Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Exploring mechanisms of FGF signalling through the lens of structural biology

Nature Reviews Molecular Cell Biology volume 14, pages 166–180 (2013)Cite this article

Subjects

Key Points

  • Fibroblast growth factor (FGF) signalling controls a myriad of processes in embryonic development and in tissue homeostasis and metabolism in the adult. Recent structural studies have provided a glimpse of the complexity of molecular control that is in place to fine-tune this signalling system to enable it to produce specific signalling outputs in diverse biological contexts.

  • The interaction of FGFs with heparan sulphate glycosaminoglycan chains of heparan sulphate proteoglycans in the pericellular and extracellular matrix defines their mode of action, that is, whether an FGF acts in a paracrine or endocrine fashion. It also determines the shape of gradient formed by a paracrine FGF ligand in the extracellular matrix, which in turn is a determinant of the biological response to that ligand.

  • In addition to mechanisms common to all FGFs, such as the interaction with heparan sulphate, the biological activity of individual ligands or ligand subfamilies is regulated by mechanisms unique to these ligands: amino-terminal alternative splicing controls the activity of FGF8 subfamily ligands; homodimerization autoinhibits the activity of FGF9 subfamily ligands; and site-specific proteolytic cleavage inactivates the phosphaturic hormone FGF23.

  • Alternative splicing in the extracellular immunoglobulin-like domain 3 (D3) of FGF receptor 1 (FGFR1), FGFR2 and FGFR3 primarily determines the ligand-binding specificity of these receptors. This splicing event is fundamental to the establishment of directional paracrine FGF signalling between the epithelium and the mesenchyme, which underlies the coordinated cellular processes that govern organ development.

  • Klotho co-receptors convert FGFRs into specific receptors for endocrine FGFs by a dual mechanism; these co-receptors not only enhance the binding affinity of FGFRs for endocrine FGFs but concomitantly suppress the binding of paracrine FGFs to FGFRs. The finding that heparan sulphate is dispensable for signalling by endocrine FGFs implies that Klotho co-receptors also promote FGFR dimerization upon endocrine FGF binding, which is required for FGFR activation.

  • The structural findings suggest that there may be no functional redundancy among FGF ligands, and genetic data support this conclusion. Hence, future studies should concentrate on identifying novel ligand-specific functions of FGF signalling.

Abstract

Fibroblast growth factors (FGFs) mediate a broad range of functions in both the developing and adult organism. The accumulated wealth of structural information on the FGF signalling pathway has begun to unveil the underlying molecular mechanisms that modulate this system to generate a myriad of distinct biological outputs in development, tissue homeostasis and metabolism. At the ligand and receptor level, these mechanisms include alternative splicing of the ligand (FGF8 subfamily) and the receptor (FGFR1–FGFR3), ligand homodimerization (FGF9 subfamily), site-specific proteolytic cleavage of the ligand (FGF23), and interaction of the ligand and the receptor with heparan sulphate cofactor and Klotho co-receptor.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The FGF signalling system.
Figure 2: FGF signalling pathways.
Figure 3: Heparan sulphate-binding affinity determines the morphogenetic activity of FGF7 subfamily ligands.
Figure 4: Autoinhibition of FGF9 by homodimerization.
Figure 5: N-terminal alternative splicing regulates the biological activity of FGF8.
Figure 6: Alternative splicing confers ligand-binding specificity on FGFR.
Figure 7: Ligand-dependent differences at the FGF–FGFR interface differentially regulate FGFR dimerization.

Similar content being viewed by others

References

  1. Itoh, N. & Ornitz, D. M. Fibroblast growth factors: from molecular evolution to roles in development, metabolism and disease. J. Biochem. 149, 121–130 (2011).

    Article  CAS  PubMed  Google Scholar 

  2. Mohammadi, M., Olsen, S. K. & Ibrahimi, O. A. Structural basis for fibroblast growth factor receptor activation. Cytokine Growth Factor Rev. 16, 107–137 (2005).

