Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

FGF (Fibroblast Growth Factor)

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_313


 Acidic FGF;  aFGF;  Basic FGF;  bFGF;  FGF;  FGF1;  FGF10;  FGF11;  FGF12;  FGF13;  FGF14;  FGF16;  FGF17;  FGF18;  FGF19;  FGF2;  FGF20;  FGF-20;  FGF21;  FGF22;  FGF23;  FGF3;  FGF4;  FGF5;  FGF6;  FGF7;  FGF8;  FGF9;  int-2;  K-FGF;  KGF

Historical Background

The founding members of the fibroblast growth factor (FGF) family are FGF1 (acidic FGF or aFGF) and FGF2 (basic FGF or bFGF), which were initially purified from bovine brain and pituitary gland as mitogens for fibroblasts. Mouse Fgf3 (int-2) was cloned and characterized as a proto-oncogene that is aberrantly upregulated in mammary tumors due to the proviral integration of mouse mammary tumor virus (MMTV). Human FGF4 (K-FGF) was cloned and characterized as a proto-oncogene following the transfection of genomic DNA from Kaposi sarcoma into mouse NIH 3T3 cells. In addition, 18 FGFs have been cloned and characterized based on their homology to FGF1 ~ FGF4 (Reviewed in Katoh 2002). Because the CCND1 – ORAOV1 – FGF19 – FGF4 – FGF3 locus at human chromosome 11q13.3 is conserved in chicken and zebra fish genomes and is syntenic to the rodent Ccnd1 – Oraov1 – Fgf15 – Fgf4Fgf3 locus, it was concluded that human FGF19, chicken fgf19, and zebra fish fgf19 are orthologs of rodent Fgf15 (Katoh and Katoh 2003). Therefore, 22, but not 23, FGF family genes are conserved in mammalian genomes.

FGF family members that are characterized by conserved FGF core domains of approximately 120 amino acid residues are classified into the following three subgroups: a paracrine FGF subgroup consisting of FGF1, FGF2, FGF3, FGF4, FGF5, FGF6, FGF7, FGF8, FGF9, FGF10, FGF16, FGF17, FGF18, FGF20, and FGF22; an endocrine FGF subgroup consisting of FGF19, FGF21, and FGF23; and an intracellular FGF subgroup consisting of FGF11, FGF12, FGF13, and FGF14 (Fig. 1a). Paracrine FGFs transduce signals through cell-surface FGF receptors (FGFRs) and heparan-sulfate proteoglycans (HSPGs), whereas endocrine FGFs transduce signals through cell-surface FGFRs and Klotho family proteins (Katoh and Nakagama 2014; Ornitz and Itoh 2015). Extracellular FGFs utilize HSPG or Klotho-type coreceptors to fine-tune their context-dependent interaction with FGFRs.
FGF (Fibroblast Growth Factor), Fig. 1

The FGF family. (a) FGF family members are classified into paracrine FGFs, endocrine FGFs, and intracellular FGFs. (b) Receptors of secreted FGFs and genetic alterations in the FGF family genes

FGF-FGFR Signaling Cascades

Signals from 18 extracellular FGFs are transduced through FGFR1b, FGFR1c, FGFR2b, FGFR2c, FGFR3b, FGFR3c, or FGFR4 (Fig. 1b), which share a common domain architecture consisting of extracellular immunoglobulin (Ig)-like domains and a cytoplasmic tyrosine kinase domain (Katoh and Nakagama 2014; Ornitz and Itoh 2015). The FGFR1, FGFR2, and FGFR3 genes encode two receptor isoforms with distinct ligand specificity due to alternative splicing in the third Ig-like domain, whereas the FGFR4 gene encodes a single receptor.

