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Gene Review

FGFR4  -  fibroblast growth factor receptor 4

Homo sapiens

Synonyms: CD334, FGFR-4, Fibroblast growth factor receptor 4, JTK2, TKF
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Disease relevance of FGFR4


High impact information on FGFR4

  • The FGF8b-FGFR2c structure shows that alternative splicing permits a single additional contact between phenylalanine 32 (F32) of FGF8b and a hydrophobic groove within Ig domain 3 of the receptor that is also present in FGFR1c, FGFR3c, and FGFR4 [5].
  • Here we show that targeted expression of ptd-FGFR4, but not FGFR4, results in pituitary tumors that morphologically recapitulate the human disease [6].
  • Only SMC and control vessels had FGFR-2 mRNA, while EC and some arteries contained FGFR-4 mRNA [7].
  • Heparin activation of FGFR-4 or of a chimeric receptor bearing FGFR-4 ectodomain and FGFR-1 cytodomain triggers downstream tyrosine phosphorylation of several signaling proteins, and induces proliferation of cells bearing the chimeric receptor [8].
  • Heparin stimulates FGFR-4 autophosphorylation on transfected myoblasts, fibroblasts and lymphoid cells, and is most potent on cells lacking surface heparan proteoglycan [8].

Chemical compound and disease context of FGFR4


Biological context of FGFR4

  • Alignment of the amino acid sequence of the intracellular part of the four FGFRs revealed several lysines conserved in FGFR1-3 but absent in FGFR4 [13].
  • The data indicate that after endocytosis, FGFR4 and its bound ligand are sorted mainly to the recycling compartment, whereas FGFR1-3 with ligand are sorted mainly to degradation in the lysosomes [13].
  • FGFR 1, 2, and 3 have a number of isoforms derived by alternative splicing, alternative initiation and exon switching; however, FGFR4 has been reported to encode a single intact receptor with three extracellular immunoglobulin (Ig)-like domains, a transmembrane domain, and a split intracellular kinase [14].
  • CONCLUSIONS: The coexpression of aFGF and FGFR4 in neoplastic enterochromaffin cells suggests that aFGF may act as an autocrine factor stimulating tumor cell growth [15].
  • Ligands binding to FGFR-4 induced receptor autophosphorylation and phosphorylation of a set of cellular polypeptides, which differed from those phosphorylated in FGFR-1-expressing cells [16].

Anatomical context of FGFR4

  • (Partanen, J., Makela, T. P., Eerola, E., Korhonen, J., Hirvonen, H., Claesson, W. L., and Alitalo, K. (1991) EMBO J. 10, 1347-1354) isolated a new FGF receptor, designated FGFR4, from the human leukemia cell line, K562 [1].
  • A myoblast line, L6E9, which lacks FGF receptors, was utilized to express high levels of FGFR4 [1].
  • These results confirm that hepatocyte FGFR4 regulates bile acid synthesis by repression of Cyp7a1 expression [17].
  • We show that the kinase domains of FGFR1, FGFR3, and FGFR4 containing the activation loop mutation, when targeted to the plasma membrane by a myristylation signal, can transform NIH3T3 cells and induce neurite outgrowth in PC12 cells [18].
  • Among the members of the fibroblast growth factor receptor family the FGFR4 has demonstrated strong dependence on heparin-like material for its activation by fibroblast growth factors [19].

