SUNY at Albany
June 19-23, 2001
Cellular Signaling by Tyrosine Phosphorylation
Growth factor binding to the extracellular ligand binding domain of receptor tyrosine kinases induces receptor dimerization. Dimerization of receptor tyrosine kinases is crucial for activation of the catalytic domain and for tyrosine autophosphorylation; both processes are mediated by an intermolecular process. Different ligands utilize different strategies for mediating receptor dimerization and activation. A large family of growth factors such as platelet derived growth factor (PDGF), stem cell factor (SCF), colony stimulating factor (CSF), and nerve growth factor (NGF) among many others are dimeric proteins. These growth factors induce receptor dimerization by virtue of their dimeric nature. Fibroblast growth factors on the other hand require heparin sulfate proteoglycans for receptor activation. The mechanism of activation of FGFR was established by determination of the crystal structure of several different FGF/FGFR complexes. Biochemical and structural studies provided new insights as to how receptor dimerization activates the protein tyrosine kinase domain. For insulin or FGF-receptors it was shown that autophosphorylation of tyrosine residues in the activation loop releases an autoinhibition leading to stimulation of PTK activity. Receptor tyrosine kinases undergo phosphorylation on tyrosine residues which serve as binding sites for SH2 and PTB domains of a variety of signaling proteins. Signaling proteins are also recruited by membrane bound docking proteins (i.e. FRS2a,b, IRS1,2,3,4, Gab1,2) that are tyrosine phosphorylated by receptor tyrosine kinases.
NYU School of Medicine, Department of Pharmacology, New York, NY 10016 USA