Skip to Main Content


Receptor Tyrosine Kinases Dimerization

Receptor tyrosine kinases undergo ligand dependent dimerization, which activates their intrinsic protein tyrosine kinase (PTK) domains. We have determined the crystal structure of Stem cell factor (SCF) and fibroblast growth factor (FGF), two ligands of receptor tyrosine kinases. The crystal structures of FGF in complex with the extracellular ligand-binding domain of FGF-receptor (FGFR) and with a heparin sulfate oligosaccharide were also determined. The structure of the ternary FGF/heparin/FGFR complex provides a molecular view of how FGF acts in concert with heparin to induce the dimerization and activation of FGF-receptors. We have also determined the crystal structure of the catalytic PTK domain of FGFR in complex with an ATP analogue or in complex with specific PTK inhibitors of FGFR activity and function.

Development of Specific Inhibitor for PTKs

These structures enabled the development of new specific inhibitor for PTKs that are currently being tested in clinical trials. Receptor tyrosine kinases undergo ligand-dependent dimerization, which activates their intrinsic protein tyrosine kinase activity resulting in autophosphorylation and subsequent interaction and recruitment of multiple cellular target proteins. The phospho rylated tyrosine residues together with their immediate flanking sequences function as binding sites for signaling molecules containing src homology 2 (SH2) domains. Many signaling proteins carry SH2 domains plus one or more small protein modules such as SH3, PH, PTB, WW or FYVE domains. These protein modules function as mediator of protein-protein or protein-lipid interactions that are critical for signal transmission.

Recruitment of Signaling Proteins

In addition to direct recruitment by RTKs, many signaling proteins are recruited by an alternative mechanism involving a family of membrane linked docking proteins such as FRS-2alpha, and ß, IRS-1 and 2, and Gab-1 and 2, among many others. Recruitment of signaling proteins by RTKs or by docking proteins leads to activation of m ultiple signaling pathways resulting in stimulation of a variety of cellular responses. The small adapter protein Grb2, for example, is bound through its SH3 domains to short, proline-rich sequences in the carboxy terminal tail of the guanine nucleotide-r eleasing factor Sos. Interaction between Grb2 and Sos with tyrosine phosphorylated RTKs or docking proteins results in translocation of Sos to the plasma membrane allowing the exchange of GDP for GTP on Ras. The activated GTP-bound form of Ras initiates t he activation of a kinase cascade composed of Raf, MAPKK, and MAPK leading to phosphorylation of prooncogene Jun on serine and threonine residues to induce transcriptional activation. These and other signaling pathways that are activated by RTKs regulate multiple cellular processes and the pleiotropic response of growth functions on multiple tissues and orgens.