    Article  CAS  PubMed  Google Scholar 

  3. Itoh, N. & Ornitz, D. M. Evolution of the Fgf and Fgfr gene families. Trends Genet. 20, 563–569 (2004).

    Article  CAS  PubMed  Google Scholar 

  4. Schlessinger, J. et al. Crystal structure of a ternary FGF–FGFR–heparin complex reveals a dual role for heparin in FGFR binding and dimerization. Mol. Cell 6, 743–750 (2000). Reveals the structural basis by which heparan sulphate promotes ligand-induced FGFR dimerization.

    Article  CAS  PubMed  Google Scholar 

  5. Chen, H. et al. A crystallographic snapshot of tyrosine trans-phosphorylation in action. Proc. Natl Acad. Sci. USA 105, 19660–19665 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Furdui, C. M., Lew, E. D., Schlessinger, J. & Anderson, K. S. Autophosphorylation of FGFR1 kinase is mediated by a sequential and precisely ordered reaction. Mol. Cell 21, 711–717 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. Gotoh, N. Regulation of growth factor signaling by FRS2 family docking/scaffold adaptor proteins. Cancer Sci. 99, 1319–1325 (2008).

    Article  CAS  PubMed  Google Scholar 

  8. Carpenter, G. & Ji, Q. Phospholipase C-γ as a signal-transducing element. Exp. Cell Res. 253, 15–24 (1999).

    Article  CAS  PubMed  Google Scholar 

  9. Bottcher, R. T. & Niehrs, C. Fibroblast growth factor signaling during early vertebrate development. Endocr. Rev. 26, 63–77 (2005).

    Article  CAS  PubMed  Google Scholar 

  10. Thisse, B. & Thisse, C. Functions and regulations of fibroblast growth factor signaling during embryonic development. Dev. Biol. 287, 390–402 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Turner, N. & Grose, R. Fibroblast growth factor signalling: from development to cancer. Nature Rev. Cancer 10, 116–129 (2010).

    Article  CAS  Google Scholar 

  12. Asada, M. et al. Glycosaminoglycan affinity of the complete fibroblast growth factor family. Biochim. Biophys. Acta 1790, 40–48 (2009).

    Article  CAS  PubMed  Google Scholar 

  13. Perrimon, N. & Bernfield, M. Specificities of heparan sulphate proteoglycans in developmental processes. Nature 404, 725–728 (2000).

    Article  CAS  PubMed  Google Scholar 

  14. Goetz, R. et al. Molecular insights into the Klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members. Mol. Cell. Biol. 27, 3417–3428 (2007). Reveals the structural basis for the endocrine mode of action of FGF19 subfamily ligands.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Rapraeger, A. C., Krufka, A. & Olwin, B. B. Requirement of heparan sulfate for bFGF-mediated fibroblast growth and myoblast differentiation. Science 252, 1705–1708 (1991).

    Article  CAS  PubMed  Google Scholar 

  16. Yayon, A., Klagsbrun, M., Esko, J. D., Leder, P. & Ornitz, D. M. Cell surface, heparin-like molecules are required for binding of basic fibroblast growth factor to its high affinity receptor. Cell 64, 841–848 (1991).

    Article  CAS  PubMed  Google Scholar 

  17. Ding, X. et al. βKlotho is required for fibroblast growth factor 21 effects on growth and metabolism. Cell Metab. 16, 387–393 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kurosu, H. et al. Tissue-specific expression of βKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21. J. Biol. Chem. 282, 26687–26695 (2007).

    Article  CAS  PubMed  Google Scholar 

  19. Kurosu, H. et al. Regulation of fibroblast growth factor-23 signaling by Klotho. J. Biol. Chem. 281, 6120–6123 (2006).

    Article  CAS  PubMed  Google Scholar 

  20. Nakatani, T., Ohnishi, M. & Razzaque, M. S. Inactivation of klotho function induces hyperphosphatemia even in presence of high serum fibroblast growth factor 23 levels in a genetically engineered hypophosphatemic (Hyp) mouse model. FASEB J. 23, 3702–3711 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ogawa, Y. et al. βKlotho is required for metabolic activity of fibroblast growth factor 21. Proc. Natl Acad. Sci. USA 104, 7432–7437 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Tomiyama, K. et al. Relevant use of Klotho in FGF19 subfamily signaling system in vivo. Proc. Natl Acad. Sci. USA 107, 1666–1671 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Urakawa, I. et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 444, 770–774 (2006).