FGF-mediated dimerization and stepwise autophosphorylation of FGFRs result in the phosphorylation of an adaptor molecule, FGFR substrate 2 (FRS2), and also recruitment and the activation of phospholipase C-γ (PLCγ) (Katoh and Nakagama 2014). The phosphorylation of FRS2 leads to the recruitment of GRB2 and the subsequent activation of the RAS-ERK and PI3K-AKT signaling cascades. The PLCγ-mediated catalysis of phosphatidylinositol diphosphate (PIP2) gives rise to inositol triphosphate (IP3) leading to the release of Ca2+ from the endoplasmic reticulum and also diacylglycerol (DAG) for the activation of protein kinase C (PKC). In addition, FGF signals activate the JAK-STAT signaling cascade via SRC family kinases. FGF signals are transduced to RAS-ERK, PI3K-AKT, JAK-STAT, Ca2+ release, and PKC signaling cascades (Fig. 2).
FGF (Fibroblast Growth Factor), Fig. 2

FGF signaling cascades. FGF signals are transduced through FGFRs to RAS-ERK, PI3K-AKT, and other signaling cascades for the self-renewal and survival of stem cells, the proliferation or differentiation of progenitor cells, angiogenesis, and would healing

Physiological Roles of FGF Signaling

Embryonic stem cells (ESCs), epiblast-derived stem cells (EpiSCs), and induced pluripotent stem cells (iPSCs) are characterized by self-renewal and pluripotency. Human ESCs and mouse EpiSCs are supported by FGF2 and Activin/Nodal, whereas mouse ESCs are supported by leukemia inhibitory factor (LIF) (Katoh 2008).

Mesenchymal stem cells (MSCs) are somatic stem cells with the potential to differentiate into mesoderm-derived chondrocytes, osteoblasts, adipocytes, fibroblasts, and myocytes, as well as nonmesoderm-derived hepatocytes and neurons. FGF signals are required for the osteoblastic differentiation of MSCs and for the adipocytic differentiation of preadipocytes (Katoh 2008).

FGF3, FGF7, FGF10, and FGF22 preferentially transduce signals through FGFR2b and/or FGFR1b on epithelial cells to function as local regulators that are involved in fetal morphogenesis, axon guidance, and wound repair (Katoh and Nakagama 2014). On the other hand, FGF19, FGF21, and FGF23 are secreted into the circulation to function as endocrine hormonal factors that are involved in the metabolism of glucose, lipids, bile acids, inorganic phosphate, and vitamin D (Degirolamo et al. 2016).

FGF signals are involved in physiological responses, such as the self-renewal of stem cells, the proliferation or differentiation of progenitor cells, angiogenesis, and would healing.

Pathological Roles of FGF Signaling

Germline mutations in human FGF3 (Tekin et al. 2008), FGF5 (Higgins et al. 2014), FGF8 (Trarbach et al. 2010), FGF10 (Milunsky et al. 2006), FGF14 (Dalski et al. 2005), FGF16 (Jamsheer et al. 2013), FGF17 (Miraoui et al. 2013), FGF20 (Barak et al. 2012), and FGF23 (ADHR Consortium 2000; Folsom and Imel 2015) occur in hereditary diseases (Fig. 1b). For example, the FGF23 gene at the human chromosome 12p13.32 is the causative gene for autosomal-dominant hypophosphatemic rickets (ADHR) that gives rise to rickets, osteomalacia, and lower limb deformity. Missense mutations of FGF23 around a proteolytic cleavage site lead to the elevation of FGF23 serum levels. FGF23 is associated with α-Klotho to transduce signals through FGFR1c, FGFR3c, and FGFR4 to the RAS-ERK signaling branch. Because FGF23 is an osteocyte-derived hormonal factor that downregulates the reabsorption of inorganic phosphate from proximal convoluted tubules in the kidney, missense mutations of FGF23 in ADHR patients result in hypophosphatemia due to decreased reabsorption of inorganic phosphate (Degirolamo et al. 2016). Germline mutations or rare variations in the FGF genes are involved in the pathogenesis of hereditary diseases (Fig. 1b).

