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Nuclear Fibroblast Growth Factor Receptor Signaling in Skeletal Development and Disease

  • Creighton T. Tuzon
  • Diana Rigueur
  • Amy E. MerrillEmail author
Skeletal Development (R Marcucio and J Feng, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Skeletal Development

Abstract

Purpose of Review

Fibroblast growth factor receptor (FGFR) signaling regulates proliferation and differentiation during development and homeostasis. While membrane-bound FGFRs play a central role in these processes, the function of nuclear FGFRs is also critical. Here, we highlight mechanisms for nuclear FGFR translocation and the effects of nuclear FGFRs on skeletal development and disease.

Recent Findings

Full-length FGFRs, internalized by endocytosis, enter the nucleus through β-importin-dependent mechanisms that recognize the nuclear localization signal within FGFs. Alternatively, soluble FGFR intracellular fragments undergo nuclear translocation following their proteolytic release from the membrane. FGFRs enter the nucleus during the cellular transition between proliferation and differentiation. Once nuclear, FGFRs interact with chromatin remodelers to alter the epigenetic state and transcription of their target genes. Dysregulation of nuclear FGFR is linked to the etiology of congenital skeletal disorders and neoplastic transformation.

Summary

Revealing the activities of nuclear FGFR will advance our understanding of 20 congenital skeletal disorders caused by FGFR mutations, as well as FGFR-related cancers.

Keywords

FGFR2 FGFR1 FGF2 Skeletal development Nuclear RTK, cancer 

Notes

Acknowledgments

The authors thank all the members of the Merrill laboratory for insightful discussions and, in particular, Lauren Bobzin for her critical review of this manuscript.

Funding Information

This work was supported by the National Institutes of Health R01DE025222 to A.E.M.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Right and Informed Consent

