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Gene Review

FGFR1  -  fibroblast growth factor receptor 1

Homo sapiens

Synonyms: BFGFR, Basic fibroblast growth factor receptor 1, CD331, CEK, FGFBR, ...
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Disease relevance of FGFR1


Psychiatry related information on FGFR1

  • FGFR1 mutations in human may lead to developmental defects and pathological conditions, including cancer and Alzheimer's disease [6].
  • We determined the distribution of hippocampal FGF-2 and its receptor (FGFR1) mRNA in post-mortem brains of people who suffered from major depression, bipolar disorder and schizophrenia and those of controls [7].
  • MECP2 truncating mutations cause histone H4 hyperacetylation in Rett syndrome [8].

High impact information on FGFR1

  • A search for congenic pairs of mice expressing the responder and nonresponder H2 haplotypes on the same background revealed that these strains responded as a function of their H2 haplotype, not of their inbred background [9].
  • These results indicate an activator-based mechanism for joint MLL1 and MOF recruitment and targeted methylation and acetylation and provide a molecular explanation for the closely correlated distribution of H3 K4 methylation and H4 K16 acetylation on active genes [10].
  • Deposition of the major histone H3 (H3.1) is coupled to DNA synthesis during DNA replication and possibly DNA repair, whereas histone variant H3.3 serves as the replacement variant for the DNA-synthesis-independent deposition pathway [11].
  • Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome [12].
  • These structures provide a molecular basis for FGF1 as a universal FGFR ligand and for modulation of FGF-FGFR specificity through primary sequence variations and alternative splicing [13].

Chemical compound and disease context of FGFR1


Biological context of FGFR1

  • Activation of FGFR1 in transfected cells resulted in tyrosine phosphorylation of a kinase-negative EphA4 mutant and activation of EphA4 led to tyrosine phosphorylation of a kinase-negative FGFR1 mutant [19].
  • In the present study, we have cloned the t(6;8)(q27;p11) translocation in two patients and found a fusion between FGFR1 and a novel gene, FOP (FGFR1 Oncogene Partner), located on chromosome band 6q27 [20].
  • The t(8;13) translocation has recently been shown to result in a fusion between the FGFR1 gene that encodes a tyrosine kinase receptor for fibroblast growth factors and a novel gene, FIM (also called RAMP or ZNF198), belonging to a novel family of zinc finger genes [20].
  • The variant domain corresponded precisely to the splicing junctions of the exon encoding the carboxyl terminal half of the third immunoglobulin-like domain, suggesting that two forms of FGFR3 result from splicing of alternate exons in a manner similar to that previously found for FGFR1 and FGFR2 [21].
  • At the lesion site, inhibition of myelination and stimulation of Schwann cell proliferation by FGF-2 via FGFR1/2 is suggested from rat and mouse studies, whereas neurite formation is very likely enhanced via FGFR3 activation [22].

Anatomical context of FGFR1

  • Expression of mRNA encoding extracellular immunoglobulin-like domains of FGFR1 was increased 35-fold in cardiac allografts compared with normal hearts and was predominantly present in cardiac myocytes and vascular structures [23].
  • Alternatively spliced mRNA that encodes transmembrane forms of FGFR1, which contain the signal-transducing tyrosine kinase domains, was induced in allografts during rejection, in infiltrating cells, vascular structures, and myocytes [23].
  • Although FGFR3 has been suggested to act as a negative regulator of long-bone growth in chrondrocytes, it produces differentiative signals similar to those of FGFR1, to which only positive effects have been ascribed, in PC12 cells [24].
  • 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 [25].
  • 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 [26].

Associations of FGFR1 with chemical compounds


Physical interactions of FGFR1

  • Therefore, we were prompted to examine if CD56 molecules on NK cells interact with FGFR expressed on T cells [33].
  • Nuclear FGFR1 binds to FGF-2 and has tyrosine kinase activity [34].
  • Here we show by isothermal titration calorimetry that the FRS2alpha PTB domain binding to peptides derived from TRKs or FGFR is thermodynamically different [35].
  • The cross-linked 125I-labeled aFGF-aFGF receptor complex was specifically immunoprecipitated with FLG antipeptide antibodies [36].
  • The present study shows that FGFR1 accumulates and interacts with the transcriptional co-activator CREB-binding protein (CBP) in nuclear speckle domains in the developing brain and in neural progenitor-like cells in vitro, which accompanies differentiation and postmitotic growth [37].

