Fibroblast growth factors (FGFs) have been implicated in diverse cellular processes including cell survival, differentiation, proliferation and epithelial-to-mesenchymal transition.
FGFs bind to their cognate receptors and activate c-Raf-1/ ERK1 (MAPK3)/ ERK2 (MAPK1) and Rac1/ p38 MAPK cascades, both of them are involved in regulation of cell proliferation and differentiation. Activation of PI3K reg class IA/ PI3K cat class IA/ AKT(PKB) promotes cells survival and epithelial-to-mesenchymal transition. PLC-gamma 1/ PKCs cascade takes part in regulation of development and stress response in different tissues.
Fibroblast growth factors (FGFs) have been implicated in diverse cellular processes including cell anti-apoptosis, cell differentiation, cell proliferation and epithelial to mesenchymal transition , .
FGFs comprise a family of 23 genes encoding structurally related proteins , . FGFs mediate their cellular responses by binding to and activating a family of four receptor tyrosine kinases with designated high affinity for FGFR1, FGFR2, FGFR3 and FGFR4 , , .
FGFs activity and specificity are regulated by heparan sulfate proteoglycans (such as Perlecan) , . Heparin associates with FGFs and FGFRs to form trimeric complexes , , .
Binding of FGF1, FGF2, FGF3, FGF4, FGF6, FGF1, FGF8, FGF9, FGF10, FGF16 and FGF19 to their cognate receptors FGFR1, FGFR2, FGFR3 and FGFR4 lead to activation of FRS2/ SHP-2/ GRB2/ SOS/ H-Ras/ c-Raf-1/ MEK1(MAP2K1)/ MEK2(MAP2K2)/ ERK1 (MAPK3)/ ERK2 (MAPK1) cascade, which regulates cell proliferation and cell differentiation , , , . Furthermore, FGFs can induce Shc/ GRB2/ SOS complex formation, resulting in activation of ERK1 (MAPK3)/ ERK2 (MAPK1) and cell proliferation , , , . In addition, FGFs can activate Rac1/ MLK3(MAP3K11)/ MEK6(MAP2K6)/ p38 MAPK pathway , ,  probably via FRS2/ SHP-2/ GRB2/ SOS , . Activation of p38 MAPK is also involved in regulation of cell proliferation and cell differentiation , , .
Assembly of FRS2/ SHP-2/ GRB2/ GAB1 complex is induced by FGFs stimulation that results in activation of PI3K reg class IA/ PI3K cat class IA/ PtdIns(3,4,5)P3 / AKT(PKB) pathway. Induction of AKT(PKB) promotes cells anti-apoptosis and epithelial to mesenchymal transition , , , .
FGFs play a critical role in membrane phospholipid hydrolysis in the cell. Upon binding to FGFR1, FGFR3, FGFR4, FGFs stimulates cytosolic form of PLC-gamma 1 . PLC-gamma 1 activation leads to PtdIns(4,5)P2 hydrolysis and generation of two second messengers, 1,2-Diacyglycerol and IP3. IP3 activates IP3 receptor and accumulation of Ca("2+) in the cytoplasm. 1,2-Diacyglycerol activates PKC-delta and PKC-epsilon , . 1,2-Diacyglycerol and Ca("2+) induce activation of PKC-alpha and PKC-beta . PLC-gamma 1/ PKCs cascade takes part in regulation of developmental process and response to stress in different tissues , , .
| 1,2-Diacyglycerol || 1,2-Diacyglycerol Compound group |
| AKT(PKB) || AKT(PKB) Protein group |
| Ca("2+) || Chemical IUPAC name calcium(+2) cation |
| ERK1 (MAPK3) || Mitogen-activated protein kinase 3 |
| ERK2 (MAPK1) || Mitogen-activated protein kinase 1 |
| FGF1 || Heparin-binding growth factor 1 |
| FGF10 || Fibroblast growth factor 10 |
| FGF16 || Fibroblast growth factor 16 |
| FGF19 || Fibroblast growth factor 19 |
| FGF2 || Heparin-binding growth factor 2 |
| FGF3 || Fibroblast growth factor 3 |
| FGF4 || Fibroblast growth factor 4 |
| FGF6 || Fibroblast growth factor 6 |
| FGF8 || Fibroblast growth factor 8 |
| FGF9 || Glia-activating factor |
| FGFR1 || Basic fibroblast growth factor receptor 1 |
| FGFR2 || Fibroblast growth factor receptor 2 |
| FGFR3 || Fibroblast growth factor receptor 3 |
| FGFR4 || Fibroblast growth factor receptor 4 |
| FRS2 || Fibroblast growth factor receptor substrate 2 |
| GAB1 || GRB2-associated-binding protein 1 |
| GRB2 || Growth factor receptor-bound protein 2 |
| H-Ras || GTPase HRas |
| Heparin || Heparin Compound group |
| IP3 || Chemical IUPAC name [(1R,2S,3R,4R,5S,6R)-2,4,5-trihydroxy-3,6-diphosphonooxycyclohexyl] dihydrogen phosphate |
| IP3 receptor || A family of receptors for the second messenger inositol 1,4,5-trisphosphate (IP3) Protein group |
| MEK1(MAP2K1) || Dual specificity mitogen-activated protein kinase kinase 1 |
| MEK2(MAP2K2) || Dual specificity mitogen-activated protein kinase kinase 2 |
| MEK6(MAP2K6) || Dual specificity mitogen-activated protein kinase kinase 6 |
| MLK3(MAP3K11) || Mitogen-activated protein kinase kinase kinase 11 |
| PI3K cat class IA || The catalytic subunit of phosphatidylinositol 3-kinase subgroups IA Protein group |
| PI3K reg class IA || The regulatory subunit of phosphatidylinositol 3-kinase subgroups IA Protein group |
| PKC-alpha || Protein kinase C alpha type |
| PKC-beta || Protein kinase C beta type |
| PKC-delta || Protein kinase C delta type |
| PKC-epsilon || Protein kinase C epsilon type |
| PLC-gamma 1 || 1-phosphatidylinositol-4,5-bisphosphate phosphodiesterase gamma-1 |
| PtdIns(3,4,5)P3 || PtdIns(3,4,5)P3 Compound group |
| PtdIns(4,5)P2 || PtdIns(4,5)P2 Compound group |
| Rac1 || Ras-related C3 botulinum toxin substrate 1 |
| SHP-2 || Tyrosine-protein phosphatase non-receptor type 11 |
| SOS || SOS Protein group |
| Shc || SHC-transforming protein 1 |
| c-Raf-1 || RAF proto-oncogene serine/threonine-protein kinase |
| ??????? p38 MAPK || p38 mitogen-activated protein kinase Protein group |
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