    Article  CAS  PubMed  Google Scholar 

  24. Dorey, K. & Amaya, E. FGF signalling: diverse roles during early vertebrate embryogenesis. Development 137, 3731–3742 (2010).

    Article  CAS  PubMed  Google Scholar 

  25. Hart, A. W., Baeza, N., Apelqvist, A. & Edlund, H. Attenuation of FGF signalling in mouse β-cells leads to diabetes. Nature 408, 864–868 (2000). Identifies a crucial role for FGF signalling in pancreatic β-cell function and glucose homeostasis in the adult.

    Article  CAS  PubMed  Google Scholar 

  26. Jonker, J. W. et al. A PPARγ–FGF1 axis is required for adaptive adipose remodelling and metabolic homeostasis. Nature 485, 391–394 (2012). Identifies a crucial role for FGF1 in the remodelling of adipose tissue in response to fluctuating nutrient availability.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhou, M. et al. Fibroblast growth factor 2 control of vascular tone. Nature Med. 4, 201–207 (1998).

    Article  CAS  PubMed  Google Scholar 

  28. Sakaue, H. et al. Requirement of fibroblast growth factor 10 in development of white adipose tissue. Genes Dev. 16, 908–912 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Potthoff, M. J., Kliewer, S. A. & Mangelsdorf, D. J. Endocrine fibroblast growth factors 15/19 and 21: from feast to famine. Genes Dev. 26, 312–324 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Quarles, L. D. Skeletal secretion of FGF-23 regulates phosphate and vitamin D metabolism. Nature Rev. Endocrinol. 8, 276–286 (2012).

    Article  CAS  Google Scholar 

  31. Razzaque, M. S. The FGF23–Klotho axis: endocrine regulation of phosphate homeostasis. Nature Rev. Endocrinol. 5, 611–619 (2009).

    Article  CAS  Google Scholar 

  32. Long, Y. C. & Kharitonenkov, A. Hormone-like fibroblast growth factors and metabolic regulation. Biochim. Biophys. Acta 1812, 791–795 (2011).

    Article  CAS  PubMed  Google Scholar 

  33. Beenken, A. & Mohammadi, M. The FGF family: biology, pathophysiology and therapy. Nature Rev. Drug Discov. 8, 235–253 (2009).

    Article  CAS  Google Scholar 

  34. Wilkie, A. O. Bad bones, absent smell, selfish testes: the pleiotropic consequences of human FGF receptor mutations. Cytokine Growth Factor Rev. 16, 187–203 (2005).

    Article  CAS  Google Scholar 

  35. Goetz, R. et al. Isolated C-terminal tail of FGF23 alleviates hypophosphatemia by inhibiting FGF23–FGFR–Klotho complex formation. Proc. Natl Acad. Sci. USA 107, 407–412 (2010).

    Article  PubMed  Google Scholar 

  36. Kalinina, J. et al. Homodimerization controls the fibroblast growth factor 9 subfamily's receptor binding and heparan sulfate-dependent diffusion in the extracellular matrix. Mol. Cell. Biol. 29, 4663–4678 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Olsen, S. K. et al. Structural basis by which alternative splicing modulates the organizer activity of FGF8 in the brain. Genes Dev. 20, 185–198 (2006). Identifies the molecular mechanism by which N-terminal splicing regulates the biological activity of FGF8 and provides structural evidence for ligand-induced differences in FGFR dimerization.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Plotnikov, A. N. et al. Crystal structure of fibroblast growth factor 9 reveals regions implicated in dimerization and autoinhibition. J. Biol. Chem. 276, 4322–4329 (2001).

    Article  CAS  PubMed  Google Scholar 

  39. Yeh, B. K. et al. Structural basis by which alternative splicing confers specificity in fibroblast growth factor receptors. Proc. Natl Acad. Sci. USA 100, 2266–2271 (2003). Reveals the molecular basis by which alternative splicing in the D3 domain of FGFR2 regulates the ligand-binding specificity of this receptor.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Gallagher, J. T. Heparan sulfate: growth control with a restricted sequence menu. J. Clin. Invest. 108, 357–361 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Chen, Y., Mohammadi, M. & Flanagan, J. G. Graded levels of FGF protein span the midbrain and can instruct graded induction and repression of neural mapping labels. Neuron 62, 773–780 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Harada, M. et al. FGF9 monomer–dimer equilibrium regulates extracellular matrix affinity and tissue diffusion. Nature Genet. 41, 289–298 (2009).