Enzymatic interactions of FGFR1


Co-localisations of FGFR1

  • Finally, we show that Zta and CBP colocalize to viral immediate-early promoters in vivo and that overexpression of Zta leads to a robust increase in H3 and H4 acetylation at various regions of the EBV genome in vivo [40].

Regulatory relationships of FGFR1

  • In cells expressing any one of these receptors, externally added FGF1 was localized to sorting/early endosomes after 15 minutes at 37 degrees C. After longer incubation times, FGF1 internalized in cells expressing FGFR1 was localized mainly to late endosomes/lysosomes, similarly to EGF [41].
  • We show here that DT/FGF6 targets myoblasts engineered to express either one of the four FGFR, as well as FGFR-expressing tumour cells [42].
  • FGFRs 1 and 3, thought to negatively regulate chondrogenesis, were expressed at greater levels and at later stages of chondrocyte differentiation, with FGFR1 upregulated in the hypertrophic zone and FGFR3 upregulated in both proliferative and hypertrophic zones [43].
  • FGF-R1 was expressed in all samples and FGF-R2 in most [44].
  • Phosphorylation by ectopic FGFR1 that promotes malignancy was much more intense and yielded a phosphorylated 85-kDa SNT1 [45].

Other interactions of FGFR1

  • Structural and functional specificity within the FGFR family exemplified by FGFR-4 may help to explain how FGFs perform their diverse functions [46].
  • These results indicate that FGFR1, 3, and 4 (i) are capable of signaling in a similar fashion; (ii) primarily use FRS2 and, perhaps, PLCgamma; and (iii) do not utilize Shc [47].
  • Mutations in the fibroblast growth factor receptor (FGFR) gene family recently have been shown to underlie several hereditary disorders of bone development, with specific FGFR3 mutations causing achondroplasia (Ach) and thanatophoric dysplasia (TD) [48].
  • Clones were identified in which the ZNF198 was fused to exon 9 of the fibroblast growth factor receptor-1 (FGFR1), a gene known to map to 8p11 [4].
  • Additionally, FGF2 binding showed positive cooperativity, suggesting the presence of two binding sites on a single FGFR or two interacting sites on an FGFR dimer [49].

