Fig. 3

Intracellular signaling pathways activated downstream of fibroblast growth factor receptors (FGFRs). Binding of FGFs to FGFRs triggers receptor dimerization and tyrosine kinase activation, resulting in autophosphorylation of the intracellular domains of the receptor and recruitment of several adaptor proteins, which activate four key downstream pathways. The MAPK pathway involves the adaptor protein FRS2α that recruits Grb2 and SOS, resulting in the formation of a multiprotein complex that activates the Ras GTPase and the downstream targets Raf and MEK. This signaling cascade culminates in transcriptional activation of effectors and feedback inhibitors that mediate most of the developmental functions of FGFs. Grb2 can also recruit the adaptor protein Gab1, which activates the anti-apoptotic PI3K/Akt pathway. The PKC/calcium pathway is initiated by recruitment of PLCγ to phosphorylated tyrosines present in FGFR, leading to its activation and consequent formation of IP₃ and DAG by hydrolysis of PIP₂. While IP₃ stimulates calcium release from intracellular stores, DAG activates PKC, events that promote the remodeling of cytoskeleton and cell membranes. PKC also reinforces the activation of the MAPK pathway by inducing RAF phosphorylation (dashed arrow). Activated FGFR also promotes the dissociation of Rnd1 from FRS2β, which in turn inhibits RhoA activity, leading to cytoskeletal rearrangements. Signaling can be negatively regulated at multiple levels by receptor internalization or the induction of negative regulators. The E3 ubiquitin ligases CBL and Nedd4 promote receptor degradation/turnover through ubiquitin-mediated mechanisms. CBL also mediates the degradation of PI3K attenuating the PI3K/Akt pathway. Proteins that antagonize FGFR signals can either interfere with ligand binding (FGFRL1 and Sef) or with intracellular signaling cascades, mainly the MAPK pathway (Sef, SPRY, MKP3). DAG, Diacylglycerol; FRS2, FGFR substrate; Grb2, Growth factor receptor-bound 2; Gab1, Grb2-associated binding protein 1; IP₃, Phosphatidylinositol-3,4,5-triphosphate; MAPK, Mitogen-activated protein kinase; MKP3, MAPK phosphatase 3; PI3K, Phosphatidylinositol-3-kinase; PIP₂, phosphatidylinositol-4,5-biphosphate; PKC, Protein kinase C; PLCγ, Phospholipase Cγ; SOS, Son of sevenless