Angiogenesis, the growth of new blood vessels, plays a key role in many physiological and pathological processes, such as ovulation, embryogenesis, wound repair, inflammation, malignant tumor growth, retinopathies, rheumatoid arthritis, and angiogenesis-dependent diseases (Ref. 1). One of the best-characterized modulators of angiogenesis is the heparin-binding FGF (Fibroblast Growth Factor). FGFs are a large family of multifunctional peptide growth factors of which there are at least 28 distinct members. The members of this peptide growth factor family have been identified in a variety of organisms and play pivotal roles in many cellular processes including mitogenesis, differentiation, migration, and cell survival. During embryonic development, FGFs play a critical role in morphogenesis by regulating cellular proliferation, differentiation, and migration. In the adult, FGFs are homeostatic factors functioning in tissue repair and wound healing, in the control of the nervous system, and in tumor angiogenesis (Ref. 2). Acidic FGFs and basic FGFs are the two prototypical members of the FGF family, which have a high affinity for heparin and are found to be associated with ECM (Extracellular Matrix Components). In contrast to VEGF (Vascular Endothelial Growth Factor), which is an endothelial cell-specific mitogen, FGF acts on a variety of different cell types, functioning as both a direct and an indirect stimulator of angiogenesis. FGFs mediate their cellular function through binding to and activating a family of Receptor Tyrosine Kinases (RTKs), which are designated the high-affinity FGF receptors FGFR1 to FGFR5. FGFs also bind to heparin or Heparin Sulfate Proteoglycans (HSPG), low-affinity receptors that do not transmit a biological signal; rather they function as accessory molecules that regulate FGF-binding and activation of the FGFRs. Like all RTKs, functional FGFRs are transmembrane proteins composed of an extracellular ligand-binding domain and a cytoplasmic domain containing the catalytic protein tyrosine kinase core. The extracellular ligand-binding domains of FGFRs are prototypically composed of three Ig-like domains. Alternative mRNA splicing of the Ig domains in FGFR1 through FGFR3 leads to distinct functional variants of these receptors. HSPG binding of FGF induces FGFR dimerization, which is followed by the transphosphorylation of receptor subunits and the initiation of intracellular signaling events (Ref. 3, 4 & 2).