This article does not present any primary studies with human or animal subjects.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Beenken A, Mohammadi M. The FGF family: biology, pathophysiology and therapy. Nat Rev Drug Discov. 2009;8(3):235–53.Google Scholar
  2. 2.
    Turner N, Grose R. Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer. 2010;10(2):116–29.Google Scholar
  3. 3.
    Ornitz DM, Marie PJ. FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease. Genes Dev. 2002;16(12):1446–65.Google Scholar
  4. 4.
    Rice DP, Aberg T, Chan Y, Tang Z, Kettunen PJ, Pakarinen L, et al. Integration of FGF and TWIST in calvarial bone and suture development. Development. 2000;127(9):1845–55.Google Scholar
  5. 5.
    Jacob AL, Smith C, Partanen J, Ornitz DM. Fibroblast growth factor receptor 1 signaling in the osteo-chondrogenic cell lineage regulates sequential steps of osteoblast maturation. Dev Biol. 2006;296(2):315–28.Google Scholar
  6. 6.
    Wang Q, Green RP, Zhao G, Ornitz DM. Differential regulation of endochondral bone growth and joint development by FGFR1 and FGFR3 tyrosine kinase domains. Development. 2001;128(19):3867–76.Google Scholar
  7. 7.
    Yu K, Ornitz DM. FGF signaling regulates mesenchymal differentiation and skeletal patterning along the limb bud proximodistal axis. Development. 2008;135(3):483–91.Google Scholar
  8. 8.
    Yu K, Xu J, Liu Z, Sosic D, Shao J, Olson EN, et al. 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(13):3063–74.Google Scholar
  9. 9.
    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(4):390–7.Google Scholar
  10. 10.
    Deng C, Wynshaw-Boris A, Zhou F, Kuo A, Leder P. Fibroblast growth factor receptor 3 is a negative regulator of bone growth. Cell. 1996;84(6):911–21.Google Scholar
  11. 11.
    Lazarus JE, Hegde A, Andrade AC, Nilsson O, Baron J. Fibroblast growth factor expression in the postnatal growth plate. Bone. 2007;40(3):577–86.Google Scholar
  12. 12.
    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(4):841–8.Google Scholar
  13. 13.
    Plotnikov AN, Hubbard SR, Schlessinger J, Mohammadi M. Crystal structures of two FGF-FGFR complexes reveal the determinants of ligand-receptor specificity. Cell. 2000;101(4):413–24.Google Scholar
  14. 14.
    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(6807):1029–34.Google Scholar
  15. 15.
    Goetz R, Ohnishi M, Kir S, Kurosu H, Wang L, Pastor J, et al. Conversion of a paracrine fibroblast growth factor into an endocrine fibroblast growth factor. J Biol Chem. 2012;287(34):29134–46.Google Scholar
  16. 16.
    •• Ornitz DM, Itoh N. The fibroblast growth factor signaling pathway. Wiley Interdiscip Rev Dev Biol. 2015;4(3):215–66 This review provides a comprehensive assessment of the genetics and molecular biology of the FGF signaling pathway. Google Scholar
  17. 17.
    Myers JM, Martins GG, Ostrowski J, Stachowiak MK. Nuclear trafficking of FGFR1: a role for the transmembrane domain. J Cell Biochem. 2003;88(6):1273–91.Google Scholar
  18. 18.
    Merrill AE, Sarukhanov A, Krejci P, Idoni B, Camacho N, Estrada KD, et al. Bent bone dysplasia-FGFR2 type, a distinct skeletal disorder, has deficient canonical FGF signaling. Am J Hum Genet. 2012;90(3):550–7.Google Scholar
  19. 19.
    Hatch NE, Hudson M, Seto ML, Cunningham ML, Bothwell M. Intracellular retention, degradation, and signaling of glycosylation-deficient FGFR2 and craniosynostosis syndrome-associated FGFR2C278F. J Biol Chem. 2006;281(37):27292–305.Google Scholar
  20. 20.
    Maher PA. Nuclear translocation of fibroblast growth factor (FGF) receptors in response to FGF-2. J Cell Biol. 1996;134(2):529–36.Google Scholar
  21. 21.
    Stachowiak MK, Maher PA, Joy A, Mordechai E, Stachowiak EK. Nuclear localization of functional FGF receptor 1 in human astrocytes suggests a novel mechanism for growth factor action. Brain Res Mol Brain Res. 1996;38(1):161–5.Google Scholar
  22. 22.
    Reilly JF, Maher PA. Importin beta-mediated nuclear import of fibroblast growth factor receptor: role in cell proliferation. J Cell Biol. 2001;152(6):1307–12.Google Scholar