    Article  CAS  PubMed  Google Scholar 

  43. Makarenkova, H. P. et al. Differential interactions of FGFs with heparan sulfate control gradient formation and branching morphogenesis. Sci. Signal. 2, ra55 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Qu, X. et al. Lacrimal gland development and Fgf10–Fgfr2b signaling are controlled by 2-O- and 6-O-sulfated heparan sulfate. J. Biol. Chem. 286, 14435–14444 (2011). Demonstrates that a specific fine structure of the heparan sulphate produced by the cell responding to an FGF ligand is required for FGF signalling.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Qu, X. et al. Glycosaminoglycan-dependent restriction of FGF diffusion is necessary for lacrimal gland development. Development 139, 2730–2739 (2012). Demonstrates that the heparan sulphate produced by the cell secreting an FGF ligand mediates the formation of an FGF gradient in the extracellular matrix and that its fine structure is a crucial determinant in this process.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Murakami, H. et al. Elbow knee synostosis (Eks): a new mutation on mouse chromosome 14. Mamm. Genome 13, 341–344 (2002).

    Article  PubMed  Google Scholar 

  47. Crossley, P. H. & Martin, G. R. The mouse Fgf8 gene encodes a family of polypeptides and is expressed in regions that direct outgrowth and patterning in the developing embryo. Development 121, 439–451 (1995).

    CAS  PubMed  Google Scholar 

  48. Gemel, J., Gorry, M., Ehrlich, G. D. & MacArthur, C. A. Structure and sequence of human FGF8. Genomics 35, 253–257 (1996).

    Article  CAS  PubMed  Google Scholar 

  49. MacArthur, C. A. et al. FGF-8 isoforms activate receptor splice forms that are expressed in mesenchymal regions of mouse development. Development 121, 3603–3613 (1995).

    CAS  PubMed  Google Scholar 

  50. Xu, J., Lawshe, A., MacArthur, C. A. & Ornitz, D. M. Genomic structure, mapping, activity and expression of fibroblast growth factor 17. Mech. Dev. 83, 165–178 (1999).

    Article  CAS  PubMed  Google Scholar 

  51. Sato, T., Araki, I. & Nakamura, H. Inductive signal and tissue responsiveness defining the tectum and the cerebellum. Development 128, 2461–2469 (2001).

    CAS  PubMed  Google Scholar 

  52. Lee, S. M., Danielian, P. S., Fritzsch, B. & McMahon, A. P. Evidence that FGF8 signalling from the midbrain-hindbrain junction regulates growth and polarity in the developing midbrain. Development 124, 959–969 (1997).

    CAS  PubMed  Google Scholar 

  53. Liu, A., Losos, K. & Joyner, A. L. FGF8 can activate Gbx2 and transform regions of the rostral mouse brain into a hindbrain fate. Development 126, 4827–4838 (1999).

    CAS  PubMed  Google Scholar 

  54. Christen, B. & Slack, J. M. FGF-8 is associated with anteroposterior patterning and limb regeneration in Xenopus. Dev. Biol. 192, 455–466 (1997).

    Article  CAS  PubMed  Google Scholar 

  55. Fletcher, R. B., Baker, J. C. & Harland, R. M. FGF8 spliceforms mediate early mesoderm and posterior neural tissue formation in Xenopus. Development 133, 1703–1714 (2006).

    Article  CAS  PubMed  Google Scholar 

  56. Falardeau, J. et al. Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice. J. Clin. Invest. 118, 2822–2831 (2008). Implicates decreased FGF8 signalling in the deficiency of gonadotropin-releasing hormone that underlies idiopathic hypogonadotropic hypogonadism and presents an example for the role of N-terminal alternative splicing in regulating the biological activity of FGF8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Shimada, T. et al. Mutant FGF-23 responsible for autosomal dominant hypophosphatemic rickets is resistant to proteolytic cleavage and causes hypophosphatemia in vivo. Endocrinology 143, 3179–3182 (2002).

