Structural analysis of receptor tyrosine kinases

Receptor tyrosine kinases (RTKs) are single-pass transmembrane receptors th at possess intrinsic cytoplasmic enzymatic activity, catalyzing the transfe r of the gamma-phosphate of ATP to tyrosine residues in protein substrates. RTKs are essential components of signal transduction pathways that affect cell proliferation, differentiation, migration and metabolism. Included in this large protein family are the insulin receptor and the receptors for gr owth factors such as epidermal growth factor, fibroblast growth factor and vascular endothelial growth factor. Receptor activation occurs through liga nd binding, which facilitates receptor dimerization and autophosphorylation of specific tyrosine residues in the cytoplasmic portion. The phosphotyros ine residues either enhance receptor catalytic activity or provide docking sites for downstream signaling proteins. Over the past several years, struc tural studies employing X-ray crystallography have advanced our understandi ng of the molecular mechanisms by which RTKs recognize their ligands and ar e activated by dimerization and tyrosine autophosphorylation. This review w ill highlight the key results that have emerged from these structural studi es. (C) 1999 Elsevier Science Ltd. All rights reserved.