Associations of FGFR4 with chemical compounds

  • They bind to at least three types of cell surface molecules, including four high affinity transmembrane tyrosine kinase receptors (FGFR1 to FGFR4) [20].
  • In addition to antibody against FGF-1, a polyclonal antiserum against the three immunoglobulin (Ig)-like loop ectodomain of FGFR4 and a monoclonal antibody to a 19-residue sequence in the NH2-terminus of the NH2-terminal Ig Loop I of the three loop splice variant of FGFR1 (FGFR1alpha) reacts with the complex [3].
  • In the FGFR4 gene transcript from MDA-MB-453 mammary carcinoma cells, a G to A conversion was discovered that results in the substitution of glycine by arginine at position 388 in the transmembrane domain of the receptor [21].
  • Expression analysis of genes encoding components of the phosphotyrosine signaling system by cDNA array hybridization revealed elevated levels of FGFR4 transcripts in several mammary carcinoma cell lines [21].
  • However, in contrast to FGFR1, when recombinant FGFR4 was expressed back in epithelial cells by transfection, it failed to bind FGF-2 unless heparan sulfate was depressed by chlorate or heparinase treatment [22].
  • More importantly, inhibition of FGFR activity with PD173074 exquisitely blocked HuH7 (high FGFR4 expression) proliferation as compared to control cell lines [23].
  • We show that FGFR4 gene expression is up-regulated in doxorubicin-treated, apoptosis-resistant cancer cell clones [24].

Physical interactions of FGFR4

  • In addition, FGF-6 was found to bind to FGFR-4 in ligand competition experiments [16].
  • Cell-free complexes of heparin and recombinant FGFR4 bound FGF-1 and FGF-2 equally [22].
  • The recently described FGF19 is unusual in that it is nonmitogenic and appears to interact only with FGF receptor-4 [25].

Regulatory relationships of FGFR4

  • By contrast, FGF1 internalized in cells expressing FGFR4 followed largely the same intracellular pathway as the recycling ligand, transferrin [13].
  • In contrast, FGFRs 2 and 4, putative positive regulators, were expressed at earlier stages of differentiation, with FGFR2 upregulated in the resting zone and FGFR4 in the resting and proliferative zones [26].
  • Examination of cell cycle regulators revealed a novel translation-mediated mechanism whereby ErbB2 and FGFR-4 cooperate to regulate cyclin D1 levels [27].
  • FGFR4 GLY388 isotype suppresses motility of MDA-MB-231 breast cancer cells by EDG-2 gene repression [11].

Other interactions of FGFR4

  • Structural and functional specificity within the FGFR family exemplified by FGFR-4 may help to explain how FGFs perform their diverse functions [16].
  • This also represents the first demonstration that activation of FGFR4, in addition to FGFR1 and FGFR3, can induce cellular transformation [18].
  • FGFR1, FGFR2 and FGFR4 were expressed at high levels in respectively 22%, 4% and 32% of tumors [28].
  • CONCLUSIONS: These results suggest a paracrine/autocrine modulation of epithelial and stromal cells of fibroadenomas through an aFGF-FGFR4 interaction [2].
  • Immunoreactivity for FGFR4 was detected in stromal cells of both cases, while EGFR-positive stromal cells were found in only 1 case [15].

