FGF Signaling

Fibroblast growth factor receptor (FGFR) belongs to the family of receptor tyrosine kinases (RTKs). Binding of fibroblast growth factor (FGF) to its receptor induces receptor dimerization and tyrosine phosphorylation. The phosphorylated form of the receptor is now capable of initiating several signal transducing pathways depending of cell specificity.FGFR phosphorylation causes the tyrosine phosphorylation of SNT1 which leads to GRB2-mediated complex formation with docking protein GAB and nucleotide exchange factor SOS. These key events then lead to the activation of one of several pathways: the Ras/Raf/MEK/ERK pathway, the Rac1/MEKK/p38MAPK pathway or the PI3K/AKT pathway. Finally, transcriptional regulators like CREB, STAT3 and ATF-2 are activated leading to various cellular processes like cell growth, differentiation and angiogenesis. This is a unique mechanism for generation of signal diversity whereby coordinated assembly of a multi-docking protein complex can activate different downstream signaling pathways. FGFR is also able to directly activate PLCγ and consequently cause the activation of protein kinase C and increased intracellular Ca+2.FGFs are heparin binding proteins. They are closely related to other heparin binding proteins like hepatocyte growth factor (HGF). Its receptor is MET. Signaling by HGF via MET involves the docking proteins GAB and CRK eventually leading to the activation of JNK and CREB and the promotion of angiogenesis.