Skip to main content
SpringerLink
Log in

The FGFR Receptor Family

  • Chapter
Receptor Tyrosine Kinases: Family and Subfamilies

  • 1809 Accesses

Abstract

Fibroblast Growth Factors (FGFs), in a complex with their receptors (FGFRs) and heparan sulphate (HS), impact on a wide range of cellular functions, regulating processes from embryogenesis to metabolism. Upon ligand binding and receptor dimerisation, four key downstream pathways are initiated: MAPK, PI3K/AKT, STAT and PLCγ. Regulation of FGF signalling is critical to ensure a balanced response to receptor stimulation. This occurs through negative feedback mechanisms, including internalisation, cleavage and induction of negative regulators. FGF signalling has been studied in depth by developmental biologists, in a variety of model systems, and plays a critical role in developmental patterning and the establishment of paracrine signalling loops. Both germ line and somatic FGFR mutations are known to play a role in a range of diseases, most notably developmentally regulated diseases such as craniosynostosis dysplasias, dwarfism and hearing loss. Because of the ability of FGFR signalling to induce cell proliferation, migration and survival, FGFRs are readily co-opted by cancer cells. Mutations in, and amplifications of, these receptors are found in a range of cancers. Here, we outline the molecular mechanisms of FGFR signalling and discuss the role of this pathway in development and disease. We also address the rationale for therapeutic intervention and the need for FGFR-targeted therapy to selectively target cancer cells in view of the fundamental roles of FGF signalling in normal physiology.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

ADAM:

A Disintegrin And Metalloprotease

CAD:

Coronary Artery Disease

CBL:

Casitas B-lineage Lymphoma Protein

CLR-1:

Cryptic Loci Regulator

c-MYC:

Cellular-Myelocytomatosis Oncogene

COSMIC:

Catalogue of Somatic Mutations in Cancer

CS:

Chondroitin Sulphate

DAG:

Diacylglycerol

DOF:

Downstream of FGFR

EGL:

Egg Laying Abnormal

EOC:

Epithelial Ovarian Cancer

ER:

Endoplasmic Reticulum

ERK:

Extracellular Signal-Regulated Kinase

FGF:

Fibroblast Growth Factor

FGFR:

Fibroblast Growth Factor Receptor

FGFRL1:

FGFR-Like 1

FRS2:

Fibroblast Growth Factor Receptor Substrate 2

GAB1:

GRB2-Associated Binding protein 1

GAG:

Glycosaminoglycan

GAS:

Gamma-Activated Site

GEF:

Guanine Exchange Factor

GRB2:

Growth Factor Receptor-Bound Protein 2

HS:

Heparan Sulphate

HSPG:

Heparan Sulphate Proteoglycan

IGF:

Insulin-like Growth Factor

INFS:

Integrative Nuclear FGFR1 Signalling

IP3 :

Inositol trisphosphate

JAK:

Janus Kinase

KDR:

Kinase Insert Domain Receptor

LADD:

Lacrimo-Auriculo-Dento-Digital

LET-756:

Lethal Protein 756

MAPK:

Mitogen-Activated Protein Kinase

MEK:

ERK Kinase

MMP:

Metalloprotease

MPS:

Myeloproliferative Syndrome

NBR1:

Neighbor of BRCA1

NCAM:

Neural Cell Adhesion Molecule

NLS:

Nuclear Localisation Signal

PI3K:

Phosphoinositide-3 Kinase

PIP2 :

Phosphatidyl-inositol-4, 5-bisphosphate

PIP3 :

Phosphatidyl-inositol (3, 4, 5)-trisphosphate

PKC:

Protein Kinase C

PLCγ:

Phospholipase C γ

PTB:

Phosphotyrosine Binding

Rab5:

Ras-Related Proteins in Brain 5

RAF:

Rapidly Accelerated Fibrosarcoma

RAS:

Rat Sarcoma

RhoG:

Ras Homology Growth-Related

RTK:

Receptor Tyrosine Kinase

S4:

Syndecan 4

SEF:

Similar Expression to FGF

SH2:

Src Homology 2

SH3:

SRC Homology 3

SNP:

Single Nucelotide Polymorphism

SOS:

Son of Sevenless

SPRED:

Sprouty-Related Enabled/Vasodilator-stimulated Phosphoprotein Homology 1 Domain-Containing Protein

SPRY:

Sprouty

STAT:

Signal Transducer and Activator of Transcription

TGFβ:

Transforming Growth Factor β

TM:

Transmembrane

VEGFR:

Vascular Endothelial Growth Factor Receptor

XFLRT3:

Xenopus Fibronectin Leucine-Rich Transmembrane Protein 3

References

  1. Yayon A, Klagsbrun M, Esko JD, Leder P, Ornitz DM. Cell surface, heparin-like molecules are required for binding of basic fibroblast growth factor to its high affinity receptor. Cell. 1991;64:841–8.

    CAS  PubMed  Google Scholar 

  2. Coughlin SR, Barr PJ, Cousens LS, Fretto LJ, Williams LT. Acidic and basic fibroblast growth factors stimulate tyrosine kinase activity in vivo. J Biol Chem. 1988;263:988–93.

    CAS  PubMed  Google Scholar 

  3. Ornitz DM, Itoh N. Fibroblast growth factors. Genome Biol. 2001; 2: REVIEWS3005.

    Google Scholar 

  4. Ornitz DM, Xu J, Colvin JS, McEwen DG, MacArthur CA, Coulier F, Gao G, Goldfarb M. Receptor specificity of the fibroblast growth factor family. J Biol Chem. 1996;271:15292–7.

    CAS  PubMed  Google Scholar 

  5. Zhang X, Ibrahimi OA, Olsen SK, Umemori H, Mohammadi M, Ornitz DM. Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family. J Biol Chem. 2006;281:15694–700.

    CAS  PubMed Central  PubMed  Google Scholar 

  6. Johnson DE, Williams LT. Structural and functional diversity in the FGF receptor multigene family. Adv Cancer Res. 1993;60:1–41.

    CAS  PubMed  Google Scholar 

  7. Kalinina J, Dutta K, Ilghari D, Beenken A, Goetz R, Eliseenkova AV, Cowburn D, Mohammadi M. The alternatively spliced acid box region plays a key role in FGF receptor autoinhibition. Structure. 2012;20:77–88.

    CAS  PubMed Central  PubMed  Google Scholar 

  8. Wheldon LM, Khodabukus N, Patey SJ, Smith TG, Heath JK, Hajihosseini MK. Identification and characterization of an inhibitory fibroblast growth factor receptor 2 (FGFR2) molecule, up-regulated in an Apert Syndrome mouse model. Biochem J. 2011;436:71–81.

    CAS  PubMed  Google Scholar 

  9. Vainikka S, Partanen J, Bellosta P, Coulier F, Birnbaum D, Basilico C, Jaye M, Alitalo K. Fibroblast growth factor receptor-4 shows novel features in genomic structure, ligand binding and signal transduction. EMBO J. 1992;11:4273–80.

    CAS  PubMed Central  PubMed  Google Scholar 

  10. Orr-Urtreger A, Bedford M, Burakova T, Arman E, Zimmer Y, Yayon A, Givol D, Lonai P. Developmental localization of the splicing alternatives of fibroblast growth-factor receptor-2 (FGFR2). Dev Biol. 1993;158:475–86.

    CAS  PubMed  Google Scholar 

  11. Yan G, Fukabori Y, McBride G, Nikolaropolous S, McKeehan WL. Exon switching and activation of stromal and embryonic fibroblast growth factor (FGF)-FGF receptor genes in prostate epithelial cells accompany stromal independence and malignancy. Mol Cell Biol. 1993;13:4513–22.

    CAS  PubMed Central  PubMed  Google Scholar 

  12. Lindahl U, Hook M. Glycosaminoglycans and their binding to biological macromolecules. Annu Rev Biochem. 1978;47:385–417.

    CAS  PubMed  Google Scholar 

  13. Gambarini AG, Miyamoto CA, Lima GA, Nader HB, Dietrich CP. Mitogenic activity of acidic fibroblast growth factor is enhanced by highly sulfated oligosaccharides derived from heparin and heparan sulfate. Mol Cell Biochem. 1993;124:121–9.