    Article  CAS  PubMed  Google Scholar 

  58. White, K. E. et al. Autosomal-dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23. Kidney Int. 60, 2079–2086 (2001).

    Article  CAS  PubMed  Google Scholar 

  59. Seidah, N. G. & Prat, A. The biology and therapeutic targeting of the proprotein convertases. Nature Rev. Drug Discov. 11, 367–383 (2012).

    Article  CAS  Google Scholar 

  60. Gram Schjoldager, K. T. et al. A systematic study of site-specific GalNAc-type O-glycosylation modulating proprotein convertase processing. J. Biol. Chem. 286, 40122–40132 (2011).

    Article  CAS  PubMed Central  Google Scholar 

  61. White, K. E. et al. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nature Genet. 26, 345–348 (2000). Identifies FGF23 as a phosphaturic hormone and missense mutations at the proteolytic cleavage site of FGF23 as the cause for the renal phosphate wasting disease autosomal dominant hypophosphatemic rickets.

    Article  CAS  Google Scholar 

  62. Frishberg, Y. et al. Hyperostosis-hyperphosphatemia syndrome: a congenital disorder of O-glycosylation associated with augmented processing of fibroblast growth factor 23. J. Bone Miner. Res. 22, 235–242 (2007).

    Article  CAS  PubMed  Google Scholar 

  63. Kato, K. et al. Polypeptide GalNAc-transferase T3 and familial tumoral calcinosis. Secretion of fibroblast growth factor 23 requires O-glycosylation. J. Biol. Chem. 281, 18370–18377 (2006).

    Article  CAS  PubMed  Google Scholar 

  64. Hsu, Y. R. et al. Human keratinocyte growth factor recombinantly expressed in Chinese hamster ovary cells: isolation of isoforms and characterization of post-translational modifications. Protein Expr. Purif. 12, 189–200 (1998).

    Article  CAS  PubMed  Google Scholar 

  65. Kim, G. Y. et al. HtrA1 is a novel antagonist controlling FGF signaling via cleavage of FGF8. Mol. Cell. Biol. 4 Sept 2012 (doi:10.1128/MCB.00872-12).

  66. Avivi, A., Yayon, A. & Givol, D. A novel form of FGF receptor-3 using an alternative exon in the immunoglobulin domain III. FEBS Lett. 330, 249–252 (1993).

    Article  CAS  PubMed  Google Scholar 

  67. Chellaiah, A. T., McEwen, D. G., Werner, S., Xu, J. & Ornitz, D. M. Fibroblast growth factor receptor (FGFR) 3. Alternative splicing in immunoglobulin-like domain III creates a receptor highly specific for acidic FGF/FGF-1. J. Biol. Chem. 269, 11620–11627 (1994).

    CAS  PubMed  Google Scholar 

  68. Johnson, D. E., Lu, J., Chen, H., Werner, S. & Williams, L. T. The human fibroblast growth factor receptor genes: a common structural arrangement underlies the mechanisms for generating receptor forms that differ in their third immunoglobulin domain. Mol. Cell. Biol. 11, 4627–4634 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Miki, T. et al. Determination of ligand-binding specificity by alternative splicing: two distinct growth factor receptors encoded by a single gene. Proc. Natl Acad. Sci. USA 89, 246–250 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Orr-Urtreger, A. et al. Developmental localization of the splicing alternatives of fibroblast growth factor receptor-2 (FGFR2). Dev. Biol. 158, 475–486 (1993).

    Article  CAS  PubMed  Google Scholar 

  71. Yan, G., Fukabori, Y., McBride, G., Nikolaropolous, S. & McKeehan, W. L. 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. 13, 4513–4522 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Yayon, A. et al. A confined variable region confers ligand specificity on fibroblast growth factor receptors: implications for the origin of the immunoglobulin fold. EMBO J. 11, 1885–1890 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Wuechner, C., Nordqvist, A. C., Winterpacht, A., Zabel, B. & Schalling, M. Developmental expression of splicing variants of fibroblast growth factor receptor 3 (FGFR3) in mouse. Int. J. Dev. Biol. 40, 1185–1188 (1996).