  23. 23.
    Chioni AM, Grose R. FGFR1 cleavage and nuclear translocation regulates breast cancer cell behavior. J Cell Biol. 2012;197(6):801–17.Google Scholar
  24. 24.
    • Mikolajczak M, Goodman T, Hajihosseini MK. Interrogation of a lacrimo-auriculo-dento-digital syndrome protein reveals novel modes of fibroblast growth factor 10 (FGF10) function. Biochem J. 2016;473(24):4593–607 Numerous mutations within FGFRs are causative for skeletal defects. This manuscript however identified mutations within the FGF10 ligand that fail to properly localize to the nucleus.Google Scholar
  25. 25.
    Wesche J, Małecki J̧, Wiȩdłocha A, Ehsani M, Marcinkowska E, Nilsen T, et al. Two nuclear localization signals required for transport from the cytosol to the nucleus of externally added FGF-1 translocated into cells. Biochemistry. 2005;44(16):6071–80.Google Scholar
  26. 26.
    Arese M, Chen Y, Florkiewicz RZ, Gualandris A, Shen B, Rifkin DB. Nuclear activities of basic fibroblast growth factor: potentiation of low-serum growth mediated by natural or chimeric nuclear localization signals. Mol Biol Cell. 1999;10(5):1429–44.Google Scholar
  27. 27.
    Arnaud E, Touriol C, Boutonnet C, Gensac MC, Vagner S, Prats H, et al. A new 34-kilodalton isoform of human fibroblast growth factor 2 is cap dependently synthesized by using a non-AUG start codon and behaves as a survival factor. Mol Cell Biol. 1999;19(1):505–14.Google Scholar
  28. 28.
    Okada-Ban M, Thiery JP, Jouanneau J. Fibroblast growth factor-2. Int J Biochem Cell Biol. 2000;32(3):263–7.Google Scholar
  29. 29.
    Sorensen V, Nilsen T, Wiedlocha A. Functional diversity of FGF-2 isoforms by intracellular sorting. Bioessays. 2006;28(5):504–14.Google Scholar
  30. 30.
    Sheng Z, Liang Y, Lin CY, Comai L, Chirico WJ. Direct regulation of rRNA transcription by fibroblast growth factor 2. Mol Cell Biol. 2005;25(21):9419–26.Google Scholar
  31. 31.
    Bryant DM, Wylie FG, Stow JL. Regulation of endocytosis, nuclear translocation, and signaling of fibroblast growth factor receptor 1 by E-cadherin. Mol Biol Cell. 2005;16(1):14–23.Google Scholar
  32. 32.
    Citores L, Khnykin D, Sørensen V, Wesche J, Klingenberg O, Wiedłocha A, et al. Modulation of intracellular transport of acidic fibroblast growth factor by mutations in the cytoplasmic receptor domain. J Cell Sci. 2001;114(Pt 9):1677–89.Google Scholar
  33. 33.
    Auciello G, Cunningham DL, Tatar T, Heath JK, Rappoport JZ. Regulation of fibroblast growth factor receptor signalling and trafficking by Src and Eps8. J Cell Sci. 2013;126(Pt 2):613–24.Google Scholar
  34. 34.
    Haugsten EM, Zakrzewska M, Brech A, Pust S, Olsnes S, Sandvig K, et al. Clathrin- and dynamin-independent endocytosis of FGFR3--implications for signalling. PLoS One. 2011;6(7):e21708.Google Scholar
  35. 35.
    Reilly JF, Mizukoshi E, Maher PA. Ligand dependent and independent internalization and nuclear translocation of fibroblast growth factor (FGF) receptor 1. DNA Cell Biol. 2004;23(9):538–48.Google Scholar
  36. 36.
    Malecki J, et al. Vesicle transmembrane potential is required for translocation to the cytosol of externally added FGF-1. EMBO J. 2002;21(17):4480–90.Google Scholar
  37. 37.
    Szczurkowska J, Pischedda F, Pinto B, Managò F, Haas CA, Summa M, et al. NEGR1 and FGFR2 cooperatively regulate cortical development and core behaviours related to autism disorders in mice. Brain. 2018;141(9):2772–94.Google Scholar
  38. 38.
    •• Stehbens SJ, et al. FGFR2-activating mutations disrupt cell polarity to potentiate migration and invasion in endometrial cancer cell models. J Cell Sci. 2018;131(15). In endometrial cancer, activating somatic mutations in FGFR2 induce Golgi fragmentation, lose cell polarity, and migrate cells aberrantly. These outcomes are prognostic for endometrial cancer and correlate with shorter survival. Google Scholar
  39. 39.
    Irschick R, Trost T, Karp G, Hausott B, Auer M, Claus P, et al. Sorting of the FGF receptor 1 in a human glioma cell line. Histochem Cell Biol. 2013;139(1):135–48.Google Scholar
