New Lessons in Regulation of the EGFR/ErbB Family of Receptor Tyrosine Kinases

The epidermal growth factor receptor (EGFR) is generally viewed as a ‘prototypic’ receptor tyrosine kinase (RTK), and is the target of several clinically important cancer therapeutics. However, as mechanistic studies advance it becomes increasingly clear that EGFR and other ErbB family members have unique properties that are not shared by other RTKs. Structural studies in 2002/3 showed that EGF promotes dimerization of the EGFR extracellular region through a unique ‘receptor-mediated’ mechanism that involves a substantial ligand-induced conformational change. Studies in 2006 revealed that the intracellular tyrosine kinase domain becomes activated through an allosteric mechanism that involves formation of an asymmetric dimer.

Numerous important questions remain unanswered. For example, current structural views of the EGFR cannot explain the apparent ‘high-affinity’ and ‘low-affinity’ binding sites for EGF seen at the cell surface – which appear to have significant functional implications. It is also not clear in the network of hetero-oligomers formed by EGFR/ErbB family members precisely how ErbB2/HER2 (an ‘orphan’ receptor) or ErbB3/HER3 (considered to be ‘kinase-dead’) are activated. Outlining our structural and biochemical studies of mammalian and Drosophila EGFR, I will describe how apparent high- and low-affinity ligand-binding sites for EGF ligands arise from negative cooperativity/half-of-the-sites reactivity, that involves an asymmetric dimer ‘intermediate’ containing only a single bound ligand. I will also describe how the intracellular juxtamembrane region of EGFR functions as an activation domain – promoting asymmetric dimerization of the receptor. Focusing on other members of the family, I will describe how our studies of the single EGFR family member from D. melanogaster argue that the ‘orphan’ human ErbB2 may in fact be subject to regulation by membrane-associated ligands. Finally, I will present recent data on ErbB3 suggesting that – rather than being ‘kinase-dead’ – it retains a level of tyrosine kinase activity that may be important for cellular signaling.