The signaling pathways of the activated FGF receptor are shown in Figure 1. In two pathways the first step is phosphorylation and activation of the FGF receptor substrate protein, FSR2α, which is localized in the cell membrane. Activated FSR2α binds and activates nearby GRB2 which recruits one or both of two adaptor proteins. SOS leads to the activation of the MAPK pathway as seen in Figure 2 and elsewhere in this book. The outcome of altered gene expression resulting from this pathway is increased cell proliferation as well as, in some cases, cell migration and differentiation. If the adaptor protein GAB1 is activated by GRB2, the PI3 kinase/AKT pathway is activated promoting cell survival by inhibiting apoptosis. Other pathways may also participate in FGF signaling. For example, activation of the phospholipase C cascade leads to, among other things, amplification of the MAPK pathway by providing for the RAS-independent phosphorylation of RAF. In some cells the JAK/STAT pathway (not shown) is also activated by FGFR.
Fig1. FGF receptor signaling. A major target for FGF receptor (FGFR) tyrosine kinase activity is FRS2α (FGFR receptor substrate 2α; FRS2) which is associated with the kinase and is activated by tyrosine phosphorylation. Activated FRS2α binds GRB2 (growth factor receptor bound-2), which then recruits either the guanine nucleotide exchange protein SOS or GAB1 (GRB2-associated binding protein), activating the MAPK pathway or PI3 kinase-mediated AKT activation pathway, respectively. In addition, the FGFR tyrosine kinase activation of PLCγ results in the release of DAG (diacylglycerol) and IP3 (inositol triphosphate), activating protein kinase C which phosphorylates and activates RAF, adding reinforcement to this pathway.
Fig2. EGFR family signaling pathways. Four intracellular signaling pathways can be initiated by a homo- or heterodimer of the EGFR/HER receptor family. The first step in each is the tyrosine kinase mediated phosphorylation of a protein that generates a second intracellular signal. For example, the phosphorylation of phospholipase C (PLCγ) leads to the release of inositol triphosphate (IP3) and diacylglycerol (DAG), leading to the activation of protein kinase C (PKC). Phosphorylation of p85 activates phosphatidylinositol-3-kinase (PI3K) leading to the activation of Akt (also known as protein kinase B, PKB). The STAT (signal transducer and activator of transcription) pathway and the MAP kinase pathway are also activated by the receptor tyrosine kinase activity as shown. Depending on the pathway(s) activated, the cell type, and its environment (e.g., exposure to other signaling inputs) these pathways, alone or in combination, will lead to changes in gene expression which will influence the ability of the cell to divide, differentiate, undergo, or resist apoptosis and survive. GRB2, growth factor receptor bound-2, an adaptor protein; SOS, son of sevenless guanine nucleotide exchange protein.