  40. 40.
    Neben CL, Idoni B, Salva JE, Tuzon CT, Rice JC, Krakow D, et al. Bent bone dysplasia syndrome reveals nucleolar activity for FGFR2 in ribosomal DNA transcription. Hum Mol Genet. 2014;23(21):5659–71.Google Scholar
  41. 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(20):3861–73.Google Scholar
  42. 42.
    Chen MK, Hung MC. Regulation of therapeutic resistance in cancers by receptor tyrosine kinases. Am J Cancer Res. 2016;6(4):827–42.Google Scholar
  43. 43.
    Carpenter G, Liao HJ. Receptor tyrosine kinases in the nucleus. Cold Spring Harb Perspect Biol. 2013;5(10):a008979.Google Scholar
  44. 44.
    • Terranova C, Narla ST, Lee YW, Bard J, Parikh A, Stachowiak EK, et al. Global developmental gene programing involves a nuclear form of fibroblast growth factor receptor-1 (FGFR1). PLoS One. 2015;10(4):e0123380 Using genome-wide sequencing, the study revealed a mechanism for gene regulation of nuclear FGFR1 to ensure that pluripotent ESCs differentiate into neuronal cells. Google Scholar
  45. 45.
    Feng D, Kan YW. The binding of the ubiquitous transcription factor Sp1 at the locus control region represses the expression of beta-like globin genes. Proc Natl Acad Sci U S A. 2005;102(28):9896–900.Google Scholar
  46. 46.
    •• Neben CL, et al. FGFR2 mutations in bent bone dysplasia syndrome activate nucleolar stress and perturb cell fate determination. Hum Mol Genet. 2017;26(17):3253–70 This study linked cell fate determination to disease pathology by characterizing FGFR2 mutations in BBDS and established rDNA as an FGFR2-regulated loci that balances self-renewal and cell fate determination. Google Scholar
  47. 47.
    Neben CL, Lay FD, Mao X, Tuzon CT, Merrill AE. Ribosome biogenesis is dynamically regulated during osteoblast differentiation. Gene. 2017;612:29–35.Google Scholar
  48. 48.
    Dailey L, Ambrosetti D, Mansukhani A, Basilico C. Mechanisms underlying differential responses to FGF signaling. Cytokine Growth Factor Rev. 2005;16(2):233–47.Google Scholar
  49. 49.
    Stachowiak MK, Fang X, Myers JM, Dunham SM, Berezney R, Maher PA, et al. Integrative nuclear FGFR1 signaling (INFS) as a part of a universal “feed-forward-and-gate” signaling module that controls cell growth and differentiation. J Cell Biochem. 2003;90(4):662–91.Google Scholar
  50. 50.
    Horbinski C, Stachowiak EK, Chandrasekaran V, Miuzukoshi E, Higgins D, Stachowiak MK. Bone morphogenetic protein-7 stimulates initial dendritic growth in sympathetic neurons through an intracellular fibroblast growth factor signaling pathway. J Neurochem. 2002;80(1):54–63.Google Scholar
  51. 51.
    Schmahl J, Kim Y, Colvin JS, Ornitz DM, Capel B. FGF9 induces proliferation and nuclear localization of FGFR2 in Sertoli precursors during male sex determination. Development. 2004;131(15):3627–36.Google Scholar
  52. 52.
    Kim Y, Bingham N, Sekido R, Parker KL, Lovell-Badge R, Capel B. Fibroblast growth factor receptor 2 regulates proliferation and Sertoli differentiation during male sex determination. Proc Natl Acad Sci U S A. 2007;104(42):16558–63.Google Scholar
  53. 53.
    Steinberg Z, Myers C, Heim VM, Lathrop CA, Rebustini IT, Stewart JS, et al. FGFR2b signaling regulates ex vivo submandibular gland epithelial cell proliferation and branching morphogenesis. Development. 2005;132(6):1223–34.Google Scholar
  54. 54.
    Lu P, Ewald AJ, Martin GR, Werb Z. Genetic mosaic analysis reveals FGF receptor 2 function in terminal end buds during mammary gland branching morphogenesis. Dev Biol. 2008;321(1):77–87.Google Scholar
  55. 55.
    Mailleux AA, Spencer-Dene B, Dillon C, Ndiaye D, Savona-Baron C, Itoh N, et al. Role of FGF10/FGFR2b signaling during mammary gland development in the mouse embryo. Development. 2002;129(1):53–60.Google Scholar
  56. 56.
    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. 2000;127(3):483–92.Google Scholar
  57. 57.
    Krakow D, Cohn DH, Wilcox WR, Noh GJ, Raffel LJ, Sarukhanov A, et al. Clinical and radiographic delineation of bent bone dysplasia-FGFR2 type or bent bone dysplasia with distinctive clavicles and angel-shaped phalanges. Am J Med Genet A. 2016;170(10):2652–61.Google Scholar
