c-erbB-2, a Tyrosine Kinase Growth Factor Receptor and its Role in Breast Cancer

Abstract

The tyrosine kinase growth factor receptors form a group of transmembrane glycoproteins with intracellular tyrosine kinase activity and extracellular ligand binding domain. The group is subdivided into four subgroups based on differences in predicted structure (1). The type I subgroup includes the epidermal growth factor receptor (EGFR), encoded by the c-erbB-1 gene, c-erbB-2 and c-erbB-3, which have two cysteine rich domains within the extracellular region and a single tyrosine kinase domain intracellularly. Subgroup II consists of the insulin receptor family, which differ in forming heterotetrameric structures covalently linked by disulphide bonds. Members of subgroup III, e.g. platelet derived growth factor receptor (PDGFR) and colony stimulating growth factor receptor (CSF-1R) have five immunoglobulin-like domains in the extracellular region instead of the cysteine rich domains of subgroups I and II and the tyrosine kinase region is divided by a kinase insert. Subgroup IV, which includes the fibroblast growth factor receptors, is essentially very similar to subgroup III but the extracellular domain has only three immunoglobulinlike structures. The kinase insert of group III and IV contains a tyrosine which can be phosphorylated and has been shown to be involved in substrate binding (2); similarly variable numbers of tyrosine residues in the C-terminus of these receptors, the so called autophosphorylation sites are thought to be involved in either substrate binding and specificity or regulation of receptor kinase activity (3). All the subgroups have a single transmembrane domain across which the mitogenic signal heralded by ligand binding must be propagated. Two theories to explain this process have been proposed.