In contrast, common variations in the FGF genes are also involved in human diseases, although their effects are relatively weak compared with those of rare mutations that cause FGF-related hereditary diseases. The FGF20 gene at human chromosome 8p22 (Kirikoshi et al. 2000) is located within the susceptibility locus of Parkinson’s disease (Zhu et al. 2014). The clinical features of Parkinson’s disease, such as resting tremor, cogwheel rigidity, bradykinesia, and impaired postural reflexes, are caused by the loss of dopaminergic neurons in the substantia nigra. FGF20 secreted from the substantia nigra activates the RAS-ERK signaling branch to induce the differentiation of dopaminergic neurons. The single-nucleotide polymorphism (SNP) rs12720208, which creates a miRNA-433 target sequence within the 3’-UTR of FGF20 mRNA, potentially contributes to the risk for Parkinson’s disease due to the miRNA-induced repression of FGF20 (Wang et al. 2008). However, because a meta-analysis of 3402 Parkinson’s disease cases and 3739 controls failed to show any association between the rs12720208 SNP and disease risk (Zhao et al. 2016), the involvement of the FGF20 SNP in the predisposition to Parkinson’s disease remains to be demonstrated in larger and stratified studies.

FGFR1, FGFR2, or FGFR3 are the causative genes for congenital skeletal abnormalities, such as Crouzon syndrome, Jackson-Weiss syndrome, Apert syndrome, Pfeiffer syndrome, Beare-Stevenson syndrome, or Saethre-Chotzen syndrome (Katoh and Nakagama 2014). Missense mutations in FGFRs around the third Ig-like domain lead to ectopic FGFR2 activation due to altered ligand-binding specificity, whereas those within the tyrosine kinase domain results in ligand-independent FGFR signaling activation due to the release of FGFR from autoinhibition.

Fgf3, Fgf4, and Fgf10 are upregulated due to the proviral integration of MMTV during mouse mammary carcinogenesis. Interestingly, Fgf3 and/or Fgf4 are activated by MMTV because Fgf3 and Fgf4 genes are clustered as mentioned above. Fgf3 was demonstrated as a proto-oncogene that is involved in mouse mammary carcinogenesis based on tumorigenesis in MMTV-Fgf3 transgenic mice that express the Fgf3 transgene under the control of the MMTV promoter. Mammary carcinogenesis in MMTV-Fgf3 transgenic mice is accelerated due to the upregulation of Wnt10b based on additional MMTV proviral integration and in MMTV-Wnt1 transgenic mice due to Fgf3 upregulation. FGF signals promote mouse mammary carcinogenesis in cooperation with canonical WNT signals (Katoh and Nakagama 2014).

In humans, the CCND1 – ORAOV1 – FGF19 – FGF4 – FGF3 locus at the chromosome 11q13.3 region is amplified in breast cancer and other types of tumors. CCND1 is overexpressed in human tumors due to copy number gain. Because the CCND1 gene encodes Cyclin D1, which is involved in cell-cycle progression, CCND1 within the 11q13.3 amplicon is a driver gene of human carcinogenesis.

FGFR genes rather than FGF genes are frequently altered in a variety of human cancers (Carter et al. 2015; Katoh 2016). FGFR1 is activated due to overexpression that is associated with gene amplification in ER-positive breast cancer and squamous cell lung cancer and is also due to chromosomal translocation in myeloproliferative syndrome. FGFR2 is activated due to overexpression that is associated with gene amplification in triple-negative breast cancer and diffuse-type gastric cancer and also due to gain-of-function mutations in endometrial cancer and gene fusions in cholangiocarcinoma. SNPs in an intronic region of the FGFR2 gene are associated with an increased risk of breast cancer through altered FGFR2 transcription due to the SNP-based creation of transcription factor–binding sites. FGFR3 is activated due to chromosomal translocation in multiple myeloma. FGFR genes are aberrantly activated in human tumors due to gene amplification, gene fusion, and missense mutations.

Together these facts indicate that aberrant FGF signaling causes a broad spectrum of pathologies, such as cancer, endocrine disease, neurodegenerative disease, and skeletal abnormalities.

Clinical Applications

Because FGFs are involved in the pathogenesis of a variety of human diseases, FGF signaling cascades are potential therapeutic targets in the fields of regenerative medicine, endocrinology and metabolism, and clinical oncology (Degirolamo et al. 2016; Katoh 2016).

Recombinant FGFs are applicable for wound healing or tissue repair. The protection of dopaminergic neurons by recombinant FGF20 is in a preclinical stage for the treatment of Parkinson’s disease (Tian et al. 2016), whereas recombinant FGF2 and FGF7 proteins are applied in the clinic for the treatment of skin ulcers and cancer therapy-associated mucosal injury, respectively (El Agha et al. 2016; Zhang and Li 2016).