Analytical, diagnostic and therapeutic context of FGFR1


  1. Fibroblast growth factor receptor 3 (FGFR3) transmembrane mutation in Crouzon syndrome with acanthosis nigricans. Meyers, G.A., Orlow, S.J., Munro, I.R., Przylepa, K.A., Jabs, E.W. Nat. Genet. (1995) [Pubmed]
  2. Ontogeny of GnRH and olfactory neuronal systems in man: novel insights from the investigation of inherited forms of Kallmann's syndrome. González-Martínez, D., Hu, Y., Bouloux, P.M. Frontiers in neuroendocrinology. (2004) [Pubmed]
  3. Endogenous retroviral sequence is fused to FGFR1 kinase in the 8p12 stem-cell myeloproliferative disorder with t(8;19)(p12;q13.3). Guasch, G., Popovici, C., Mugneret, F., Chaffanet, M., Pontarotti, P., Birnbaum, D., Pébusque, M.J. Blood (2003) [Pubmed]
  4. Consistent fusion of ZNF198 to the fibroblast growth factor receptor-1 in the t(8;13)(p11;q12) myeloproliferative syndrome. Reiter, A., Sohal, J., Kulkarni, S., Chase, A., Macdonald, D.H., Aguiar, R.C., Gonçalves, C., Hernandez, J.M., Jennings, B.A., Goldman, J.M., Cross, N.C. Blood (1998) [Pubmed]
  5. 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]
  6. Zebrafish fgfr1 is a member of the fgf8 synexpression group and is required for fgf8 signalling at the midbrain-hindbrain boundary. Scholpp, S., Groth, C., Lohs, C., Lardelli, M., Brand, M. Dev. Genes Evol. (2004) [Pubmed]
  7. Hippocampal FGF-2 and FGFR1 mRNA expression in major depression, schizophrenia and bipolar disorder. Gaughran, F., Payne, J., Sedgwick, P.M., Cotter, D., Berry, M. Brain Res. Bull. (2006) [Pubmed]
  8. MECP2 truncating mutations cause histone H4 hyperacetylation in Rett syndrome. Wan, M., Zhao, K., Lee, S.S., Francke, U. Hum. Mol. Genet. (2001) [Pubmed]
  9. Discovering the role of the major histocompatibility complex in the immune response. McDevitt, H.O. Annu. Rev. Immunol. (2000) [Pubmed]
  10. Physical association and coordinate function of the H3 K4 methyltransferase MLL1 and the H4 K16 acetyltransferase MOF. Dou, Y., Milne, T.A., Tackett, A.J., Smith, E.R., Fukuda, A., Wysocka, J., Allis, C.D., Chait, B.T., Hess, J.L., Roeder, R.G. Cell (2005) [Pubmed]
  11. Histone H3.1 and H3.3 complexes mediate nucleosome assembly pathways dependent or independent of DNA synthesis. Tagami, H., Ray-Gallet, D., Almouzni, G., Nakatani, Y. Cell (2004) [Pubmed]
  12. Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome. Dodé, C., Levilliers, J., Dupont, J.M., De Paepe, A., Le Dû, N., Soussi-Yanicostas, N., Coimbra, R.S., Delmaghani, S., Compain-Nouaille, S., Baverel, F., Pêcheux, C., Le Tessier, D., Cruaud, C., Delpech, M., Speleman, F., Vermeulen, S., Amalfitano, A., Bachelot, Y., Bouchard, P., Cabrol, S., Carel, J.C., Delemarre-van de Waal, H., Goulet-Salmon, B., Kottler, M.L., Richard, O., Sanchez-Franco, F., Saura, R., Young, J., Petit, C., Hardelin, J.P. Nat. Genet. (2003) [Pubmed]
  13. Crystal structures of two FGF-FGFR complexes reveal the determinants of ligand-receptor specificity. Plotnikov, A.N., Hubbard, S.R., Schlessinger, J., Mohammadi, M. Cell (2000) [Pubmed]
  14. 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]
  15. Anosmin-1 modulates fibroblast growth factor receptor 1 signaling in human gonadotropin-releasing hormone olfactory neuroblasts through a heparan sulfate-dependent mechanism. González-Martínez, D., Kim, S.H., Hu, Y., Guimond, S., Schofield, J., Winyard, P., Vannelli, G.B., Turnbull, J., Bouloux, P.M. J. Neurosci. (2004) [Pubmed]
  16. Angiogenic growth factors and their receptors in non-small cell lung carcinomas and their relationships to drug response in vitro. Volm, M., Koomägi, R., Mattern, J., Stammler, G. Anticancer Res. (1997) [Pubmed]
