ann Surg Oncol. 2010 Dec;17(12):3354-61 Wang J, Yu W, Cai Y, Ren C, Ittmann MM. Altered fibroblast growth factor receptor 4 stability promotes prostate cancer progression. Neoplasia. 2008 Aug;10(8):847-56 Babel I, Barderas R, Díaz-Uriarte R, Martínez-Torrecuadrada JL, Sánchez-Carbayo M, Casal JI. Identification of tumorassociated autoantigens for the diagnosis of colorectal cancer in serum using high density protein microarrays. Mol Cell Proteomics. 2009 Oct;8(10):2382-95 Liwei L, Chunyu L, Jie L, Ruifa H. Association between fibroblast growth factor receptor-4 gene polymorphism and risk of prostate cancer: a meta-analysis. Urol Int. 2011;87(2):15964 Motoda N, Matsuda Y, Onda M, Ishiwata T, Uchida E, Naito Z. Overexpression of fibroblast growth factor receptor 4 in highgrade pancreatic intraepithelial neoplasia and pancreatic ductal adenocarcinoma. Int J Oncol. 2011 Jan;38(1):133-43 Ho HK, Pok S, Streit S, Ruhe JE, Hart S, Lim KS, Loo HL, Aung MO, Lim SG, Ullrich A. 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. J Hepatol. 2009 Jan;50(1):118-27 Ye YW, Zhou Y, Yuan L, Wang CM, Du CY, Zhou XY, Zheng BQ, Cao X, Sun MH, Fu H, Shi YQ. Fibroblast growth factor receptor 4 regulates proliferation and antiapoptosis during gastric cancer progression. Cancer. 2011 Dec 1;117(23):530413 Taylor JG 6th, Cheuk AT, Tsang PS, Chung JY, Song YK, Desai K, Yu Y, Chen QR, Shah K, Youngblood V, Fang J, Kim SY, Yeung C, Helman LJ, Mendoza A, Ngo V, Staudt LM, Wei JS, Khanna C, Catchpoole D, Qualman SJ, Hewitt SM, Merlino G, Chanock SJ, Khan J. Identification of FGFR4-activating mutations in human rhabdomyosarcomas that promote metastasis in xenotransplanted models. J Clin Invest. 2009 Nov;119(11):3395-407 Barderas R, Babel I, Díaz-Uriarte R, Moreno V, Suárez A, Bonilla F, Villar-Vázquez R, Capellá G, Casal JI. An optimized predictor panel for colorectal cancer diagnosis based on the combination of tumor-associated antigens obtained from protein and phage microarrays. J Proteomics. 2012 Aug 3;75(15):4647-55 Roidl A, Foo P, Wong W, Mann C, Bechtold S, Berger HJ, Streit S, Ruhe JE, Hart S, Ullrich A, Ho HK. The FGFR4 Y367C mutant is a dominant oncogene in MDA-MB453 breast cancer cells. Oncogene. 2010 Mar 11;29(10):1543-52 This article should be referenced as such: Peláez-García A, Barderas R, Casal JI. FGFR4 (fibroblast growth factor receptor 4). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(11):802-808. Sugiyama N, Varjosalo M, Meller P, Lohi J, Hyytiäinen M, Kilpinen S, Kallioniemi O, Ingvarsen S, Engelholm LH, Taipale J, Alitalo K, Keski-Oja J, Lehti K. Fibroblast growth factor Atlas Genet Cytogenet Oncol Haematol. 2012; 16(11) 808