Human antibodies and small molecule inhibitors are applicable for therapeutic FGF signaling blockade. An anti-FGF23 human monoclonal antibody (KRN23) is in clinical trials for the treatment of X-linked hypophosphatemia that is caused by the aberrant elevation of serum FGF23 (Carpenter et al. 2014). Small-molecule FGFR inhibitors, such as AZD4547, erdafitinib (JNJ-42756493), infigratinib (BGJ398), and dovitinib (TKI258), are in clinical trials for the treatment of human cancers that have genetic alterations in the FGFR family genes (Katoh 2016).


FGF1, FGF2, FGF3, FGF4, FGF5, FGF6, FGF7, FGF8, FGF9, FGF10, FGF16, FGF17, FGF18, FGF20, and FGF22 are paracrine FGFs that transduce signals through FGFRs and HSPGs; FGF19, FGF21, and FGF23 are endocrine FGFs that transduce signals through FGFRs and Klotho family proteins; and FGF11, FGF12, FGF13, and FGF14 are intracellular FGFs. Genetic alterations in FGF signaling molecules cause congenital disorders, as well as cancers, because the FGF signaling pathway plays a key role in fetal morphogenesis, adult homeostasis, and tumorigenesis. Recombinant FGF2 and FGF7 are utilized for the treatment of skin ulcers and mucositis, respectively, in the clinical setting. The anti-FGF23 monoclonal antibody is in clinical trials for the treatment of X-linked hypophosphatemia, whereas small-molecule FGFR inhibitors are in clinical trials for the treatment of cancers that contain FGFR alterations. Therapeutics targeting the FGF signaling cascades will be applied to precision medicine that utilizes “omics” data for diagnosis and therapeutic optimization.