    CAS  PubMed  Google Scholar 

  14. Ornitz DM, Yayon A, Flanagan JG, Svahn CM, Levi E, Leder P. Heparin is required for cell-free binding of basic fibroblast growth factor to a soluble receptor and for mitogenesis in whole cells. Mol Cell Biol. 1992;12:240–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  15. Ornitz DM, Herr AB, Nilsson M, Westman J, Svahn CM, Waksman G. FGF binding and FGF receptor activation by synthetic heparan-derived di- and trisaccharides. Science. 1995;268:432–6.

    CAS  PubMed  Google Scholar 

  16. Schlessinger J, Plotnikov AN, Ibrahimi OA, Eliseenkova AV, Yeh BK, Yayon A, Linhardt RJ, Mohammadi M. Crystal structure of a ternary FGF-FGFR-heparin complex reveals a dual role for heparin in FGFR binding and dimerization. Mol Cell. 2000;6:743–50.

    CAS  PubMed  Google Scholar 

  17. Guimond SE, Turnbull JE. Fibroblast growth factor receptor signalling is dictated by specific heparan sulphate saccharides. Curr Biol. 1999;9:1343–6.

    CAS  PubMed  Google Scholar 

  18. Ornitz DM. FGFs, heparan sulfate and FGFRs: complex interactions essential for development. Bioessays. 2000;22:108–12.

    CAS  PubMed  Google Scholar 

  19. McDowell LM, Frazier BA, Studelska DR, Giljum K, Chen J, Liu J, Yu K, Ornitz DM, Zhang L. Inhibition or activation of Apert syndrome FGFR2 (S252W) signaling by specific glycosaminoglycans. J Biol Chem. 2006;281:6924–30.

    CAS  PubMed  Google Scholar 

  20. Guimond S, Maccarana M, Olwin BB, Lindahl U, Rapraeger AC. Activating and inhibitory heparin sequences for FGF-2 (basic FGF). Distinct requirements for FGF-1, FGF-2, and FGF-4. J Biol Chem. 1993;268:23906–14.

    CAS  PubMed  Google Scholar 

  21. Pye DA, Vives RR, Turnbull JE, Hyde P, Gallagher JT. Heparan sulfate oligosaccharides require 6-O-sulfation for promotion of basic fibroblast growth factor mitogenic activity. J Biol Chem. 1998;273:22936–42.

    CAS  PubMed  Google Scholar 

  22. Taylor KR, Rudisill JA, Gallo RL. Structural and sequence motifs in dermatan sulfate for promoting fibroblast growth factor-2 (FGF-2) and FGF-7 activity. J Biol Chem. 2005;280:5300–6.

    CAS  PubMed  Google Scholar 

  23. Trowbridge JM, Rudisill JA, Ron D, Gallo RL. Dermatan sulfate binds and potentiates activity of keratinocyte growth factor (FGF-7). J Biol Chem. 2002;277:42815–20.

    CAS  PubMed  Google Scholar 

  24. Pellegrini L, Burke DF, von Delft F, Mulloy B, Blundell TL. Crystal structure of fibroblast growth factor receptor ectodomain bound to ligand and heparin. Nature. 2000;407:1029–34.

    CAS  PubMed  Google Scholar 

  25. Furdui CM, Lew ED, Schlessinger J, Anderson KS. Autophosphorylation of FGFR1 kinase is mediated by a sequential and precisely ordered reaction. Mol Cell. 2006;21:711–7.

    CAS  PubMed  Google Scholar 

  26. Mohammadi M, Dionne CA, Li W, Li N, Spivak T, Honegger AM, Jaye M, Schlessinger J. Point mutation in FGF receptor eliminates phosphatidylinositol hydrolysis without affecting mitogenesis. Nature. 1992;358:681–4.

    CAS  PubMed  Google Scholar 

  27. Mohammadi M, Schlessinger J, Hubbard SR. Structure of the FGF receptor tyrosine kinase domain reveals a novel autoinhibitory mechanism. Cell. 1996;86:577–87.

    CAS  PubMed  Google Scholar 

  28. Mohammadi M, Dikic I, Sorokin A, Burgess WH, Jaye M, Schlessinger J. Identification of six novel autophosphorylation sites on fibroblast growth factor receptor 1 and elucidation of their importance in receptor activation and signal transduction. Mol Cell Biol. 1996; 16:977–89.

    CAS  PubMed Central  PubMed  Google Scholar 

  29. Raffioni S, Thomas D, Foehr ED, Thompson LM, Bradshaw RA. Comparison of the intracellular signaling responses by three chimeric fibroblast growth factor receptors in PC12 cells. Proc Natl Acad Sci USA. 1999;96:7178–83.

    CAS  PubMed Central  PubMed  Google Scholar 

  30. Dhalluin C, Yan KS, Plotnikova O, Lee KW, Zeng L, Kuti M, Mujtaba S, Goldfarb MP, Zhou MM. Structural basis of SNT PTB domain interactions with distinct neurotrophic receptors. Mol Cell. 2000;6:921–9.

    CAS  PubMed  Google Scholar 

  31. Ong SH, Guy GR, Hadari YR, Laks S, Gotoh N, Schlessinger J, Lax I. FRS2 proteins recruit intracellular signaling pathways by binding to diverse targets on fibroblast growth factor and nerve growth factor receptors. Mol Cell Biol. 2000;20:979–89.

    CAS  PubMed Central  PubMed  Google Scholar 

  32. Gotoh N. Regulation of growth factor signaling by FRS2 family docking/scaffold adaptor proteins. Cancer Sci. 2008;99:1319–25.

    CAS  PubMed  Google Scholar 

  33. Eswarakumar VP, Lax I, Schlessinger J. Cellular signaling by fibroblast growth factor receptors. Cytokine Growth Factor Rev. 2005;16:139–49.

    CAS  PubMed  Google Scholar 

  34. Mohammadi M, Honegger AM, Rotin D, Fischer R, Bellot F, Li W, Dionne CA, Jaye M, Rubinstein M, Schlessinger J. A tyrosine-phosphorylated carboxy-terminal peptide of the fibroblast growth factor receptor (Flg) is a binding site for the SH2 domain of phospholipase C-gamma 1. Mol Cell Biol. 1991;11:5068–78.

    CAS  PubMed Central  PubMed  Google Scholar 

  35. Falasca M, Iurisci C, Carvelli A, Sacchetti A, Corda D. Release of the mitogen lysophosphatidylinositol from H-Ras-transformed fibroblasts; a possible mechanism of autocrine control of cell proliferation. Oncogene. 1998;16:2357–65.

    CAS  PubMed  Google Scholar 

  36. Klint P, Claesson-Welsh L. Signal transduction by fibroblast growth factor receptors. Front Biosci. 1999;4:165–77.

    Google Scholar 

  37. Rameh LE, Rhee SG, Spokes K, Kazlauskas A, Cantley LC, Cantley LG. Phosphoinositide 3-kinase regulates phospholipase Cgamma-mediated calcium signaling. J Biol Chem. 1998;273:23750–7.

    CAS  PubMed  Google Scholar 

  38. Ebong S, Yu CR, Carper DA, Chepelinsky AB, Egwuagu CE. Activation of STAT signaling pathways and induction of suppressors of cytokine signaling (SOCS) proteins in mammalian lens by growth factors. Invest Ophthalmol Vis Sci. 2004;45:872–8.

    PubMed  Google Scholar 

  39. Darnell Jr JE. STATs and gene regulation. Science. 1997;277:1630–5.

    CAS  PubMed  Google Scholar 

  40. Wang L, Rudert WA, Loutaev I, Roginskaya V, Corey SJ. Repression of c-Cbl leads to enhanced G-CSF Jak-STAT signaling without increased cell proliferation. Oncogene. 2002;21:5346–55.

    CAS  PubMed  Google Scholar 

  41. Degnin CR, Laederich MB, Horton WA. Ligand activation leads to regulated intramembrane proteolysis of fibroblast growth factor receptor 3. Mol Biol Cell. 2011;22:3861–73.

    CAS  PubMed Central  PubMed  Google Scholar 

  42. Blobel CP, Carpenter G, Freeman M. The role of protease activity in ErbB biology. Exp Cell Res. 2009;315:671–82.

    CAS  PubMed Central  PubMed  Google Scholar 

  43. Brown MS, Ye J, Rawson RB, Goldstein JL. Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans. Cell. 2000;100:391–8.

    CAS  PubMed  Google Scholar 

  44. Levi E, Fridman R, Miao HQ, Ma YS, Yayon A, Vlodavsky I. Matrix metalloproteinase 2 releases active soluble ectodomain of fibroblast growth factor receptor 1. Proc Natl Acad Sci USA. 1996;93:7069–74.