  17. FGFR1 Emerges as a Potential Therapeutic Target for Lobular Breast Carcinomas. Reis-Filho, J.S., Simpson, P.T., Turner, N.C., Lambros, M.B., Jones, C., Mackay, A., Grigoriadis, A., Sarrio, D., Savage, K., Dexter, T., Iravani, M., Fenwick, K., Weber, B., Hardisson, D., Schmitt, F.C., Palacios, J., Lakhani, S.R., Ashworth, A. Clin. Cancer Res. (2006) [Pubmed]
  18. Phosphotyrosine profiling identifies the KG-1 cell line as a model for the study of FGFR1 fusions in acute myeloid leukemia. Gu, T.L., Goss, V.L., Reeves, C., Popova, L., Nardone, J., Macneill, J., Walters, D.K., Wang, Y., Rush, J., Comb, M.J., Druker, B.J., Polakiewicz, R.D. Blood (2006) [Pubmed]
  19. Trans-activation of EphA4 and FGF receptors mediated by direct interactions between their cytoplasmic domains. Yokote, H., Fujita, K., Jing, X., Sawada, T., Liang, S., Yao, L., Yan, X., Zhang, Y., Schlessinger, J., Sakaguchi, K. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  20. The t(6;8)(q27;p11) translocation in a stem cell myeloproliferative disorder fuses a novel gene, FOP, to fibroblast growth factor receptor 1. Popovici, C., Zhang, B., Grégoire, M.J., Jonveaux, P., Lafage-Pochitaloff, M., Birnbaum, D., Pébusque, M.J. Blood (1999) [Pubmed]
  21. Identification of a novel variant form of fibroblast growth factor receptor 3 (FGFR3 IIIb) in human colonic epithelium. Murgue, B., Tsunekawa, S., Rosenberg, I., deBeaumont, M., Podolsky, D.K. Cancer Res. (1994) [Pubmed]
  22. Physiological function and putative therapeutic impact of the FGF-2 system in peripheral nerve regeneration--lessons from in vivo studies in mice and rats. Grothe, C., Haastert, K., Jungnickel, J. Brain Res. Brain Res. Rev. (2006) [Pubmed]
  23. Modification of alternative messenger RNA splicing of fibroblast growth factor receptors in human cardiac allografts during rejection. Zhao, X.M., Frist, W.H., Yeoh, T.K., Miller, G.G. J. Clin. Invest. (1994) [Pubmed]
  24. Chimeras of the native form or achondroplasia mutant (G375C) of human fibroblast growth factor receptor 3 induce ligand-dependent differentiation of PC12 cells. Thompson, L.M., Raffioni, S., Wasmuth, J.J., Bradshaw, R.A. Mol. Cell. Biol. (1997) [Pubmed]
  25. 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]
  26. 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]
  27. Kinetic model for FGF, FGFR, and proteoglycan signal transduction complex assembly. Ibrahimi, O.A., Zhang, F., Hrstka, S.C., Mohammadi, M., Linhardt, R.J. Biochemistry (2004) [Pubmed]
  28. Downregulation of differentiation specific gene expression by oxidative stress in ARPE-19 cells. Alizadeh, M., Wada, M., Gelfman, C.M., Handa, J.T., Hjelmeland, L.M. Invest. Ophthalmol. Vis. Sci. (2001) [Pubmed]
  29. Comparative localization of fibroblast growth factor receptor-1, -2, and -3 mRNAs in the rat brain: in situ hybridization analysis. Belluardo, N., Wu, G., Mudo, G., Hansson, A.C., Pettersson, R., Fuxe, K. J. Comp. Neurol. (1997) [Pubmed]
  30. FGFR1 and WT1 are markers of human prostate cancer progression. Devilard, E., Bladou, F., Ramuz, O., Karsenty, G., Dal??s, J.P., Gravis, G., Nguyen, C., Bertucci, F., Xerri, L., Birnbaum, D. BMC Cancer (2006) [Pubmed]
  31. MDA-MB-134 breast carcinoma cells overexpress fibroblast growth factor (FGF) receptors and are growth-inhibited by FGF ligands. McLeskey, S.W., Ding, I.Y., Lippman, M.E., Kern, F.G. Cancer Res. (1994) [Pubmed]
  32. Translating the therapeutic potential of AZD4547 in FGFR1-amplified non-small cell lung cancer through the use of patient-derived tumor xenograft models. Zhang, J., Zhang, L., Su, X., Li, M., Xie, L., Malchers, F., Fan, S., Yin, X., Xu, Y., Liu, K., Dong, Z., Zhu, G., Qian, Z., Tang, L., Schöttle, J., Zhan, P., Ji, Q., Kilgour, E., Smith, P.D., Brooks, A.N., Thomas, R.K., Gavine, P.R. Clin. Cancer Res. (2012) [Pubmed]