  1. ADHR Consortium. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet. 2000;26:345–8.CrossRefGoogle Scholar
  2. Barak H, Huh SH, Chen S, Jeanpierre C, Martinovic J, Parisot M, et al. FGF9 and FGF20 maintain the stemness of nephron progenitors in mice and man. Dev Cell. 2012;22:1191–207.PubMedPubMedCentralCrossRefGoogle Scholar
  3. Carpenter TO, Imel EA, Ruppe MD, Weber TJ, Klausner MA, Wooddell MM, et al. Randomized trial of the anti-FGF23 antibody KRN23 in X-linked hypophosphatemia. J Clin Invest. 2014;124:1587–97.PubMedPubMedCentralCrossRefGoogle Scholar
  4. Carter EP, Fearon AE, Grose RP. Careless talk costs lives: fibroblast growth factor receptor signalling and the consequences of pathway malfunction. Trends Cell Biol. 2015;25:221–33.PubMedCrossRefGoogle Scholar
  5. Dalski A, Atici J, Kreuz FR, Hellenbroich Y, Schwinger E, Zühlke C. Mutation analysis in the fibroblast growth factor 14 gene: frameshift mutation and polymorphisms in patients with inherited ataxias. Eur J Hum Genet. 2005;13:118–20.PubMedCrossRefGoogle Scholar
  6. Degirolamo C, Sabba C, Moschetta A. Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23. Nat Rev Drug Discov. 2016;15:51–69.PubMedCrossRefGoogle Scholar
  7. El Agha E, Kosanovic D, Schermuly RT, Bellusci S. Role of fibroblast growth factors in organ regeneration and repair. Semin Cell Dev Biol. 2016;53:76–84.PubMedCrossRefGoogle Scholar
  8. Folsom LJ, Imel EA. Hyperphosphatemic familial tumoral calcinosis: genetic models of deficient FGF23 action. Curr Osteoporos Rep. 2015;13:78–87.PubMedCrossRefGoogle Scholar
  9. Higgins CA, Petukhova L, Harel S, Ho YY, Drill E, Shapiro L, et al. FGF5 is a crucial regulator of hair length in humans. Proc Natl Acad Sci USA. 2014;111:10648–53.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Jamsheer A, Zemojtel T, Kolanczyk M, Stricker S, Hecht J, Krawitz P, et al. Whole exome sequencing identifies FGF16 nonsense mutations as the cause of X-linked recessive metacarpal 4/5 fusion. J Med Genet. 2013;50:579–84.PubMedCrossRefGoogle Scholar
  11. Katoh M. WNT and FGF gene clusters. Int J Oncol. 2002;21:1269–73.PubMedGoogle Scholar
  12. Katoh M. WNT signaling in stem cell biology and regenerative medicine. Curr Drug Targets. 2008;9:565–70.PubMedCrossRefGoogle Scholar
  13. Katoh M. Therapeutics targeting FGF signaling network in human diseases. Prends Pharmacol Sci. 2016;37:1081–96.Google Scholar
  14. Katoh M, Katoh M. Evolutionary conservation of CCND1 – ORAOV1 – FGF19 – FGF4 locus from zebrafish to human. Int J Mol Med. 2003;12:45–50.PubMedGoogle Scholar
  15. Katoh M, Nakagama H. FGF receptors: cancer biology and therapeutics. Med Res Rev. 2014;34:280–300.PubMedCrossRefGoogle Scholar
  16. Kirikoshi H, Sagara N, Saitoh T, Sekihara H, Shiokawa K, Katoh M. Molecular cloning and characterization of human FGF-20 on chromosome 8p21.3-p22. Biochem Biophys Res Commun. 2000;274:337–43.PubMedCrossRefGoogle Scholar
  17. Milunsky JM, Zhao G, Maher TA, Colby R, Everman DB. LADD syndrome is caused by FGF10 mutations. Clin Genet. 2006;69:349–54.PubMedCrossRefGoogle Scholar
  18. Miraoui H, Dwyer AA, Sykiotis GP, Plummer L, Chung W, Feng B, et al. Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism. Am J Hum Genet. 2013;92:725–43.PubMedPubMedCentralCrossRefGoogle Scholar
  19. Ornitz DM, Itoh N. The fibroblast growth factor signaling pathway. Wiley Interdiscip Rev Dev Biol. 2015;4:215–66. .xPubMedPubMedCentralCrossRefGoogle Scholar
  20. Tekin M, Oztürkmen Akay H, Fitoz S, Birnbaum S, Cengiz FB, et al. Homozygous FGF3 mutations result in congenital deafness with inner ear agenesis, microtia, and microdontia. Clin Genet. 2008;73:554–65.PubMedCrossRefGoogle Scholar
  21. Tian H, Zhao Y, Chen N, Wu M, Gong W, Zheng J, et al. High production in E. coli of biologically active recombinant human fibroblast growth factor 20 and its neuroprotective effects. Appl Microbiol Biotechnol. 2016;100:3023–34.PubMedCrossRefGoogle Scholar
  22. Trarbach EB, Abreu AP, Silveira LF, Garmes HM, Baptista MT, Teles MG, et al. Nonsense mutations in FGF8 gene causing different degrees of human gonadotropin-releasing deficiency. J Clin Endocrinol Metab. 2010;95:3491–6.PubMedPubMedCentralCrossRefGoogle Scholar
  23. Wang G, van der Walt JM, Mayhew G, Li YJ, Züchner S, Scott WK, et al. Variation in the miRNA-433 binding site of FGF20 confers risk for Parkinson disease by overexpression of a-synuclein. Am J Hum Genet. 2008;82:283–9.PubMedPubMedCentralCrossRefGoogle Scholar
  24. Zhang J, Li Y. Therapeutic uses of FGFs. Semin Cell Dev Biol. 2016;53:144–54.PubMedCrossRefGoogle Scholar
  25. Zhao X, Wu Y, Zhao C, Feng M. Association between FGF20 rs12720208 gene polymorphism and Parkinson’s disease: a meta-analysis. Neurol Sci. 2016;37:1119–26.PubMedCrossRefGoogle Scholar
  26. Zhu R, Zhu Y, Liu X, He Z. Fibroblast growth factor 20 (FGF20) gene polymorphism and risk of Parkinson’s disease: a meta-analysis. Neurol Sci. 2014;35:1889–94.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Omics NetworkNational Cancer CenterTokyoJapan