Development FGF-family signaling

FGF-family signaling

Fibroblast growth factors ( FGFs ) have been implicated in diverse cellularprocesses 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 offour receptor tyrosine kinases (RTKs) with designated high affinity for Fibroblast growthfactor receptors FGFR1 - FGFR4.

FGFR s have different ligand-binding characteristics. FGFR1 bindsFGF1, FGF2, FGF3, FGF4 and FGF10. FGFR2 bindsFGF1, FGF2, FGF3, FGF4, FGF7 and FGF10.FGFR3 binds FGF1, FGF2, FGF8 and FGF9. FGFR4 bindsFGF1, FGF2, FGF6, FGF16 and FGF19.

FGF activity and specificity are further regulated by heparan sulfateproteoglycans (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 proteinkinase (MAPK) pathway. It involves lipid-anchored docking protein fibroblast growthfactor receptor substrate 2 ( FRS2 ) that constitutively binds with FGFR1,FGFR2 and FGFR3, but not FGFR4. FRS2 tyrosinephosphorylation sites are recognized and bound by the adapter protein Growth factorreceptor-bound protein 2 ( GRB2 ) and the protein tyrosine phosphatase (PTP)Tyrosine phosphatase non-receptor type 11 ( SHP-2 ) , as an adapterprotein. FGFR1, FGFR3, FGFR4 are able to phosphorylate SHC transforming protein (Shc ) directly. Shc and GRB2 form a complex with the guaninenucleotide exchange factor Son of sevenless ( SOS ) via its SH3 domain.Translocation of this complex to the plasma membrane by binding to phosphorylatedFRS2 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 effectorproteins 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 ofPhosphatidylinositol-3 kinase ( PI3K ) and downstream effector proteins, such asV-akt murine thymoma viral oncogene homolog 1 ( AKT(PKB) ), whose cellularlocalization and activity are regulated by products of PI3K, Phosphatidylinositol3,4,5-triphosphate ( PtdIns(3,4,5)P3 )[3].

FGF plays a critical role in membrane phospholipid hydrolysis in the cell. Uponbinding to FGFR1, FGFR3, FGFR4, FGFs stimulates cytosolicform of Phospholipase C-gamma1 ( PLC-gamma 1 ). PLC-gamma activation byFGF leads to Phosphatidylinositol 4,5-biphosphate ( PtdIns(4,5)P2 )hydrolysis and generation of two second messengers, Diacylglycerol ( DAG ) andIP3. IP3 activates IP3 receptor ( IP3 receptor ) and accumulationof Ca 2+ in the cytoplasm. DAG activates Protein kinase C delta( PKC-delta ) [4].

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