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FGFs signal to the nucleus by binding to FGFR and activating multiple signal transduction pathways, including those involving Ras, MAPKs (Mitogen-Activated Protein Kinases), ERKs (Extracellular Signal-Regulated Kinases), Src, p38MAPKs, PLC-Gamma (Phospholipase-C-Gamma), Crk, JNK (Jun N-terminal Kinase), and PKC (Protein Kinase-C) (Ref. 5). These pathways are negatively regulated in part by the activities of DUSPs (Dual-Specificity Phosphatases). FGFR activation induces tyrosine phosphorylation of FRS2 (SNT) (FGFR Stimulated2 Grb2 binding protein), which in turn induces recruitment of GRB2 (Growth Factor Receptor Bound Protein-2), SOS, GAB1 (GRB2 Associated Binding protein-1), and SHP2 (Src Homology 2 Phosphatase-2). These initial events promote the sustained activation of Ras, which in turn activates the Raf1-MEK-MAPK pathway, leading to changes in gene transcription. Activation of PI3K (Phosphatidylinositol-3 Kinase), STAT1, and Src tyrosine kinase by FGF receptors also contributes to certain FGF-induced biological responses. Both the Raf1-MEK-MAPK and PI3K pathways are essential for proper mesoderm development. Active PLC-Gamma hydrolyzes the membrane phospholipid PIP2 (Phosphatidylinositol 4, 5-Bisphosphate), generating IP3 (Inositol 1, 4, 5-Trisphosphate) and DAG (Diacylglycerol). IP3 is responsible for mobilization of intracellular calcium stores that influence Ca2+-sensitive transcription factors whereas DAG activates certain PKC isoforms. FGF activation of p38 and its downstream target MAPKAPK2 (MAPK-Activated Protein Kinase-2) via a Ras-dependent pathway leads to transcriptional activation of CREB (cAMP Response Element-Binding Protein) and ATF2 (Activating Transcription Factor-2). MKK3 and MKK6 are relatively specific upstream regulators of p38, which are activated through Rac1 and MEKK (MAP/ERK Kinase Kinase) (Ref. 6 & 5). Receptor-mediated induction of the SHP2-Ras-ERK pathway is a central, evolutionarily conserved mechanism by which FGFs elicit a broad spectrum of biological activities, including cell growth, differentiation and morphogenesis (Ref. 7). Several members of FGFs have been identified as oncogenes and are implicated in the development and pathogenesis of human pancreatic cancers, pituitary cancer, astrocytomas, salivary gland adenosarcomas, Kaposi's sarcomas, ovarian cancers, and prostate cancers (Ref. 6). Mutations in the genes encoding FGF receptors 1, 2 and 3 causes various disorders broadly classified into two groups: (1) the dwarfing chondrodysplasia syndromes, which include HCH (Hypochondroplasia), ACH (Achondroplasia), TD (Thanatophoric Dysplasia); and (2) the Craniosynostosis syndromes, which include AS (Apert syndrome), Beare-Stevenson cutis gyrata, CS (Crouzon syndrome), PS (Pfeiffer syndrome), JWS (Jackson-Weiss syndrome), CDS (Crouzonodermoskeletal syndrome [Crouzon syndrome and acanthosis nigricans]), and a NSC (Non-syndromic Craniosynostosis). All of these mutations are autosomal dominant and frequently arise sporadically (Ref. 8). FGFs play very important role in determining the differentiation events during lens development. Specifically, FGF1 is involved in lens-inductive interactions between ectoderm and optic vesicle (Ref. 9). FGF1 and 2 and their tyrosine kinase receptor (FGFR) have also been implicated in otic development. In particular, FGF3 is essential for inner ear development and is crucial for the later stages of otic induction. In addition to roles in otic development, FGFs are involved in caudalization of the neuroectoderm, partly by signaling through the paraxial mesoderm (Ref. 10). FGF1 protects selective neuronal populations against the neurotoxic effects of molecules involved in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease and HIV encephalitis (Ref. 8).

Pathway

FGF Pathway

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Pathway Key
References
  1. Angiogenic targets for potential disorders. Bhadada SV, Goyal BR, Patel MM. Fundam Clin Pharmacol. 2011 Feb;25(1):29-47.
  2. Cellular signaling by fibroblast growth factors (FGFs) and their receptors (FGFRs) in male reproduction. Cotton LM, O'Bryan MK, Hinton BT. Endocr Rev. 2008 Apr;29(2):193-216.
  3. Oncologic Angiogenesis Imaging in the clinic---how and why. Kurdziel KA, Lindenberg L, Choyke PL. Imaging Med. 2011 Sep;3(4):445-457.
  4. Rationale for targeting VEGF, FGF, and PDGF for the treatment of NSCLC. Ballas MS, Chachoua A. Onco Targets Ther. 2011;4:43-58.
  5. Mitogen-activated protein kinase signaling in the heart: angels versus demons in a heart-breaking tale. Rose BA, Force T, Wang Y. Physiol Rev. 2010 Oct;90(4):1507-46.
  6. Fibroblast growth factor signalling: from development to cancer. Turner N, Grose R. Nat Rev Cancer. 2010 Feb;10(2):116-29.
  7. Signaling by fibroblast growth factors: the inside story. Goldfarb M. Sci STKE. 2001 Oct 30;2001(106):pe37.
  8. FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease. Ornitz DM, Marie PJ. Genes Dev. 2002 Jun 15;16(12):1446-65.
  9. Evaluation of fibroblast growth factor signaling during lens fiber cell differentiation. Huang JX, Feldmeier M, Shui YB, Beebe DC. Invest Ophthalmol Vis Sci. 2003 Feb;44(2):680-90.
  10. Expression and functions of FGF ligands during early otic development. Schimmang T. Int J Dev Biol. 2007;51(6-7):473-81.

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