ABSTRACT
In this chapter we will describe structural features of a family of glycosylated cell surface receptors that cross the membrane through a single helix and carry a tyrosine protein kinase domain in their intracellular segment. Tyrosine kinases transfer gamma-phosphate of adenosine triphosphate (ATP) to tyrosine residues but not serine or threonine. The majority of ligands for these receptors are classied as growth factors, of which epidermal growth factor (EGF), broblast growth factor (FGF), insulin-like growth factor (IGF), platelet-derived growth factor (PDGF), vascular-endothelial growth factor (VEGF), and insulin are the most cited examples. The domain architecture of the members of this family of receptors is illustrated in Figure 4.1. As their name indicates, they play a role in the regulation of cell proliferation (growth), and that is a research area in which they are best studied, but they certainly play other roles. Insulin regulates glucose uptake and storage into glycogen but also imposes survival signals upon cells. Other growth factors, too, provide survival signals but are also implicated in cell motility, differentiation, and cell matrix reconstruction. In the case of aberrant functioning, certain growth factor receptors not only cause an excess of cells, or tumor
4.1 Introduction .......................................................................................................................... 111 4.2 Conserved Substructures That Control Protein Kinase Activity ......................................... 114 4.3 Color Illustrations ................................................................................................................. 115 4.4 The Epidermal Growth Factor Receptor .............................................................................. 115
4.4.1 Extracellular Segment............................................................................................... 115 4.4.2 Intracellular Segment ................................................................................................ 117
4.5 The Insulin Receptor ............................................................................................................ 119 4.5.1 Extracellular Segment............................................................................................... 119 4.5.2 Intracellular Segment ................................................................................................ 120 4.5.3 Tyrosine Phosphatase PTP1B Controls the Phosphorylation State
of the Insulin Receptor ............................................................................................. 122 4.6 Fibroblast Growth Factor ...................................................................................................... 123
4.6.1 Extracellular Segment............................................................................................... 123 4.6.2 Intracellular Segment ................................................................................................ 125
4.7 Erythropoietin Receptor ....................................................................................................... 126 4.7.1 Extracellular Segment............................................................................................... 127 4.7.2 Intracellular Segment ................................................................................................ 127
4.8 Receptor Tyrosine Kinases as Targets for Cancer Therapy.................................................. 129 4.8.1 Antibody Approach .................................................................................................. 131 4.8.2 The Tyrosine Kinase Inhibitor Approach ................................................................. 131 4.8.3 Future Developments ................................................................................................ 134
Further Reading ............................................................................................................................. 135
formation, but they also contribute toward malignant cell transformation, leading to subsequent dissemination of cells in other tissues (metastases).