Analytical, diagnostic and therapeutic context of FGFR4


  1. Fibroblast growth factor receptor 4 is a high affinity receptor for both acidic and basic fibroblast growth factor but not for keratinocyte growth factor. Ron, D., Reich, R., Chedid, M., Lengel, C., Cohen, O.E., Chan, A.M., Neufeld, G., Miki, T., Tronick, S.R. J. Biol. Chem. (1993) [Pubmed]
  2. Expression of acidic fibroblast growth factor (aFGF) and fibroblast growth factor receptor 4 (FGFR4) in breast fibroadenomas. La Rosa, S., Sessa, F., Colombo, L., Tibiletti, M.G., Furlan, D., Capella, C. J. Clin. Pathol. (2001) [Pubmed]
  3. Nuclear localization of a complex of fibroblast growth factor(FGF)-1 and an NH2-terminal fragment of FGF receptor isoforms R4 and R1alpha in human liver cells. Feng, S., Xu, J., Wang, F., Kan, M., McKeehan, W.L. Biochim. Biophys. Acta (1996) [Pubmed]
  4. An overexpression of fibroblast growth factor (FGF) and FGF receptor 4 in a severe clinical phenotype of facioscapulohumeral muscular dystrophy. Saito, A., Higuchi, I., Nakagawa, M., Saito, M., Uchida, Y., Inose, M., Kasai, T., Niiyama, T., Fukunaga, H., Arimura, K., Osame, M. Muscle Nerve (2000) [Pubmed]
  5. Structural basis by which alternative splicing modulates the organizer activity of FGF8 in the brain. Olsen, S.K., Li, J.Y., Bromleigh, C., Eliseenkova, A.V., Ibrahimi, O.A., Lao, Z., Zhang, F., Linhardt, R.J., Joyner, A.L., Mohammadi, M. Genes Dev. (2006) [Pubmed]
  6. Targeted expression of a human pituitary tumor-derived isoform of FGF receptor-4 recapitulates pituitary tumorigenesis. Ezzat, S., Zheng, L., Zhu, X.F., Wu, G.E., Asa, S.L. J. Clin. Invest. (2002) [Pubmed]
  7. Distinct patterns of expression of fibroblast growth factors and their receptors in human atheroma and nonatherosclerotic arteries. Association of acidic FGF with plaque microvessels and macrophages. Brogi, E., Winkles, J.A., Underwood, R., Clinton, S.K., Alberts, G.F., Libby, P. J. Clin. Invest. (1993) [Pubmed]
  8. Heparin can activate a receptor tyrosine kinase. Gao, G., Goldfarb, M. EMBO J. (1995) [Pubmed]
  9. Localization of the fibroblast growth factor receptor-4 gene to chromosome region 5q33-qter. Armstrong, E., Partanen, J., Cannizzaro, L., Huebner, K., Alitalo, K. Genes Chromosomes Cancer (1992) [Pubmed]
  10. Involvement of the FGFR4 Arg388 allele in head and neck squamous cell carcinoma. Streit, S., Bange, J., Fichtner, A., Ihrler, S., Issing, W., Ullrich, A. Int. J. Cancer (2004) [Pubmed]
  11. FGFR4 GLY388 isotype suppresses motility of MDA-MB-231 breast cancer cells by EDG-2 gene repression. Stadler, C.R., Knyazev, P., Bange, J., Ullrich, A. Cell. Signal. (2006) [Pubmed]
  12. The fibroblast growth factor receptor-4 Arg388 allele is associated with prostate cancer initiation and progression. Wang, J., Stockton, D.W., Ittmann, M. Clin. Cancer Res. (2004) [Pubmed]
  13. Different intracellular trafficking of FGF1 endocytosed by the four homologous FGF receptors. Haugsten, E.M., Sørensen, V., Brech, A., Olsnes, S., Wesche, J. J. Cell. Sci. (2005) [Pubmed]
  14. A soluble dominant negative fibroblast growth factor receptor 4 isoform in human MCF-7 breast cancer cells. Ezzat, S., Zheng, L., Yu, S., Asa, S.L. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  15. High expression of growth factors and growth factor receptors in ovarian metastases from ileal carcinoids: an immunohistochemical study of 2 cases. Facco, C., La Rosa, S., Dionigi, A., Uccella, S., Riva, C., Capella, C. Arch. Pathol. Lab. Med. (1998) [Pubmed]
  16. Fibroblast growth factor receptor-4 shows novel features in genomic structure, ligand binding and signal transduction. Vainikka, S., Partanen, J., Bellosta, P., Coulier, F., Birnbaum, D., Basilico, C., Jaye, M., Alitalo, K. EMBO J. (1992) [Pubmed]
