ABSTRACT
The epidermal growth factor receptor (EGFR) family consists of four members: EFGR, Human epidermal growth factor receptor-2 (HER2), HER3, and HER4. All members of the EGFR family contain an extracellular ligand binding region, a membrane spanning region and cytoplasmic region that possesses tyrosine kinase activity. The binding of a ligand to the receptor leads to the formation of either homo-or heterodimers between the members of the epidermal growth factor receptor family and activation of tyrosine kinase activity.2 This leads to the binding of adenosine triphosphate (ATP) and phosphorylation of the cytoplasmic component of the kinase. This phosphorylation event allows adaptor proteins to interact with the receptor and initiate the downstream signaling pathways2 (see Fig. 6.1). Without ligand, the EGFR receptor is found in a closed conformation with the dimerization interface blocked. Unlike EGFR, HER2 has a different extracellular region and has a fixed conformation, which results in permanent exposure of the dimerization domain.3 In addition, HER2 is unique among the receptor family in that it binds none of the potential EGF ligands. As a result, it appears that its primary role in the pathway is to form heterodimers with the other receptors.4 HER3 also plays a distinct role in the HER family signaling network. Although it is kinase inactive and therefore incapable of initiating downstream signaling pathways on its own, HER3 can dimerize with other receptors, particularly HER2, for potent cellular signaling. Evidence is growing to show that the transactivating nature of HER3 is an essential aspect of oncogenic function of the related receptors HER1/EGFR and HER2.