    CAS  PubMed Central  PubMed  Google Scholar 

  45. Maretzky T, Le Gall SM, Worpenberg-Pietruk S, Eder J, Overall CM, Huang XY, Poghosyan Z, Edwards DR, Blobel CP. Src stimulates fibroblast growth factor receptor-2 shedding by an ADAM15 splice variant linked to breast cancer. Cancer Res. 2009;69:4573–6.

    CAS  PubMed  Google Scholar 

  46. Peduto L, Reuter VE, Shaffer DR, Scher HI, Blobel CP. Critical function for ADAM9 in mouse prostate cancer. Cancer Res. 2005;65:9312–9.

    CAS  PubMed  Google Scholar 

  47. Ancot F, Foveau B, Lefebvre J, Leroy C, Tulasne D. Proteolytic cleavages give receptor tyrosine kinases the gift of ubiquity. Oncogene. 2009;28:2185–95.

    CAS  PubMed  Google Scholar 

  48. Loeb CR, Harris JL, Craik CS. Granzyme B proteolyzes receptors important to proliferation and survival, tipping the balance toward apoptosis. J Biol Chem. 2006;281:28326–35.

    CAS  PubMed  Google Scholar 

  49. Chioni AM, Grose R. FGFR1 cleavage and nuclear translocation regulates breast cancer cell behavior. J Cell Biol. 2012;197:801–17.

    CAS  PubMed Central  PubMed  Google Scholar 

  50. Hacohen N, Kramer S, Sutherland D, Hiromi Y, Krasnow MA. Sprouty encodes a novel antagonist of FGF signaling that patterns apical branching of the Drosophila airways. Cell. 1998;92:253–63.

    CAS  PubMed  Google Scholar 

  51. Thisse B, Thisse C. Functions and regulations of fibroblast growth factor signaling during embryonic development. Dev Biol. 2005;287:390–402.

    CAS  PubMed  Google Scholar 

  52. Sasaki A, Taketomi T, Kato R, Saeki K, Nonami A, Sasaki M, Kuriyama M, Saito N, Shibuya M, Yoshimura A. Mammalian Sprouty4 suppresses Ras-independent ERK activation by binding to Raf1. Cell Cycle. 2003;2:281–2.

    CAS  PubMed  Google Scholar 

  53. Wakioka T, Sasaki A, Kato R, Shouda T, Matsumoto A, Miyoshi K, Tsuneoka M, Komiya S, Baron R, Yoshimura A. Spred is a Sprouty-related suppressor of Ras signalling. Nature. 2001;412:647–51.

    CAS  PubMed  Google Scholar 

  54. Mardakheh FK, Yekezare M, Machesky LM, Heath JK. Spred2 interaction with the late endosomal protein NBR1 down-regulates fibroblast growth factor receptor signaling. J Cell Biol. 2009;187:265–77.

    CAS  PubMed Central  PubMed  Google Scholar 

  55. Yang RB, Ng CK, Wasserman SM, Komuves LG, Gerritsen ME, Topper JN. A novel interleukin-17 receptor-like protein identified in human umbilical vein endothelial cells antagonizes basic fibroblast growth factor-induced signaling. J Biol Chem. 2003;278:33232–8.

    CAS  PubMed  Google Scholar 

  56. Kovalenko D, Yang X, Nadeau RJ, Harkins LK, Friesel R. Sef inhibits fibroblast growth factor signaling by inhibiting FGFR1 tyrosine phosphorylation and subsequent ERK activation. J Biol Chem. 2003;278:14087–91.

    CAS  PubMed  Google Scholar 

  57. Tsang M, Friesel R, Kudoh T, Dawid IB. Identification of Sef, a novel modulator of FGF signalling. Nat Cell Biol. 2002;4:165–9.

    CAS  PubMed  Google Scholar 

  58. Xiong S, Zhao Q, Rong Z, Huang G, Huang Y, Chen P, Zhang S, Liu L, Chang Z. hSef inhibits PC-12 cell differentiation by interfering with Ras-mitogen-activated protein kinase MAPK signaling. J Biol Chem. 2003;278:50273–82.

    CAS  PubMed  Google Scholar 

  59. Torii S, Kusakabe M, Yamamoto T, Maekawa M, Nishida E. Sef is a spatial regulator for Ras/MAP kinase signaling. Dev Cell. 2004;7:33–44.

    CAS  PubMed  Google Scholar 

  60. Buday L, Warne PH, Downward J. Downregulation of the Ras activation pathway by MAP kinase phosphorylation of Sos. Oncogene. 1995;11:1327–31.

    CAS  PubMed  Google Scholar 

  61. Ueki K, Matsuda S, Tobe K, Gotoh Y, Tamemoto H, Yachi M, Akanuma Y, Yazaki Y, Nishida E, Kadowaki T. Feedback regulation of mitogen-activated protein kinase kinase kinase activity of c-Raf-1 by insulin and phorbol ester stimulation. J Biol Chem. 1994;269:15756–61.

    CAS  PubMed  Google Scholar 

  62. Gual P, Giordano S, Anguissola S, Parker PJ, Comoglio PM. Gab1 phosphorylation: a novel mechanism for negative regulation of HGF receptor signaling. Oncogene. 2001;20:156–66.

    CAS  PubMed  Google Scholar 

  63. Plotnikov AN, Schlessinger J, Hubbard SR, Mohammadi M. Structural basis for FGF receptor dimerization and activation. Cell. 1999;98:641–50.

    CAS  PubMed  Google Scholar 

  64. Stauber DJ, DiGabriele AD, Hendrickson WA. Structural interactions of fibroblast growth factor receptor with its ligands. Proc Natl Acad Sci USA. 2000;97:49–54.

    CAS  PubMed Central  PubMed  Google Scholar 

  65. Olsen SK, Ibrahimi OA, Raucci A, Zhang F, Eliseenkova AV, Yayon A, Basilico C, Linhardt RJ, Schlessinger J, Mohammadi M. Insights into the molecular basis for fibroblast growth factor receptor autoinhibition and ligand-binding promiscuity. Proc Natl Acad Sci USA. 2004;101:935–40.

    CAS  PubMed Central  PubMed  Google Scholar 

  66. Kobrin MS, Yamanaka Y, Friess H, Lopez ME, Korc M. Aberrant expression of type I fibroblast growth factor receptor in human pancreatic adenocarcinomas. Cancer Res. 1993;53:4741–4.

    CAS  PubMed  Google Scholar 

  67. Mansson PE, Adams P, Kan M, McKeehan WL. Heparin-binding growth factor gene expression and receptor characteristics in normal rat prostate and two transplantable rat prostate tumors. Cancer Res. 1989;49:2485–94.

    CAS  PubMed  Google Scholar 

  68. Itoh N, Ornitz DM. Evolution of the Fgf and Fgfr gene families. Trends Genet. 2004;20:563–9.

    CAS  PubMed  Google Scholar 

  69. Goetz R, Beenken A, Ibrahimi OA, Kalinina J, Olsen SK, Eliseenkova AV, Xu C, Neubert TA, Zhang F, Linhardt RJ, Yu X, White KE, Inagaki T, Kliewer SA, Yamamoto M, Kurosu H, Ogawa Y, Kuro-o M, Lanske B, Razzaque MS, Mohammadi M. Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members. Mol Cell Biol. 2007;27:3417–28.

    CAS  PubMed Central  PubMed  Google Scholar 

  70. Harmer NJ, Pellegrini L, Chirgadze D, Fernandez-Recio J, Blundell TL. The crystal structure of fibroblast growth factor (FGF) 19 reveals novel features of the FGF family and offers a structural basis for its unusual receptor affinity. Biochemistry. 2004;43:629–40.

    CAS  PubMed  Google Scholar 

  71. Kurosu H, Kuro OM. The Klotho gene family as a regulator of endocrine fibroblast growth factors. Mol Cell Endocrinol. 2009;299:72–8.

    CAS  PubMed  Google Scholar 

  72. Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K, Fujita T, Fukumoto S, Yamashita T. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature. 2006;444:770–4.

    CAS  PubMed  Google Scholar 

  73. Polanska UM, Edwards E, Fernig DG, Kinnunen TK. The cooperation of FGF receptor and Klotho is involved in excretory canal development and regulation of metabolic homeostasis in Caenorhabditis elegans. J Biol Chem. 2011;286:5657–66.

