Figure 2. Structure and signaling downstream of FGFRs. A) FGFRs possess three extracellular immunoglobulin-like domains (Ig I to III), a transmembrane domain (TM) and an intracellular protein tyrosine kinase domain (PTK).The third Ig-like domain (III) is thought to confer ligand specificity. The C-terminal half of this IgIII domain (dotted line) is alternatively encoded by either exon 8 or 9 of the receptor gene, which create the two main isoforms of FGFR1, 2 and 3 (IIIb for exon 8 and IIIc for exon 9). Other isoforms also exist (no PTK domain, no TM domain) but are less abundant. B) Creation of the ternary complex between heparan sulfate proteoglycans (HSPGs), FGF ligands, and FGFRs leads to autophosphorylation of the PTK domains and activation of a number of intracellular pathways downstream. FRS2 and Grb2 and the main mediators of the signaling and activate various effectors such as PI3K/AKT and MAPKs. Other pathways (Shp2, PLC-γ) are also activated. Note that activation of the PI3K pathway can lead to phosphorylation of MDM2 on Ser186, leading to its translocation to the nucleus and subsequent degradation of p53.