  17. Independent repression of bile acid synthesis and activation of c-Jun N-terminal kinase (JNK) by activated hepatocyte fibroblast growth factor receptor 4 (FGFR4) and bile acids. Yu, C., Wang, F., Jin, C., Huang, X., McKeehan, W.L. J. Biol. Chem. (2005) [Pubmed]
  18. Transformation and Stat activation by derivatives of FGFR1, FGFR3, and FGFR4. Hart, K.C., Robertson, S.C., Kanemitsu, M.Y., Meyer, A.N., Tynan, J.A., Donoghue, D.J. Oncogene (2000) [Pubmed]
  19. Production and characterization of the extracellular domain of recombinant human fibroblast growth factor receptor 4. Loo, B.B., Darwish, K.K., Vainikka, S.S., Saarikettu, J.J., Vihko, P.P., Hermonen, J.J., Goldman, A.A., Alitalo, K.K., Jalkanen, M.M. Int. J. Biochem. Cell Biol. (2000) [Pubmed]
  20. Cytotoxic activity of a diptheria toxin/FGF6 mitotoxin on human tumour cell lines. Coll-Fresno, P.M., Batoz, M., Tarquin, S., Birnbaum, D., Coulier, F. Oncogene (1997) [Pubmed]
  21. Cancer progression and tumor cell motility are associated with the FGFR4 Arg(388) allele. 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, H.U., Knayzev, P., Iacobelli, S., Höfler, H., Ullrich, A. Cancer Res. (2002) [Pubmed]
  22. Specificity for fibroblast growth factors determined by heparan sulfate in a binary complex with the receptor kinase. Kan, M., Wu, X., Wang, F., McKeehan, W.L. J. Biol. Chem. (1999) [Pubmed]
  23. 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. Ho, H.K., Pok, S., Streit, S., Ruhe, J.E., Hart, S., Lim, K.S., Loo, H.L., Aung, M.O., Lim, S.G., Ullrich, A. J. Hepatol. (2009) [Pubmed]
  24. Resistance to chemotherapy is associated with fibroblast growth factor receptor 4 up-regulation. Roidl, A., Berger, H.J., Kumar, S., Bange, J., Knyazev, P., Ullrich, A. Clin. Cancer Res. (2009) [Pubmed]
  25. Transgenic mice expressing human fibroblast growth factor-19 display increased metabolic rate and decreased adiposity. Tomlinson, E., Fu, L., John, L., Hultgren, B., Huang, X., Renz, M., Stephan, J.P., Tsai, S.P., Powell-Braxton, L., French, D., Stewart, T.A. Endocrinology (2002) [Pubmed]
  26. Fibroblast growth factor expression in the postnatal growth plate. Lazarus, J.E., Hegde, A., Andrade, A.C., Nilsson, O., Baron, J. Bone (2007) [Pubmed]
  27. Cooperation between fibroblast growth factor receptor-4 and ErbB2 in regulation of cyclin D1 translation. Koziczak, M., Hynes, N.E. J. Biol. Chem. (2004) [Pubmed]
  28. Expression of FGF and FGF receptor genes in human breast cancer. Penault-Llorca, F., Bertucci, F., Adélaïde, J., Parc, P., Coulier, F., Jacquemier, J., Birnbaum, D., deLapeyrière, O. Int. J. Cancer (1995) [Pubmed]
  29. Acidic fibroblast growth factor (FGF-1) and FGF receptor 1 signaling in human Y79 retinoblastoma. Siffroi-Fernandez, S., Cinaroglu, A., Fuhrmann-Panfalone, V., Normand, G., Bugra, K., Sahel, J., Hicks, D. Arch. Ophthalmol. (2005) [Pubmed]
  30. Fibroblast growth factor receptor 4 (FGFR4) is expressed in adult rat and human retinal photoreceptors and neurons. Fuhrmann, V., Kinkl, N., Leveillard, T., Sahel, J., Hicks, D. J. Mol. Neurosci. (1999) [Pubmed]
  31. Generation and characterization of a panel of monoclonal antibodies specific for human fibroblast growth factor receptor 4 (FGFR4). Chen, C., Patel, S., Corisdeo, S., Liu, X., Micolochick, H., Xue, J., Yang, Q., Lei, Y., Wang, B., Soltis, D. Hybridoma (2005) (2005) [Pubmed]
  32. Binding of heparin/heparan sulfate to fibroblast growth factor receptor 4. Loo, B.M., Kreuger, J., Jalkanen, M., Lindahl, U., Salmivirta, M. J. Biol. Chem. (2001) [Pubmed]
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