  58. 58.
    Salva JE, Roberts RR, Stucky TS, Merrill AE. Nuclear FGFR2 regulates musculoskeletal integration within the developing limb. Dev Dyn. 2019;248:233–46.Google Scholar
  59. 59.
    Anderson J, Burns HD, Enriquez-Harris P, Wilkie AO, Heath JK. Apert syndrome mutations in fibroblast growth factor receptor 2 exhibit increased affinity for FGF ligand. Hum Mol Genet. 1998;7(9):1475–83.Google Scholar
  60. 60.
    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(19):2313–24.Google Scholar
  61. 61.
    Robertson SC, Meyer AN, Hart KC, Galvin BD, Webster MK, Donoghue DJ. Activating mutations in the extracellular domain of the fibroblast growth factor receptor 2 function by disruption of the disulfide bond in the third immunoglobulin-like domain. Proc Natl Acad Sci U S A. 1998;95(8):4567–72.Google Scholar
  62. 62.
    Coleman SJ, Chioni AM, Ghallab M, Anderson RK, Lemoine NR, Kocher HM, et al. Nuclear translocation of FGFR1 and FGF2 in pancreatic stellate cells facilitates pancreatic cancer cell invasion. EMBO Mol Med. 2014;6(4):467–81.Google Scholar
  63. 63.
    Pollock PM, et al. Frequent activating FGFR2 mutations in endometrial carcinomas parallel germline mutations associated with craniosynostosis and skeletal dysplasia syndromes. Oncogene. 2007;26(50):7158–62.Google Scholar
  64. 64.
    Gatius S, Velasco A, Azueta A, Santacana M, Pallares J, Valls J, et al. FGFR2 alterations in endometrial carcinoma. Mod Pathol. 2011;24(11):1500–10.Google Scholar
  65. 65.
    Martin AJ, Grant A, Ashfield AM, Palmer CN, Baker L, Quinlan PR, et al. FGFR2 protein expression in breast cancer: nuclear localisation and correlation with patient genotype. BMC Res Notes. 2011;4:72.Google Scholar
  66. 66.
    Cerliani JP, Vanzulli SI, Piñero CP, Bottino MC, Sahores A, Nuñez M, et al. Associated expressions of FGFR-2 and FGFR-3: from mouse mammary gland physiology to human breast cancer. Breast Cancer Res Treat. 2012;133(3):997–1008.Google Scholar
  67. 67.
    Sun S, Jiang Y, Zhang G, Song H, Zhang X, Zhang Y, et al. Increased expression of fibroblastic growth factor receptor 2 is correlated with poor prognosis in patients with breast cancer. J Surg Oncol. 2012;105(8):773–9.Google Scholar
  68. 68.
    • May M, Mosto J, Vazquez PM, Gonzalez P, Rojas P, Gass H, et al. Nuclear staining of FGFR-2/STAT-5 and RUNX-2 in mucinous breast cancer. Exp Mol Pathol. 2016;100(1):39–44 Mucinous breast carcinoma (MBC) is a rare subtype of breast cancer. When compared to non-MBC, higher expression of nuclear FGFR2 and RUNX2 was observed in MBC suggesting a role for these proteins in the progression of the mucinous phenotype. Google Scholar
  69. 69.
    Zammit C, Barnard R, Gomm J, Coope R, Shousha S, Coombes C, et al. Altered intracellular localization of fibroblast growth factor receptor 3 in human breast cancer. J Pathol. 2001;194(1):27–34.Google Scholar
  70. 70.
    Rotterud R, Fossa SD, Nesland JM. Protein networking in bladder cancer: immunoreactivity for FGFR3, EGFR, ERBB2, KAI1, PTEN, and RAS in normal and malignant urothelium. Histol Histopathol. 2007;22(4):349–63.Google Scholar
  71. 71.
    • Zhou L, Yao LT, Liang ZY, Zhou WX, You L, Shao QQ, et al. Nuclear translocation of fibroblast growth factor receptor 3 and its significance in pancreatic cancer. Int J Clin Exp Pathol. 2015;8(11):14640–8 This study suggests that the nuclear translocation of FGFR3 not only is frequent but also prognostic for pancreatic cancer. Google Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Creighton T. Tuzon
    • 1
  • Diana Rigueur
    • 1
  • Amy E. Merrill
    • 1
    • 2
    Email author
  1. 1.Center for Craniofacial Molecular Biology, Herman Ostrow School of DentistryUniversity of Southern CaliforniaLos AngelesUSA
  2. 2.Department of Biochemistry and Molecular Medicine, Keck School of MedicineUniversity of Southern CaliforniaLos AngelesUSA

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