FGFR Interacts with Intracellular Signaling Molecule
FGF cell surface signaling. The current state of the structural biology of FGFR activation at the cell surface is presented. In the past few years, we have elucidated the structural basis by which heparin/HS assists FGF and FGFR to form a symmetric 2:2 FGF-FGFR dimer. We have also resolved the crystal structure of the intracellular FGFR1 kinase domain. The structurally unresolved regions of FGFR are drawn as gray lines. The N-terminal and C-terminal lobes of the kinase domain are colored green and red, respectively. The activation loop (A-loop) in the C-terminal kinase lobe is colored yellow and the side chains of tyrosines 653 and 654 are rendered in black. Domain organization of PLCγ-1 and FRS2α, two major intracellular targets, are shown.
Receptor dimerization is a universal mechanism in RTK activation. The structural basis for receptor dimerization has been elucidated for several RTK subfamilies including EGFR, VEGF, TRK. These studies reveal that the mode of receptor dimerization varies greatly among RTK subfamilies and is likely tailored to meet their individual biological functions. The mechanism by which FGFs transduce their signal across cell membranes has been intensely studied over the past 30 years. Recent X-ray crystallographic studies have transformed FGF signaling into is one of the foremost structurally understood ligand-receptor systems among RTKs (Fig above). The symmetric "two-end" model for FGFR dimerization unifies a wealth of biochemical data, provides a structural basis for FGF-FGFR binding specificity and explains how pathogenic mutations in FGFR result in human skeletal disorders. The mode of receptor dimerization observed in the symmetric "two-end" model is highly cooperative and is well-suited to execute the essential roles of FGF signaling in development. This model is based on several synergestic binding events, including secondary ligand-receptor and direct receptor-receptor interactions, which are facilitated by HS. Importantly, the dimer interface is adjacent to the FGF-D2 portion of the primary interface and therefore binding events at the dimer interface are intimately coupled with binding events at the primary binding site. Importantly, this mode of dimerization is capable of sensing and responding to the dynamic changes in extracellular HSPGs that occur during development. Future challenges include structural and biochemical studies of how these HS changes modulate dimer assembly and will provide greater insight into the role of FGF signaling in physiological and pathophysiological settings.