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FGF Pathway

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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. One of the best-characterized modulators of angiogenesis is the heparin-binding FGF (Fibroblast Growth Factor). FGF induces neovascularization in vivo and is implicated in the growth of new blood vessels during wound healing and embryogenesis. In vitro, FGF induces cell proliferation, migration, and production of proteases in endothelial cells by interacting with specific co-receptor system consisting of tyrosine kinase receptors (FGFRs) and HLGAG (Heparin-Like Glycosaminoglycan), the polysaccharide component of the cell surface HSPGs (Heparan Sulfate Proteoglycans). The macromolecular interactions of the growth factor, HLGAGs, and FGFR mediate FGF dimerization or oligomerization (Ref.1). In addition, FGF2 modulates integrin expression in endothelium.

The FGFRs belong to a family of five genes (FGFR1-5), from which alternative splicing generates diverse isoforms including FGF3 (or Int-2), FGF4 (or Kaposi FGF), FGF5, FGF6, FGF7 (or Keratinocyte Growth Factor), FGF8 (or Androgen-Induced Factor), and FGF9. These receptors are widely expressed in multiple-organ systems, including vascular endothelium, suggesting functional roles in a number of homeostatic mechanisms. Acidic FGF and basic FGF 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) (Ref.2). 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 signal to the nucleus by binding to FGFR and activate multiple signal transduction pathways, including those involving Ras, MAPKs (Mitogen-Activated Protein Kinases), ERKs (Extracellular Signal-Regulated Kinases), Src, p38 MAPKs, PLC-Gamma (Phospholipase-C-Gamma), Crk, JNK (Jun N-terminal Kinase), and PKC (Protein Kinase-C). 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 (Ref.3). 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.4).

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.3). 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.5). 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.6). 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.7). 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.8). 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.9).

References:
  1. Venkataraman G,Raman R,Sasisekharan V,Sasisekharan R.
    Molecular characteristics of fibroblast growth factor-fibroblast growth factor receptor-heparin-like glycosaminoglycan complex.
    Proc Natl Acad Sci U S A. 1999 Mar 30; 96(7): 3658-63.
  2. Favoni RE,de Cupis A.
    The role of polypeptide growth factors in human carcinomas: new targets for a novel pharmacological approach.
    Pharmacol Rev. 2000 Jun; 52(2): 179-206. Review.
  3. Goldfarb M.
    Signaling by fibroblast growth factors: the inside story.
    Sci STKE. 2001 Oct 30; 2001(106): PE37. Review.
  4. Matsumoto T,Turesson I,Book M,Gerwins P,Claesson-Welsh L.
    P38 MAP kinase negatively regulates endothelial cell survival,proliferation,and differentiation in FGF-2-stimulated angiogenesis.
    J Cell Biol. 2002 Jan 7; 156(1): 149-60.
  5. Mohammadi M,McMahon G,Sun L,Tang C,Hirth P,Yeh BK,Hubbard SR,Schlessinger J.
    Structures of the tyrosine kinase domain of fibroblast growth factor receptor in complex with inhibitors.
    Science. 1997 May 9; 276(5314): 955-60.
  6. Ornitz DM,Marie PJ.
    FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease.
    Genes Dev. 2002 Jun 15; 16(12): 1446-65. Review. No abstract available.
  7. Del Rio-Tsonis K,Jung JC,Chiu IM,Tsonis PA.
    Conservation of fibroblast growth factor function in lens regeneration.
    Proc Natl Acad Sci U S A. 1997 Dec 9; 94(25): 13701-6.
  8. Ladher RK,Anakwe KU,Gurney AL,Schoenwolf GC,Francis-West PH.
    Identification of synergistic signals initiating inner ear development.
    Science. 2000 Dec 8; 290(5498): 1965-7.
  9. Hashimoto M,Sagara Y,Langford D,Everall IP,Mallory M,Everson A,Digicaylioglu M,Masliah,E.
    Fibroblast growth factor 1 regulates signaling via the glycogen synthase kinase-3beta pathway. Implications for neuroprotection.
    J Biol Chem. 2002 Sep 6; 277(36): 32985-91.