Pathway maps

Development_FGF-family signaling
Development_FGF-family signaling

Object List (links open in MetaCore):

DAG, IP3 receptor, FGFR4, FGF6, None, Perlecan, PI3K cat class IA, PI3K reg class IA (p85), FGF4, Ca('2+) endoplasmic reticulum lumen, GAB1, H-Ras, SHP-2, IP3, GRB2, FGF9, FGFR1, FGF8, FGF16, FGF2, FGF7, Shc, FGF3, 3.1.4.11, FGFR3, PLC-gamma 1, FGF19, Heparin, FRS2, FGFR2, FGF10, FGF1, SOS, PKC-delta, Ca('2+) cytosol

Description

FGF-family signaling

Fibroblast growth factors ( FGFs ) have been implicated in diverse cellular processes including apoptosis, cell survival, chemotaxis, cell adhesion, migration, differentiation, and proliferation [1].

FGFs comprise a family of 22 genes encoding structurally related proteins. FGFs mediate their cellular responses by binding to and activating a family of four receptor tyrosine kinases (RTKs) with designated high affinity for Fibroblast growth factor receptors FGFR1 - FGFR4.

FGFR s have different ligand-binding characteristics. FGFR1 binds FGF1, FGF2, FGF3, FGF4 and FGF10. FGFR2 binds FGF1, FGF2, FGF3, FGF4, FGF7 and FGF10. FGFR3 binds FGF1, FGF2, FGF8 and FGF9. FGFR4 binds FGF1, FGF2, FGF6, FGF16 and FGF19.

FGF activity and specificity are further regulated by heparan sulfate proteoglycans (such as Heparan sulfate proteoglycan 2 ( Perlecan )). Heparin associates with FGFs and FGFRs to form trimeric complexes [2].

The most common pathway employed by FGFs is the Mitogen-activated protein kinase (MAPK) pathway. It involves lipid-anchored docking protein fibroblast growth factor receptor substrate 2 ( FRS2 ) that constitutively binds with FGFR1, FGFR2 and FGFR3, but not FGFR4. FRS2 tyrosine phosphorylation sites are recognized and bound by the adapter protein Growth factor receptor-bound protein 2 ( GRB2 ) and the protein tyrosine phosphatase (PTP) Tyrosine phosphatase non-receptor type 11 ( SHP-2 ) , as an adapter protein. FGFR1, FGFR3, FGFR4 are able to phosphorylate SHC transforming protein ( Shc ) directly. Shc and GRB2 form a complex with the guanine nucleotide exchange factor Son of sevenless ( SOS ) via its SH3 domain. Translocation of this complex to the plasma membrane by binding to phosphorylated FRS2 allows SOS to activate Harvey rat sarcoma viral oncogene homolog ( H-Ras ) by GTP exchange due to its close proximity to membrane-bound H-Ras. Once in the active GTP-bound state, H-Ras interacts with several effector proteins leading to the activation of the Mitogen-activated protein kinase ( ERK ) signaling cascade. This cascade leads to cell proliferation.

Assembly of FRS2/ GRB2/ GRB2-associated binding protein 1 ( GAB1 ) complex is induced by FGF stimulation that results in activation of Phosphatidylinositol-3 kinase ( PI3K ) and downstream effector proteins, such as V-akt murine thymoma viral oncogene homolog 1 ( AKT(PKB) ), whose cellular localization and activity are regulated by products of PI3K, Phosphatidylinositol 3,4,5-triphosphate ( PtdIns(3,4,5)P3 ) [3].

FGF plays a critical role in membrane phospholipid hydrolysis in the cell. Upon binding to FGFR1, FGFR3, FGFR4, FGFs stimulates cytosolic form of Phospholipase C-gamma1 ( PLC-gamma 1 ). PLC-gamma activation by FGF leads to Phosphatidylinositol 4,5-biphosphate ( PtdIns(4,5)P2 ) hydrolysis and generation of two second messengers, Diacylglycerol ( DAG ) and IP3. IP3 activates IP3 receptor ( IP3 receptor ) and accumulation of Ca 2+ in the cytoplasm. DAG activates Protein kinase C delta ( PKC-delta ) [4].

References:

  1. Bottcher RT, Niehrs C
    Fibroblast growth factor signaling during early vertebrate development. Endocrine reviews 2005 Feb;26(1):63-77
  2. Presta M, Oreste P, Zoppetti G, Belleri M, Tanghetti E, Leali D, Urbinati C, Bugatti A, Ronca R, Nicoli S, Moroni E, Stabile H, Camozzi M, Hernandez GA, Mitola S, Dell'Era P, Rusnati M, Ribatti D
    Antiangiogenic activity of semisynthetic biotechnological heparins: low-molecular-weight-sulfated Escherichia coli K5 polysaccharide derivatives as fibroblast growth factor antagonists. Arteriosclerosis, thrombosis, and vascular biology 2005 Jan;25(1):71-6
  3. Ong SH, Hadari YR, Gotoh N, Guy GR, Schlessinger J, Lax I
    Stimulation of phosphatidylinositol 3-kinase by fibroblast growth factor receptors is mediated by coordinated recruitment of multiple docking proteins. Proceedings of the National Academy of Sciences of the United States of America 2001 May 22;98(11):6074-9
  4. Kim HJ, Kim JH, Bae SC, Choi JY, Kim HJ, Ryoo HM
    The protein kinase C pathway plays a central role in the fibroblast growth factor-stimulated expression and transactivation activity of Runx2. The Journal of biological chemistry 2003 Jan 3;278(1):319-26