Development - FGF-family signaling

FGF-family signaling

Abstract:

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.

Details:

Fibroblast growth factors (FGFs) have been implicated in  diverse cellular processes including cell anti-apoptosis, cell differentiation, cell proliferation and epithelial to mesenchymal transition [1], [2].

FGFs comprise a family of 23 genes encoding structurally  related proteins [2], [3]. 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 [2], [3], [4].

FGFs activity and specificity are regulated by heparan  sulfate proteoglycans (such as Perlecan) [5], [6].  Heparin associates with  FGFs and FGFRs to form trimeric  complexes [7], [8], [9].

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 [2], [10], [11], [12]. Furthermore, FGFs can induce  Shc/ GRB2/ SOS complex formation,  resulting in activation of ERK1 (MAPK3)/  ERK2 (MAPK1) and cell proliferation [13], [14], [15], [16]. In  addition, FGFs can activate Rac1/ MLK3(MAP3K11)/  MEK6(MAP2K6)/ p38 MAPK pathway [17], [18], [19] probably via FRS2/  SHP-2/ GRB2/ SOS [2], [11]. Activation of p38 MAPK is also involved in regulation of cell proliferation  and cell differentiation [2], [19], [20].

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  [2], [21], [22], [23].

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 [2].  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 [24], [25]. 1,2-Diacyglycerol and Ca("2+) induce activation of PKC-alpha and PKC-beta [25]. PLC-gamma 1/  PKCs cascade takes part in regulation of developmental process and response to stress in different tissues [2], [25], [26].

Objects list:

References:

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