  33. Costimulation of T cell receptor-triggered IL-2 production by Jurkat T cells via fibroblast growth factor receptor 1 upon its engagement by CD56. Kos, F.J., Chin, C.S. Immunol. Cell Biol. (2002) [Pubmed]
  34. Nuclear localization of functional FGF receptor 1 in human astrocytes suggests a novel mechanism for growth factor action. Stachowiak, M.K., Maher, P.A., Joy, A., Mordechai, E., Stachowiak, E.K. Brain Res. Mol. Brain Res. (1996) [Pubmed]
  35. FRS2 PTB domain conformation regulates interactions with divergent neurotrophic receptors. Yan, K.S., Kuti, M., Yan, S., Mujtaba, S., Farooq, A., Goldfarb, M.P., Zhou, M.M. J. Biol. Chem. (2002) [Pubmed]
  36. Receptor for acidic fibroblast growth factor is related to the tyrosine kinase encoded by the fms-like gene (FLG). Ruta, M., Burgess, W., Givol, D., Epstein, J., Neiger, N., Kaplow, J., Crumley, G., Dionne, C., Jaye, M., Schlessinger, J. Proc. Natl. Acad. Sci. U.S.A. (1989) [Pubmed]
  37. Control of CREB-binding protein signaling by nuclear fibroblast growth factor receptor-1: a novel mechanism of gene regulation. Fang, X., Stachowiak, E.K., Dunham-Ems, S.M., Klejbor, I., Stachowiak, M.K. J. Biol. Chem. (2005) [Pubmed]
  38. p21-activated kinase 1 interacts with and phosphorylates histone H3 in breast cancer cells. Li, F., Adam, L., Vadlamudi, R.K., Zhou, H., Sen, S., Chernoff, J., Mandal, M., Kumar, R. EMBO Rep. (2002) [Pubmed]
  39. Phosphorylation of histones by tissue transglutaminase. Mishra, S., Saleh, A., Espino, P.S., Davie, J.R., Murphy, L.J. J. Biol. Chem. (2006) [Pubmed]
  40. The CBP bromodomain and nucleosome targeting are required for Zta-directed nucleosome acetylation and transcription activation. Deng, Z., Chen, C.J., Chamberlin, M., Lu, F., Blobel, G.A., Speicher, D., Cirillo, L.A., Zaret, K.S., Lieberman, P.M. Mol. Cell. Biol. (2003) [Pubmed]
  41. 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]
  42. 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]
  43. Fibroblast growth factor expression in the postnatal growth plate. Lazarus, J.E., Hegde, A., Andrade, A.C., Nilsson, O., Baron, J. Bone (2007) [Pubmed]
  44. Fibroblast growth factors and their receptors in parathyroid disease. Lambert, D., Eaton, C.L., Harrison, B.J. World journal of surgery. (1998) [Pubmed]
  45. Cell- and receptor isotype-specific phosphorylation of SNT1 by fibroblast growth factor receptor tyrosine kinases. Wang, F. In Vitro Cell. Dev. Biol. Anim. (2002) [Pubmed]
  46. 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]
  47. Comparison of the intracellular signaling responses by three chimeric fibroblast growth factor receptors in PC12 cells. Raffioni, S., Thomas, D., Foehr, E.D., Thompson, L.M., Bradshaw, R.A. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  48. Mutations causing achondroplasia and thanatophoric dysplasia alter bFGF-induced calcium signals in human diploid fibroblasts. Nguyen, H.B., Estacion, M., Gargus, J.J. Hum. Mol. Genet. (1997) [Pubmed]
  49. Mapping ligand binding domains in chimeric fibroblast growth factor receptor molecules. Multiple regions determine ligand binding specificity. Chellaiah, A., Yuan, W., Chellaiah, M., Ornitz, D.M. J. Biol. Chem. (1999) [Pubmed]
  50. Nuclear accumulation of fibroblast growth factor receptors in human glial cells--association with cell proliferation. Stachowiak, E.K., Maher, P.A., Tucholski, J., Mordechai, E., Joy, A., Moffett, J., Coons, S., Stachowiak, M.K. Oncogene (1997) [Pubmed]
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