Figure 2.

Intracellular signal transduction pathways of FGFs. Activation of FGFRs by tyrosine phosphorylation leads to signal transduction through multiple pathways, including phospholipase Cγ (PLCγ), PI3K–AKT pathway, RAS–MAPK pathway and STAT and NFκB pathway. Tumour suppressor Lipid phosphatase (PTEN) negatively regulates the PI3K signalling pathway,122 which can prevent the signal transduction by promoting dephosphorylation PIP3 into PIP2. Class I PI3K can also be stimulated by RAS, which directly binds to the p110 catalytic subunit of PI3K. Activation of the mTORC2–AKT and ERK signalling pathways promotes cell survival and invasion. AKT promotes cells survival by inhibiting BCL‐2 antagonist of cell death (BAD and BAX),forkhead box class O (FOXO) transcription factors and Caspase 9. The PI3K–Akt‐regulated mTOR is crucial for the FGFs signalling axis to suppress autophagy. Recruited SOS activates RAS GTPase, which stimulates activation of the mitogen‐activated protein kinase (MAPK) cascade and downstream FOS to induce cell proliferation. FGFR substrate 2α (FRS2α) is major substrates of FGFR kinases, which is constitutively associated with the receptor kinase and phospholipase Cγ1 (PLCγ1). Activated PLCγ1 catalyses the hydrolysis of the membrane phospholipid phosphatidylinositol‐4,5‐bisphosphate (PtdIns 4, 5(P2) into diacylglycerol (DAG) and inositol‐1,4,5,‐trisphosphate (IP3). Ca²⁺ can activate Cacineurin to regulate transcription factor NFAT and promote cell migration. Whereas Ca²⁺ together with DAG stimulates cytosolic protein kinase C (PKC), which further activates its substrate myristoylatedalanine‐rich C‐kinase substrate (MARCKS) by phosphorylation. δ‐PKC‐mediated MARCKS phosphorylation is important for cancer cell migration and adhesion. In addition, PLCγ–AKT interaction regulates the M‐phase of cell cycle. The activated FGFR stimulates STAT‐1/3/5, which induces cell migration and invasion by regulating STAT pathway target gene expression. NFκB is the downstream molecule of FGFR–PI3K–AKT pathway, which modulates MMP‐7/9 expression to increase cancer cell migration