    CAS  PubMed  Google Scholar 

  74. Zhang, X. et al. Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family. J. Biol. Chem. 281, 15694–15700 (2006).

    Article  CAS  PubMed  Google Scholar 

  75. Alarid, E. T. et al. Keratinocyte growth factor functions in epithelial induction during seminal vesicle development. Proc. Natl Acad. Sci. USA 91, 1074–1078 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Colvin, J. S., White, A. C., Pratt, S. J. & Ornitz, D. M. Lung hypoplasia and neonatal death in Fgf9-null mice identify this gene as an essential regulator of lung mesenchyme. Development 128, 2095–2106 (2001).

    CAS  PubMed  Google Scholar 

  77. De Moerlooze, L. et al. An important role for the IIIb isoform of fibroblast growth factor receptor 2 (FGFR2) in mesenchymal–epithelial signalling during mouse organogenesis. Development 127, 483–492 (2000).

    CAS  PubMed  Google Scholar 

  78. Min, H. et al. Fgf-10 is required for both limb and lung development and exhibits striking functional similarity to Drosophila branchless. Genes Dev. 12, 3156–3161 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Sekine, K. et al. Fgf10 is essential for limb and lung formation. Nature Genet. 21, 138–141 (1999).

    Article  CAS  PubMed  Google Scholar 

  80. Xu, X. et al. Fibroblast growth factor receptor 2 (FGFR2)-mediated reciprocal regulation loop between FGF8 and FGF10 is essential for limb induction. Development 125, 753–765 (1998). Provides genetic evidence for the crucial role of FGFR2 in bidirectional paracrine FGF signalling between the epithelium and the mesenchyme that initiates the outgrowth of limb buds.

    CAS  PubMed  Google Scholar 

  81. Zhang, X. et al. Reciprocal epithelial–mesenchymal FGF signaling is required for cecal development. Development 133, 173–180 (2006).

    Article  CAS  PubMed  Google Scholar 

  82. Plotnikov, A. N., Hubbard, S. R., Schlessinger, J. & Mohammadi, M. Crystal structures of two FGF–FGFR complexes reveal the determinants of ligand-receptor specificity. Cell 101, 413–424 (2000).

    Article  CAS  PubMed  Google Scholar 

  83. Wang, F., Kan, M., Xu, J., Yan, G. & McKeehan, W. L. Ligand-specific structural domains in the fibroblast growth factor receptor. J. Biol. Chem. 270, 10222–10230 (1995).

    Article  CAS  PubMed  Google Scholar 

  84. Lajeunie, E. et al. FGFR2 mutations in Pfeiffer syndrome. Nature Genet. 9, 108 (1995).

    Article  CAS  PubMed  Google Scholar 

  85. Nagase, T., Nagase, M., Hirose, S. & Ohmori, K. Mutations in fibroblast growth factor receptor 2 gene and craniosynostotic syndromes in Japanese children. J. Craniofac. Surg. 9, 162–170 (1998).

    Article  CAS  PubMed  Google Scholar 

  86. Ibrahimi, O. A. et al. Biochemical analysis of pathogenic ligand-dependent FGFR2 mutations suggests distinct pathophysiological mechanisms for craniofacial and limb abnormalities. Hum. Mol. Genet. 13, 2313–2324 (2004).

    Article  CAS  PubMed  Google Scholar 

  87. Olsen, S. K. et al. Insights into the molecular basis for fibroblast growth factor receptor autoinhibition and ligand-binding promiscuity. Proc. Natl Acad. Sci. USA 101, 935–940 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Plotnikov, A. N., Schlessinger, J., Hubbard, S. R. & Mohammadi, M. Structural basis for FGF receptor dimerization and activation. Cell 98, 641–650 (1999).

    Article  CAS  PubMed  Google Scholar 

  89. Stauber, D. J., DiGabriele, A. D. & Hendrickson, W. A. Structural interactions of fibroblast growth factor receptor with its ligands. Proc. Natl Acad. Sci. USA 97, 49–54 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Goetz, R. et al. Conversion of a paracrine fibroblast growth factor into an endocrine fibroblast growth factor. J. Biol. Chem. 287, 29134–29146 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Ito, S., Fujimori, T., Hayashizaki, Y. & Nabeshima, Y. Identification of a novel mouse membrane-bound family 1 glycosidase-like protein, which carries an atypical active site structure. Biochim. Biophys. Acta 1576, 341–345 (2002).