    CAS  PubMed Central  PubMed  Google Scholar 

  74. Polanska UM, Fernig DG, Kinnunen T. Extracellular interactome of the FGF receptor-ligand system: complexities and the relative simplicity of the worm. Dev Dyn. 2009;238:277–93.

    CAS  PubMed  Google Scholar 

  75. Ghabrial A, Luschnig S, Metzstein MM, Krasnow MA. Branching morphogenesis of the Drosophila tracheal system. Annu Rev Cell Dev Biol. 2003;19:623–47.

    CAS  PubMed  Google Scholar 

  76. Bottcher RT, Niehrs C. Fibroblast growth factor signaling during early vertebrate development. Endocr Rev. 2005;26:63–77.

    PubMed  Google Scholar 

  77. Dorey K, Amaya E. FGF signalling: diverse roles during early vertebrate embryogenesis. Development. 2010;137:3731–42.

    CAS  PubMed Central  PubMed  Google Scholar 

  78. Huang P, Stern MJ. FGF signaling in flies and worms: more and more relevant to vertebrate biology. Cytokine Growth Factor Rev. 2005;16:151–8.

    CAS  PubMed  Google Scholar 

  79. DeVore DL, Horvitz HR, Stern MJ. An FGF receptor signaling pathway is required for the normal-cell migrations of the sex myoblasts in C-elegans hermaphrodites. Cell. 1995;83:611–20.

    CAS  PubMed  Google Scholar 

  80. Burdine RD, Branda CS, Stern MJ. EGL-17(FGF) expression coordinates the attraction of the migrating sex myoblasts with vulval induction in C. elegans. Development. 1998;125:1083–93.

    CAS  PubMed  Google Scholar 

  81. Popovici C, Conchonaud F, Birnbaum D, Roubin R. Functional phylogeny relates LET-756 to fibroblast growth factor 9. J Biol Chem. 2004;279:40146–52.

    CAS  PubMed  Google Scholar 

  82. Roubin R, Naert K, Popovici C, Vatcher G, Coulier F, Thierry-Mieg J, Pontarotti P, Birnbaum D, Baillie D, Thierry-Mieg D. let-756, a C. elegans fgf essential for worm development. Oncogene. 1999;18:6741–7.

    CAS  PubMed  Google Scholar 

  83. Kokel M, Borland CZ, DeLong L, Horvitz HR, Stern MJ. clr-1 encodes a receptor tyrosine phosphatase that negatively regulates an FGF receptor signaling pathway in Caenorhabditis elegans. Genes Dev. 1998;12:1425–37.

    CAS  PubMed Central  PubMed  Google Scholar 

  84. Borland CZ, Schutzman JL, Stern MJ. Fibroblast growth factor signaling in Caenorhabditis elegans. Bioessays. 2001;23:1120–30.

    CAS  PubMed  Google Scholar 

  85. Chateau MT, Araiz C, Descamps S, Galas S. Klotho interferes with a novel FGF-signalling pathway and insulin/Igf-like signalling to improve longevity and stress resistance in Caenorhabditis elegans. Aging. 2010;2:567–81.

    CAS  PubMed Central  PubMed  Google Scholar 

  86. Glazer L, Shilo B-Z. The Drosophila FGF-R homolog is expressed in the embryonic tracheal system and appears to be required for directed tracheal cell extension. Genes Dev. 1991;5:697–705.

    CAS  PubMed  Google Scholar 

  87. Sutherland D, Samakovlis C, Krasnow MA. branchless encodes a Drosophila FGF homolog that controls tracheal cell migration and the pattern of branching. Cell. 1996;87:1091–101.

    CAS  PubMed  Google Scholar 

  88. Ghabrial AS, Krasnow MA. Social interactions among epithelial cells during tracheal branching morphogenesis. Nature. 2006;441:746–9.

    CAS  PubMed  Google Scholar 

  89. Tsang M, Dawid IB. Promotion and attenuation of FGF signaling through the Ras-MAPK pathway. Sci STKE. 2004:pe17.

    Google Scholar 

  90. Beiman M, Shilo BZ, Volk T. Heartless, a Drosophila FGF receptor homolog, is essential for cell migration and establishment of several mesodermal lineages. Genes Dev. 1996;10:2993–3002.

    CAS  PubMed  Google Scholar 

  91. Gisselbrecht S, Skeath JB, Doe CQ, Michelson AM. Heartless encodes a fibroblast growth factor receptor (DFR1/DFGF-R2) involved in the directional migration of early mesodermal cells in the Drosophila embryo. Genes Dev. 1996;10:3003–17.

    CAS  PubMed  Google Scholar 

  92. Gryzik T, Muller HA. FGF8-like1 and FGF8-like2 encode putative ligands of the FGF receptor Htl and are required for mesoderm migration in the Drosophila gastrula. Curr Biol. 2004;14:659–67.

    CAS  PubMed  Google Scholar 

  93. Stathopoulos A, Tam B, Ronshaugen M, Frasch M, Levine M. pyramus and thisbe: FGF genes that pattern the mesoderm of Drosophila embryos. Genes Dev. 2004;18:687–99.

    CAS  PubMed Central  PubMed  Google Scholar 

  94. Vincent S, Wilson R, Coelho C, Affolter M, Leptin M. The Drosophila protein Dof is specifically required for FGF signaling. Mol Cell. 1998;2:515–25.

    CAS  PubMed  Google Scholar 

  95. Rodaway A, Takeda H, Koshida S, Broadbent J, Price B, Smith JC, Patient R, Holder N. Induction of the mesendoderm in the zebrafish germ ring by yolk cell-derived TGF-beta family signals and discrimination of mesoderm and endoderm by FGF. Development. 1999;126:3067–78.

    CAS  PubMed  Google Scholar 

  96. Griffin K, Patient R, Holder N. Analysis of FGF function in normal and no tail zebrafish embryos reveals separate mechanisms for formation of the trunk and the tail. Development. 1995;121:2983–94.

    CAS  PubMed  Google Scholar 

  97. Griffin KJ, Amacher SL, Kimmel CB, Kimelman D. Molecular identification of spadetail: regulation of zebrafish trunk and tail mesoderm formation by T-box genes. Development. 1998;125:3379–88.

    CAS  PubMed  Google Scholar 

  98. Furthauer M, Thisse C, Thisse B. A role for FGF-8 in the dorsoventral patterning of the zebrafish gastrula. Development. 1997;124:4253–64.

    CAS  PubMed  Google Scholar 

  99. Furthauer M, Lin W, Ang SL, Thisse B, Thisse C. Sef is a feedback-induced antagonist of Ras/MAPK-mediated FGF signalling. Nat Cell Biol. 2002;4:170–4.

    CAS  PubMed  Google Scholar 

  100. Brand M, Heisenberg CP, Jiang YJ, Beuchle D, Lun K, Furutani-Seiki M, Granato M, Haffter P, Hammerschmidt M, Kane DA, Kelsh RN, Mullins MC, Odenthal J, van Eeden FJ, Nusslein-Volhard C. Mutations in zebrafish genes affecting the formation of the boundary between midbrain and hindbrain. Development. 1996;123:179–90.

    CAS  PubMed  Google Scholar 

  101. Reifers F, Bohli H, Walsh EC, Crossley PH, Stainier DY, Brand M. Fgf8 is mutated in zebrafish acerebellar (ace) mutants and is required for maintenance of midbrain-hindbrain boundary development and somitogenesis. Development. 1998;125:2381–95.

    CAS  PubMed  Google Scholar 

  102. Shanmugalingam S, Houart C, Picker A, Reifers F, Macdonald R, Barth A, Griffin K, Brand M, Wilson SW. Ace/Fgf8 is required for forebrain commissure formation and patterning of the telencephalon. Development. 2000;127:2549–61.

    CAS  PubMed  Google Scholar 

  103. Kimelman D, Kirschner M. Synergistic induction of mesoderm by FGF and TGF-beta and the identification of an mRNA coding for FGF in the early Xenopus embryo. Cell. 1987;51:869–77.

    CAS  PubMed  Google Scholar 

  104. Slack JM, Darlington BG, Heath JK, Godsave SF. Mesoderm induction in early Xenopus embryos by heparin-binding growth factors. Nature. 1987;326:197–200.

    CAS  PubMed  Google Scholar 

  105. Amaya E, Musci T, Kirschner M. Expression of a dominant negative mutant of the FGF receptor disrupts mesoderm formation in xenopus embryos. Cell. 1991;66:257–70.

    CAS  PubMed  Google Scholar 

  106. Smith JC, Price BM, Green JB, Weigel D, Herrmann BG. Expression of a Xenopus homolog of Brachyury (T) is an immediate-early response to mesoderm induction. Cell. 1991;67:79–87.

    CAS  PubMed  Google Scholar 

  107. Sivak JM, Petersen LF, Amaya E. FGF signal interpretation is directed by Sprouty and Spred proteins during mesoderm formation. Dev Cell. 2005;8:689–701.

    CAS  PubMed  Google Scholar 

  108. Fisher ME, Isaacs HV, Pownall ME. eFGF is required for activation of XmyoD expression in the myogenic cell lineage of Xenopus laevis. Development. 2002;129:1307–15.

    CAS  PubMed  Google Scholar 

  109. Fletcher RB, Baker JC, Harland RM. FGF8 spliceforms mediate early mesoderm and posterior neural tissue formation in Xenopus. Development. 2006;133:1703–14.

    CAS  PubMed  Google Scholar 

  110. Amaya E, Stein PA, Musci TJ, Kirschner MW. FGF signalling in the early specification of mesoderm in Xenopus. Development. 1993;118:477–87.

    CAS  PubMed  Google Scholar 

  111. Hongo I, Kengaku M, Okamoto H. FGF signaling and the anterior neural induction in Xenopus. Dev Biol. 1999;216:561–81.

    CAS  PubMed  Google Scholar 

  112. Cohn MJ, Izpisua-Belmonte JC, Abud H, Heath JK, Tickle C. Fibroblast growth factors induce additional limb development from the flank of chick embryos. Cell. 1995;80:739–46.

    CAS  PubMed  Google Scholar 

  113. Laufer E, Nelson CE, Johnson RL, Morgan BA, Tabin C. Sonic hedgehog and Fgf-4 act through a signaling cascade and feedback loop to integrate growth and patterning of the developing limb bud. Cell. 1994;79:993–1003.

    CAS  PubMed  Google Scholar 

  114. Benazeraf B, Francois P, Baker RE, Denans N, Little CD, Pourquie O. A random cell motility gradient downstream of FGF controls elongation of an amniote embryo. Nature. 2010;466:248–52.

    CAS  PubMed Central  PubMed  Google Scholar 

  115. Dubrulle J, McGrew MJ, Pourquie O. FGF signaling controls somite boundary position and regulates segmentation clock control of spatiotemporal Hox gene activation. Cell. 2001;106:219–32.

    CAS  PubMed  Google Scholar 

  116. Dubrulle J, Pourquie O. fgf8 mRNA decay establishes a gradient that couples axial elongation to patterning in the vertebrate embryo. Nature. 2004;427:419–22.

    CAS  PubMed  Google Scholar 

  117. Streit A, Berliner AJ, Papanayotou C, Sirulnik A, Stern CD. Initiation of neural induction by FGF signalling before gastrulation. Nature. 2000;406:74–8.

    CAS  PubMed  Google Scholar 

  118. Wilson SI, Graziano E, Harland R, Jessell TM, Edlund T. An early requirement for FGF signalling in the acquisition of neural cell fate in the chick embryo. Curr Biol. 2000;10:421–9.

    CAS  PubMed  Google Scholar 

  119. Itoh N, Ornitz DM. Fibroblast growth factors: from molecular evolution to roles in development, metabolism and disease. J Biochem. 2010;149:121–30.

    PubMed Central  PubMed  Google Scholar 

  120. Elfenbein A, Simons M. Auxiliary and autonomous proteoglycan signaling networks. Methods Enzymol. 2010;480:3–31.

    CAS  PubMed Central  PubMed  Google Scholar 

  121. Elfenbein A, Lanahan A, Zhou TX, Yamasaki A, Tkachenko E, Matsuda M, Simons M. Syndecan 4 regulates FGFR1 signaling in endothelial cells by directing macropinocytosis. Sci Signal. 2012;5:ra36.

    PubMed  Google Scholar 

  122. Bryant DM, Stow JL. Nuclear translocation of cell-surface receptors: lessons from fibroblast growth factor. Traffic. 2005;6:947–54.

    CAS  PubMed  Google Scholar 

  123. Reilly JF, Maher PA. Importin beta-mediated nuclear import of fibroblast growth factor receptor: role in cell proliferation. J Cell Biol. 2001;152:1307–12.

    CAS  PubMed Central  PubMed  Google Scholar 

  124. Stachowiak MK, Maher PA, Stachowiak EK. Integrative nuclear signaling in cell development–a role for FGF receptor-1. DNA Cell Biol. 2007;26:811–26.

    CAS  PubMed  Google Scholar 

  125. Wilkie AO. Bad bones, absent smell, selfish testes: the pleiotropic consequences of human FGF receptor mutations. Cytokine Growth Factor Rev. 2005;16:187–203.

    CAS  PubMed  Google Scholar 

  126. Ibrahimi OA, Eliseenkova AV, Plotnikov AN, Yu K, Ornitz DM, Mohammadi M. Structural basis for fibroblast growth factor receptor 2 activation in Apert syndrome. Proc Natl Acad Sci USA. 2001;98:7182–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  127. Yu K, Herr AB, Waksman G, Ornitz DM. Loss of fibroblast growth factor receptor 2 ligand-binding specificity in Apert syndrome. Proc Natl Acad Sci USA. 2000;97:14536–41.

    CAS  PubMed Central  PubMed  Google Scholar 

  128. Oldridge M, Lunt PW, Zackai EH, McDonald-McGinn DM, Muenke M, Moloney DM, Twigg SR, Heath JK, Howard TD, Hoganson G, Gagnon DM, Jabs EW, Wilkie AO. Genotype-phenotype correlation for nucleotide substitutions in the IgII-IgIII linker of FGFR2. Hum Mol Genet. 1997;6:137–43.

    CAS  PubMed  Google Scholar 

  129. Webster MK, Donoghue DJ. FGFR activation in skeletal disorders: too much of a good thing. Trends Genet. 1997;13:178–82.

    CAS  PubMed  Google Scholar 

  130. Wang Y, Xiao R, Yang F, Karim BO, Iacovelli AJ, Cai J, Lerner CP, Richtsmeier JT, Leszl JM, Hill CA, Yu K, Ornitz DM, Elisseeff J, Huso DL, Jabs EW. Abnormalities in cartilage and bone development in the Apert syndrome FGFR2(+/S252W) mouse. Development. 2005;132:3537–48.

    CAS  PubMed  Google Scholar 

  131. Ahmed Z, Schuller AC, Suhling K, Tregidgo C, Ladbury JE. Extracellular point mutations in FGFR2 elicit unexpected changes in intracellular signalling. Biochem J. 2008;413:37–49.

    CAS  PubMed  Google Scholar 

  132. Pollock PM, Gartside MG, Dejeza LC, Powell MA, Mallon MA, Davies H, Mohammadi M, Futreal PA, Stratton MR, Trent JM, Goodfellow PJ. Frequent activating FGFR2 mutations in endometrial carcinomas parallel germline mutations associated with craniosynostosis and skeletal dysplasia syndromes. Oncogene. 2007;26:7158–62.

    CAS  PubMed Central  PubMed  Google Scholar 

  133. Greulich H, Pollock PM. Targeting mutant fibroblast growth factor receptors in cancer. Trends Mol Med. 2011;17:283–92.

    CAS  PubMed  Google Scholar 

  134. Wilkie AO, Patey SJ, Kan SH, van den Ouweland AM, Hamel BC. FGFs, their receptors, and human limb malformations: clinical and molecular correlations. Am J Med Genet. 2002;112:266–78.

    PubMed  Google Scholar 

  135. Rousseau F, el Ghouzzi V, Delezoide AL, Legeai-Mallet L, Le Merrer M, Munnich A, Bonaventure J. Missense FGFR3 mutations create cysteine residues in thanatophoric dwarfism type I (TD1). Hum Mol Genet. 1996;5:509–12.

    CAS  PubMed  Google Scholar 

  136. Tavormina PL, Shiang R, Thompson LM, Zhu YZ, Wilkin DJ, Lachman RS, Wilcox WR, Rimoin DL, Cohn DH, Wasmuth JJ. Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3. Nat Genet. 1995;9:321–8.

    CAS  PubMed  Google Scholar 

  137. Rousseau F, Bonaventure J, Legeai-Mallet L, Pelet A, Rozet JM, Maroteaux P, Le Merrer M, Munnich A. Mutations of the fibroblast growth factor receptor-3 gene in achondroplasia. Horm Res. 1996;45:108–10.

    CAS  PubMed  Google Scholar 

  138. Shiang R, Thompson LM, Zhu YZ, Church DM, Fielder TJ, Bocian M, Winokur ST, Wasmuth JJ. Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell. 1994;78:335–42.

    CAS  PubMed  Google Scholar 

  139. Knowles MA. Novel therapeutic targets in bladder cancer: mutation and expression of FGF receptors. Future Oncol. 2008;4:71–83.

    CAS  PubMed  Google Scholar 

  140. Meyers GA, Orlow SJ, Munro IR, Przylepa KA, Jabs EW. Fibroblast growth factor receptor 3 (FGFR3) transmembrane mutation in Crouzon syndrome with acanthosis nigricans. Nat Genet. 1995;11:462–4.

    CAS  PubMed  Google Scholar 

  141. van Rhijn BW, van Tilborg AA, Lurkin I, Bonaventure J, de Vries A, Thiery JP, van der Kwast TH, Zwarthoff EC, Radvanyi F. Novel fibroblast growth factor receptor 3 (FGFR3) mutations in bladder cancer previously identified in non-lethal skeletal disorders. Eur J Hum Genet. 2002;10:819–24.

    PubMed  Google Scholar 

  142. Li E, You M, Hristova K. FGFR3 dimer stabilization due to a single amino acid pathogenic mutation. J Mol Biol. 2006;356:600–12.

    CAS  PubMed  Google Scholar 

  143. Chen F, Degnin C, Laederich M, Horton WA, Hristova K. The A391E mutation enhances FGFR3 activation in the absence of ligand. Biochim Biophys Acta. 2011;1808:2045–50.

    CAS  PubMed Central  PubMed  Google Scholar 

  144. Chen Q, Jiang Y, An Y, Zhao N, Zhao Y, Yu C. Soluble FGFR4 extracellular domain inhibits FGF19-induced activation of FGFR4 signaling and prevents nonalcoholic fatty liver disease. Biochem Biophys Res Commun. 2011;409:651–6.

    CAS  PubMed  Google Scholar 

  145. Zhu Q, Liu T. Fibroblast growth factor receptor 4 polymorphisms and coronary artery disease: a case control study. Mol Biol Rep. 2012;39:8679–85.

    CAS  PubMed  Google Scholar 

  146. Wang J, Yu W, Cai Y, Ren C, Ittmann MM. Altered fibroblast growth factor receptor 4 stability promotes prostate cancer progression. Neoplasia. 2008;10:847–56.

    CAS  PubMed Central  PubMed  Google Scholar 

  147. Frullanti E, Berking C, Harbeck N, Jezequel P, Haugen A, Mawrin C, Parise Jr O, Sasaki H, Tsuchiya N, Dragani TA. Meta and pooled analyses of FGFR4 Gly388Arg polymorphism as a cancer prognostic factor. Eur J Cancer Prev. 2011;20:340–7.

    CAS  PubMed  Google Scholar 

  148. Sleeman M, Fraser J, McDonald M, Yuan S, White D, Grandison P, Kumble K, Watson JD, Murison JG. Identification of a new fibroblast growth factor receptor, FGFR5. Gene. 2001;271:171–82.

    CAS  PubMed  Google Scholar 

  149. Trueb B, Zhuang L, Taeschler S, Wiedemann M. Characterization of FGFRL1, a novel fibroblast growth factor (FGF) receptor preferentially expressed in skeletal tissues. J Biol Chem. 2003;278:33857–65.

    CAS  PubMed  Google Scholar 

  150. Wiedemann M, Trueb B. Characterization of a novel protein (FGFRL1) from human cartilage related to FGF receptors. Genomics. 2000;69:275–9.

    CAS  PubMed  Google Scholar 

  151. Rieckmann T, Zhuang L, Fluck CE, Trueb B. Characterization of the first FGFRL1 mutation identified in a craniosynostosis patient. Biochim Biophys Acta. 2009;1792:112–21.

    CAS  PubMed  Google Scholar 

  152. Zhuang L, Karotki AV, Bruecker P, Trueb B. Comparison of the receptor FGFRL1 from sea urchins and humans illustrates evolution of a zinc binding motif in the intracellular domain. BMC Biochem. 2009;10:33.

    PubMed Central  PubMed  Google Scholar 

  153. Steinberg F, Zhuang L, Beyeler M, Kalin RE, Mullis PE, Brandli AW, Trueb B. The FGFRL1 receptor is shed from cell membranes, binds fibroblast growth factors (FGFs), and antagonizes FGF signaling in Xenopus embryos. J Biol Chem. 2010;285:2193–202.

    CAS  PubMed Central  PubMed  Google Scholar 

  154. Ibrahimi OA, Zhang F, Eliseenkova AV, Itoh N, Linhardt RJ, Mohammadi M. Biochemical analysis of pathogenic ligand-dependent FGFR2 mutations suggests distinct pathophysiological mechanisms for craniofacial and limb abnormalities. Hum Mol Genet. 2004;13:2313–24.

    CAS  PubMed Central  PubMed  Google Scholar 

  155. Trueb B. Biology of FGFRL1, the fifth fibroblast growth factor receptor. Cell Mol Life Sci. 2011;68:951–64.

    CAS  PubMed  Google Scholar 

  156. Powell AK, Fernig DG, Turnbull JE. Fibroblast growth factor receptors 1 and 2 interact differently with heparin/heparan sulfate. Implications for dynamic assembly of a ternary signaling complex. J Biol Chem. 2002;277:28554–63.

    CAS  PubMed  Google Scholar 

  157. Rieckmann T, Kotevic I, Trueb B. The cell surface receptor FGFRL1 forms constitutive dimers that promote cell adhesion. Exp Cell Res. 2008;314:1071–81.

    CAS  PubMed  Google Scholar 

  158. Beenken A, Mohammadi M. The FGF family: biology, pathophysiology and therapy. Nat Rev Drug Discov. 2009;8:235–53.

    CAS  PubMed Central  PubMed  Google Scholar 

  159. Schild C, Trueb B. Aberrant expression of FGFRL1, a novel FGF receptor, in ovarian tumors. Int J Mol Med. 2005;16:1169–73.

    CAS  PubMed  Google Scholar 

  160. Gartside MG, Chen H, Ibrahimi OA, Byron SA, Curtis AV, Wellens CL, Bengston A, Yudt LM, Eliseenkova AV, Ma J, Curtin JA, Hyder P, Harper UL, Riedesel E, Mann GJ, Trent JM, Bastian BC, Meltzer PS, Mohammadi M, Pollock PM. Loss-of-function fibroblast growth factor receptor-2 mutations in melanoma. Mol Cancer Res. 2009;7:41–54.

    CAS  PubMed Central  PubMed  Google Scholar 

  161. Turner N, Grose R. Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer. 2010;10:116–29.

    CAS  PubMed  Google Scholar 

  162. Grose R, Dickson C. Fibroblast growth factor signaling in tumorigenesis. Cytokine Growth Factor Rev. 2005;16:179–86.

    CAS  PubMed  Google Scholar 

  163. Fioretos T, Panagopoulos I, Lassen C, Swedin A, Billstrom R, Isaksson M, Strombeck B, Olofsson T, Mitelman F, Johansson B. Fusion of the BCR and the fibroblast growth factor receptor-1 (FGFR1) genes as a result of t(8;22)(p11;q11) in a myeloproliferative disorder: the first fusion gene involving BCR but not ABL. Genes Chromosomes Cancer. 2001;32:302–10.

    CAS  PubMed  Google Scholar 

  164. Courjal F, Cuny M, Simony-Lafontaine J, Louason G, Speiser P, Zeillinger R, Rodriguez C, Theillet C. Mapping of DNA amplifications at 15 chromosomal localizations in 1875 breast tumors: definition of phenotypic groups. Cancer Res. 1997;57:4360–7.

    CAS  PubMed  Google Scholar 

  165. Turner N, Pearson A, Sharpe R, Lambros M, Geyer F, Lopez-Garcia MA, Natrajan R, Marchio C, Iorns E, Mackay A, Gillett C, Grigoriadis A, Tutt A, Reis-Filho JS, Ashworth A. FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer. Cancer Res. 2010;70:2085–94.

    CAS  PubMed Central  PubMed  Google Scholar 

  166. Zecchini S, Bombardelli L, Decio A, Bianchi M, Mazzarol G, Sanguineti F, Aletti G, Maddaluno L, Berezin V, Bock E, Casadio C, Viale G, Colombo N, Giavazzi R, Cavallaro U. The adhesion molecule NCAM promotes ovarian cancer progression via FGFR signalling. EMBO Mol Med. 2011;3:480–94.

    CAS  PubMed Central  PubMed  Google Scholar 

  167. Francavilla C, Loeffler S, Piccini D, Kren A, Christofori G, Cavallaro U. Neural cell adhesion molecule regulates the cellular response to fibroblast growth factor. J Cell Sci. 2007;120:4388–94.

    CAS  PubMed  Google Scholar 

  168. Francavilla C, Cattaneo P, Berezin V, Bock E, Ami D, de Marco A, Christofori G, Cavallaro U. The binding of NCAM to FGFR1 induces a specific cellular response mediated by receptor trafficking. J Cell Biol. 2009;187:1101–16.

    CAS  PubMed Central  PubMed  Google Scholar 

  169. Christensen C, Lauridsen JB, Berezin V, Bock E, Kiselyov VV. The neural cell adhesion molecule binds to fibroblast growth factor receptor 2. FEBS Lett. 2006;580:3386–90.

    CAS  PubMed  Google Scholar 

  170. Byron SA, Gartside MG, Wellens CL, Mallon MA, Keenan JB, Powell MA, Goodfellow PJ, Pollock PM. Inhibition of activated fibroblast growth factor receptor 2 in endometrial cancer cells induces cell death despite PTEN abrogation. Cancer Res. 2008;68:6902–7.

    CAS  PubMed  Google Scholar 

  171. Trudel S, Li ZH, Wei E, Wiesmann M, Chang H, Chen C, Reece D, Heise C, Stewart AK. CHIR-258, a novel, multitargeted tyrosine kinase inhibitor for the potential treatment of t(4;14) multiple myeloma. Blood. 2005;105:2941–8.

    CAS  PubMed  Google Scholar 

  172. Fabbro D, Manley PW. Su-6668. SUGEN. Curr Opin Investig Drugs. 2001;2:1142–8.

    CAS  PubMed  Google Scholar 

  173. Gavine PR, Mooney L, Kilgour E, Thomas AP, Al-Kadhimi K, Beck S, Rooney C, Coleman T, Baker D, Mellor MJ, Brooks AN, Klinowska T. AZD4547: an orally bioavailable, potent, and selective inhibitor of the fibroblast growth factor receptor tyrosine kinase family. Cancer Res. 2012;72:2045–56.

    CAS  PubMed  Google Scholar 

  174. Celli G, Larochelle WJ, MacKem S, Sharp R, Merlino G. Soluble dominant-negative receptor uncovers essential roles for fibroblast growth-factors in multiorgan induction and patterning. EMBO J. 1998;17:1642–55.

    Google Scholar 

  175. Ciruna B, Rossant J. FGF signaling regulates mesoderm cell fate specification and morphogenetic movement at the primitive streak. Dev Cell. 2001;1:37–49.

    Google Scholar 

  176. Ciruna BG, Schwartz L, Harpal K, Yamaguchi TP, Rossant J. Chimeric analysis of fibroblast growth-factor receptor-1 (FGFR1) function—a role for FGFR1 in morphogenetic movement through the primitive streak. Development. 1997;124:2829–41.

    Google Scholar 

  177. Deng CX, Wynshawboris A, Shen MM, Daugherty C, Ornitz DM, Leder P. Murine FGFR-1 is required for early postimplantation growth and axial organization. Genes Dev. 1994;8:3045–57.

    Google Scholar 

  178. Freeman KW, Gangula RD, Welm BE, Ozen M, Foster BA, Rosen JM, Ittmann M, Greenberg NM, Spencer DM. Conditional activation of fibroblast growth factor receptor (FGFR) 1, but not FGFR2, in prostate cancer cells leads to increased osteopontin induction, extracellular signal-regulated kinase activation, and in vivo proliferation. Cancer Res. 2003;63:6237–43.

    Google Scholar 

  179. Freeman KW, Welm BE, Gangula RD, Rosen JM, Ittmann M, Greenberg NM, Spencer DM. Inducible prostate intraepithelial neoplasia with reversible hyperplasia in conditional FGFR1-expressing mice. Cancer Res. 2003;63:8256–63.

    Google Scholar 

  180. Partanen J, Schwartz L, Rossant J. Opposite phenotypes of hypomorphic and Y766 phosphorylation site mutations reveal a function for Fgfr1 in anteroposterior patterning of mouse embryos. Genes Dev. 1998;12:2332–44.

    Google Scholar 

  181. Robinson ML, MacMillancrow LA, Thompson JA, Overbeek PA. Expression of a truncated FGF receptor results in defective lens development in transgenic mice. Development. 1995;121:3959–67.

    Google Scholar 

  182. Verheyden JM, Lewandoski M, Deng C, Harfe BD, Sun X. Conditional inactivation of Fgfr1 in mouse defines its role in limb bud establishment, outgrowth and digit patterning. Development. 2005;132:4235–45.

    Google Scholar 

  183. Welm BE, Freeman KW, Chen M, Contreras A, Spencer DM, Rosen JM. Inducible dimerization of FGFR1: development of a mouse model to analyze progressive transformation of the mammary gland. J Cell Biol. 2002;157:703–14.

    Google Scholar 

  184. Winter SF, Acevedo VD, Gangula RD, Freeman KW, Spencer DM, Greenberg NM. Conditional activation of FGFR1 in the prostate epithelium induces angiogenesis with concomitant differential regulation of Ang-1 and Ang-2. Oncogene. 2007;26:4897–907.

    Google Scholar 

  185. Xu X, Li C, Takahashi K, Slavkin HC, Shum L, Deng CX. Murine fibroblast growth factor receptor 1alpha isoforms mediate node regression and are essential for posterior mesoderm development. Dev Biol. 1999;208:293–306.

    Google Scholar 

  186. Yamaguchi TP, Harpal K, Henkemeyer M, Rossant J. FGFR-1 is required for embryonic growth and mesodermal patterning during mouse gastrulation. Genes Dev. 1994;8:3032–44.

    Google Scholar 

  187. Yang J, Meyer M, Muller AK, Bohm F, Grose R, Dauwalder T, Verrey F, Kopf M, Partanen J, Bloch W, Ornitz DM, Werner S. Fibroblast growth factor receptors 1 and 2 in keratinocytes control the epidermal barrier and cutaneous homeostasis. J Cell Biol. 2010;188:935–52.

    Google Scholar 

  188. Zhang H, Dessimoz J, Beyer TA, Krampert M, Williams LT, Werner S, Grose R. Fibroblast growth factor receptor 1-IIIb is dispensable for skin morphogenesis and wound healing. Eur J Cell Biol. 2004;83:3–11.

    Google Scholar 

  189. Zhao H, Kegg H, Grady S, Truong HT, Robinson ML, Baum M, Bates CM. Role of fibroblast growth factor receptors 1 and 2 in the ureteric bud. Dev Biol. 2004;276:403–15.

    Google Scholar 

  190. De Moerlooze L, Spencer-Dene B, Revest J, Hajihosseini M, Rosewell I, Dickson C. An important role for the IIIb isoform of fibroblast growth factor receptor 2 (FGFR2) in mesenchymal-epithelial signalling during mouse organogenesis. Development. 2000;127:483–92.

    Google Scholar 

  191. Eswarakumar VP, Monsonego-Ornan E, Pines M, Antonopoulou I, Morriss-Kay GM, Lonai P. The IIIc alternative of Fgfr2 is a positive regulator of bone formation. Development. 2002;129:3783–93.

    Google Scholar 

  192. Jackson D, Bresnick J, Rosewell I, Crafton T, Poulsom R, Stamp G, Dickson C. Fibroblast growth factor receptor signalling has a role in lobuloalveolar development of the mammary gland. J Cell Sci. 1997;110(Pt 11):1261–8.

    Google Scholar 

  193. Lin Y, Liu G, Zhang Y, Hu YP, Yu K, Lin C, McKeehan K, Xuan JW, Ornitz DM, Shen MM, Greenberg N, McKeehan WL, Wang F. Fibroblast growth factor receptor 2 tyrosine kinase is required for prostatic morphogenesis and the acquisition of strict androgen dependency for adult tissue homeostasis. Development. 2007;134:723–34.

    Google Scholar 

  194. Mailleux AA, Spencer-Dene B, Dillon C, Ndiaye D, Savona-Baron C, Itoh N, Kato S, Dickson C, Thiery JP, Bellusci S. Role of FGF10/FGFR2b signaling during mammary gland development in the mouse embryo. Development. 2002;129:53–60.

    Google Scholar 

  195. Parsa S, Kuremoto K, Seidel K, Tabatabai R, Mackenzie B, Yamaza T, Akiyama K, Branch J, Koh CJ, Al Alam D, Klein OD, Bellusci S. Signaling by FGFR2b controls the regenerative capacity of adult mouse incisors. Development. 2010;137:3743–52.

    Google Scholar 

  196. Peters K, Werner S, Liao X, Wert S, Whitsett J, Williams L. Targeted expression of a dominant negative FGF receptor blocks branching morphogenesis and epithelial differentiation of the mouse lung. EMBO J. 1994;13:3296–301.

    Google Scholar 

  197. Revest JM, Spencer-Dene B, Kerr K, De Moerlooze L, Rosewell I, Dickson C. Fibroblast growth factor receptor 2-IIIb acts upstream of Shh and Fgf4 and is required for limb bud maintenance but not for the induction of Fgf8, Fgf10, Msx1, or Bmp4. Dev Biol. 2001;231:47–62.

    Google Scholar 

  198. Werner S, Smola H, Liao X, Longaker M, Krieg T, Hofschneider P, Williams L. The function of KGF in morphogenesis of epithelium and reepithelialization of wounds. Science. 1994;266:819–22.

    Google Scholar 

  199. Werner S, Weinberg W, Liao X, Peters K, Blessing M, Yuspa S, Weiner R, Williams L. Targeted expression of a dominant-negative FGF receptor mutant in the epidermis of transgenic mice reveals a role of FGF in keratinocyte organization and differentiation. EMBO J. 1993;12:2635–43.

    Google Scholar 

  200. Xu XL, Weinstein M, Li CL, Naski M, Cohen RI, Ornitz DM, Leder P, Deng CX. Fibroblast-growth-factor-receptor-2 (FGFR2)-mediated reciprocal regulation loop between FGF8 and FGF10 is essential for limb induction. Development. 1998;125:753–65.

    Google Scholar 

  201. Yu K, Xu J, Liu Z, Sosic D, Shao J, Olson EN, Towler DA, Ornitz DM. Conditional inactivation of FGF receptor 2 reveals an essential role for FGF signaling in the regulation of osteoblast function and bone growth. Development. 2003;130:3063–74.

    Google Scholar 

  202. Colvin JS, Bohne BA, Harding GW, McEwen DG, Ornitz DM. Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3. Nat Genet. 1996;12:390–7.

    Google Scholar 

  203. Deng C, Wynshaw BA, Zhou F, Kuo A, Leder P. Fibroblast growth factor receptor 3 is a negative regulator of bone growth. Cell. 1996;84:911–21.

    Google Scholar 

  204. L’Hote CG, Knowles MA. Cell responses to FGFR3 signalling: growth, differentiation and apoptosis. Exp Cell Res. 2005;304:417–31.

    Google Scholar 

  205. Su N, Xu X, Li C, He Q, Zhao L, Chen S, Luo F, Yi L, Du X, Huang H, Deng C, Chen L. Generation of Fgfr3 conditional knockout mice. Int J Biol Sci. 2010;6:327–32.

    Google Scholar 

  206. Wang JM, Du XL, Li CL, Yin LJ, Chen B, Sun J, Su N, Zhao L, Song RH, Song WW, Chen L, Deng CX. Gly374Arg mutation in Fgfr3 causes achondroplasia in mice. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2004;21:537–41.

    Google Scholar 

  207. Wang Y, Spatz MK, Kannan K, Hayk H, Avivi A, Gorivodsky M, Pines M, Yayon A, Lonai P, Givol D. A mouse model for achondroplasia produced by targeting fibroblast growth factor receptor 3. Proc Natl Acad Sci USA. 1999;96:4455–60.

    Google Scholar 

  208. Weinstein M, Xu XL, Ohyama K, Deng CX. FGFR-3 and FGFR-4 function cooperatively to direct alveogenesis in the murine lung. Development. 1998;125:3615–23.

    Google Scholar 

  209. Yu C, Wang F, Jin C, Wu X, Chan WK, McKeehan WL. Increased carbon tetrachloride-induced liver injury and fibrosis in FGFR4-deficient mice. Am J Pathol. 2002;161:2003–10.

    Google Scholar 

  210. 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;275:15482–9.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Barts Cancer institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK

    Abbie E. Fearon, Athina-Myrto Chioni & Richard P. Grose

Authors
  1. Abbie E. Fearon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Athina-Myrto Chioni
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Richard P. Grose
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Richard P. Grose .

Editor information

Editors and Affiliations

  1. School of Medicine and Public Health Department of Human Oncology, University of Wisconsin, Madison, Wisconsin, USA

    Deric L. Wheeler

  2. Department of Biological Regulation, Rehovot, Israel

    Yosef Yarden

FGFR1–4 at a glance

FGFR1–4 at a glance

 

FGFR1

FGFR2

FGFR3

FGFR4

Alternative names

BFGFR, FLT2, FGFBR, FLG, CEK, CD331, H2, H3, H4, KAL2, N-SAM, c-Fgr, HBGFR, FLJ14326

BEK, KGFR, KSAM, CD332, BFR-1, CEK3, CFD1, ECT1, TK14, TK25

CD333, JTK4, ACH, CEK2, HBGFR

CD334, JTK2, TKF

Chromosome location

8p12

10q26

4p16.3

5q35.1-qter

Gene size (bp)

57,696

120,128

15,560

11,206

Intron/exon number

18 exons

18 exons

17 exons

18 exons

mRNA size (5′, ORF, 3′)

Up to ~5900 bp

Up to ~4250 bp

Up to ~4150 bp

Up to ~3120 bp

Amino acid number

Up to 853

Up to 830

Up to 808

Up to 802

Protein size

Up to 95 kDa

Up to 93 kDa

Up to 88 kDa

88 kDa

Post-translational modifications

Autophosphorylated, ubiquitinated, N-glycosylated

Autophosphorylated, ubiquitinated, N-glycosylated

Autophosphorylated, ubiquitinated, N-glycosylated

Autophosphorylated, ubiquitinated, N-glycosylated

Domains

Up to three Ig domains, transmembrane domain, tyrosine kinase domain

Up to three Ig domains, transmembrane domain, tyrosine kinase domain

Up to three Ig domains, transmembrane domain, tyrosine kinase domain

Up to three Ig domains, transmembrane domain, tyrosine kinase domain

Pathways activated

MAPK, PI3K/AKT, PLCγ, STAT

MAPK, PI3K/AKT, PLCγ, STAT

MAPK, PI3K/AKT, PLCγ, STAT

MAPK, PI3K/AKT, PLCγ, STAT

Knockout mouse phenotype

FGFR1−/− embryonic lethal around gastrulation

FGFR2−/− embryonic lethal around gastrulation

FGFR3 mutant alleles show skeletal phenotypes and hearing defects

FGFR4 null mice show no overt phenotype barring a reduction in body weight

FGFR1-IIIb−/− no phenotype

FGFR2-IIIb−/− multiple defects in organogenesis

Conditional knockout available

 

Conditional knockouts show multiple phenotypes in brain, limb and bone

Isoform specific conditional knockouts exist for IIIb, showing multiple phenotypes, and for IIIc, mimicking IIIb activity in Apert Syndrome

  
  

Conditional knockout of entire gene gives multiple phenotypes

  

References

[174–189]

[187, 189–201]

[202–208]

[208–210]

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Fearon, A.E., Chioni, AM., Grose, R.P. (2015). The FGFR Receptor Family. In: Wheeler, D., Yarden, Y. (eds) Receptor Tyrosine Kinases: Family and Subfamilies. Springer, Cham. https://doi.org/10.1007/978-3-319-11888-8_6

Download citation

Publish with us

Policies and ethics

Search

Navigation