    Article  CAS  PubMed  Google Scholar 

  92. Ito, S. et al. Molecular cloning and expression analyses of mouse βKlotho, which encodes a novel Klotho family protein. Mech. Dev. 98, 115–119 (2000).

    Article  CAS  PubMed  Google Scholar 

  93. Kuro-o, M. et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390, 45–51 (1997).

    Article  CAS  PubMed  Google Scholar 

  94. Yahata, K. et al. Molecular cloning and expression of a novel Klotho-related protein. J. Mol. Med. (Berl.) 78, 389–394 (2000).

    Article  CAS  Google Scholar 

  95. Henrissat, B. A classification of glycosyl hydrolases based on amino acid sequence similarities. Biochem. J. 280, 309–316 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Henrissat, B. & Bairoch, A. New families in the classification of glycosyl hydrolases based on amino acid sequence similarities. Biochem. J. 293, 781–788 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Henrissat, B. & Bairoch, A. Updating the sequence-based classification of glycosyl hydrolases. Biochem. J. 316, 695–696 (1996).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Fon Tacer, K. et al. Research resource: comprehensive expression atlas of the fibroblast growth factor system in adult mouse. Mol. Endocrinol. 24, 2050–2064 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Goetz, R. et al. Klotho coreceptors inhibit signaling by paracrine fibroblast growth factor 8 subfamily ligands. Mol. Cell. Biol. 32, 1944–1954 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Kharitonenkov, A. et al. FGF-21/FGF-21 receptor interaction and activation is determined by βKlotho. J. Cell. Physiol. 215, 1–7 (2008).

    Article  CAS  PubMed  Google Scholar 

  101. Li, S. A. et al. Immunohistochemical localization of Klotho protein in brain, kidney, and reproductive organs of mice. Cell Struct. Funct. 29, 91–99 (2004).

    Article  CAS  PubMed  Google Scholar 

  102. Machado, M. F. et al. Regulation and action of fibroblast growth factor 17 in bovine follicles. J. Endocrinol. 202, 347–353 (2009).

    Article  CAS  PubMed  Google Scholar 

  103. Portela, V. M. et al. Expression and function of fibroblast growth factor 18 in the ovarian follicle in cattle. Biol. Reprod. 83, 339–346 (2010).

    Article  CAS  PubMed  Google Scholar 

  104. Gabrielsson, B. G. et al. Depot-specific expression of fibroblast growth factors in human adipose tissue. Obes. Res. 10, 608–616 (2002).

    Article  CAS  PubMed  Google Scholar 

  105. Jaskoll, T. et al. FGF10/FGFR2b signaling plays essential roles during in vivo embryonic submandibular salivary gland morphogenesis. BMC Dev. Biol. 5, 11 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Mailleux, A. A. et al. Role of FGF10/FGFR2b signaling during mammary gland development in the mouse embryo. Development 129, 53–60 (2002).

    CAS  PubMed  Google Scholar 

  107. Qiao, J. et al. FGF-7 modulates ureteric bud growth and nephron number in the developing kidney. Development 126, 547–554 (1999).

    CAS  PubMed  Google Scholar 

  108. Terauchi, A. et al. Distinct FGFs promote differentiation of excitatory and inhibitory synapses. Nature 465, 783–787 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Dutchak, P. A. et al. Fibroblast growth factor-21 regulates PPARγ activity and the antidiabetic actions of thiazolidinediones. Cell 148, 556–567 (2012). Identifies FGF21 as a mediator of the metabolic actions of PPARγ and hence provides new insight into the mechanism of action of the thiazolidinedione class of antidiabetic drugs, which are PPARγ agonists.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Tontonoz, P. & Spiegelman, B. M. Fat and beyond: the diverse biology of PPARγ. Annu. Rev. Biochem. 77, 289–312 (2008).

    Article  CAS  PubMed  Google Scholar 

  111. Hotta, Y. et al. Fibroblast growth factor 21 regulates lipolysis in white adipose tissue but is not required for ketogenesis and triglyceride clearance in liver. Endocrinology 150, 4625–4633 (2009).

    Article  CAS  PubMed  Google Scholar 

  112. Ming, A. Y. et al. Dynamics and distribution of Klothoβ (KLB) and fibroblast growth factor receptor-1 (FGFR1) in living cells reveal the fibroblast growth factor-21 (FGF21)-induced receptor complex. J. Biol. Chem. 287, 19997–20006 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Kouhara, H. et al. A lipid-anchored Grb2-binding protein that links FGF-receptor activation to the Ras/MAPK signaling pathway. Cell 89, 693–702 (1997).

    Article  CAS  PubMed  Google Scholar 

  114. Lamothe, B. et al. The docking protein Gab1 is an essential component of an indirect mechanism for fibroblast growth factor stimulation of the phosphatidylinositol 3-kinase/Akt antiapoptotic pathway. Mol. Cell. Biol. 24, 5657–5666 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Brunet, A. et al. Akt promotes cell survival by phosphorylating and inhibiting a forkhead transcription factor. Cell 96, 857–868 (1999).

    Article  CAS  PubMed  Google Scholar 

  116. Datta, S. R. et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91, 231–241 (1997).

    Article  CAS  PubMed  Google Scholar 

  117. Hartwig, J. H. et al. MARCKS is an actin filament crosslinking protein regulated by protein kinase C and calcium-calmodulin. Nature 356, 618–622 (1992).

    Article  CAS  PubMed  Google Scholar 

  118. Li, H., Rao, A. & Hogan, P. G. Interaction of calcineurin with substrates and targeting proteins. Trends Cell Biol. 21, 91–103 (2011).

    Article  CAS  PubMed  Google Scholar 

  119. Ye, S. et al. Structural basis for interaction of FGF-1, FGF-2, and FGF-7 with different heparan sulfate motifs. Biochemistry 40, 14429–14439 (2001).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank J. Ma for help with preparing the structures. Studies on the structural basis of FGF signalling in the Mohammadi laboratory are funded by the U.S. National Institutes of Health grant DE13686.

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, 10016, New York, USA

    Regina Goetz & Moosa Mohammadi

Authors
  1. Regina Goetz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Moosa Mohammadi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Regina Goetz or Moosa Mohammadi.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Moosa Mohammadi's homepage

Glossary

Paracrine

Refers to a mode of signalling in which the cell responding to a signalling molecule is near the cell secreting the molecule.

Endocrine

Refers to a mode of signalling in which the cell responding to a signalling molecule is far away from the cell secreting the molecule.

Transphosphorylation

The process by which one kinase molecule in a kinase dimer phosphorylates the other (also referred to as autophosphorylation).

Proteoglycans

Protein–glycan conjugates that consist of a core protein to which one or more glycosaminoglycan chains are attached.

Morphogenesis

Process of cell movement during embryonic development that controls the size, shape and patterning of tissues and organs.

β-trefoil

Portion of a protein that consists of 12 β-strands arranged into 3 similar sets of 4-stranded β-sheets.

Epimerization

Process by which an epimer of a molecule is converted into its stereoisomeric counterpart.

Submandibular gland

Gland located under the mandible bone that secretes saliva into the mouth.

Elbow knee synostosis

(Eks). Mouse skeletal phenotype characterized by bone fusion at elbow and knee joints.

Lacrimal gland

Gland of the eye that produces tear fluid to keep the eye lubricated.

Idiopathic hypogonadotropic hypogonadism

Hereditary disorder characterized by the failure of sexual maturation and infertility due to deficiency of gonadotropin-releasing hormone.

Renal phosphate wasting disease

Inherited or acquired condition characterized by excessive renal excretion of phosphate due to impaired tubular reabsorption.

Hyperphosphatemia

Increase in blood phosphate levels above normal.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Goetz, R., Mohammadi, M. Exploring mechanisms of FGF signalling through the lens of structural biology. Nat Rev Mol Cell Biol 14, 166–180 (2013). https://doi.org/10.1038/nrm3528

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm3528

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing