We made a breakthrough in understanding how the epidermal growth factor receptor (EGFR) is activated, leading to major shifts in how the field views kinase activation by dimerization. We showed that activation of EGFR involves the formation of an asymmetric dimer between the kinase domains of the receptor, in which one kinase domain serves as an activator of the other, analogous to the activation of cyclin-dependent kinases by the cell cycle control proteins known as cyclins (Zhang et al., Cell 2006
; Zhang et al., Nature 2007
). This new paradigm for the activation of a receptor tyrosine kinase explained why two human EGFR family members, HER2 and HER3, are particularly potent in combination even though HER3 lacks catalytic activity. The interaction between HER2 and HER3 underlies many cancers, including glioblastomas, and the results from our group provided the first clear mechanistic insights into how these two receptors form an active signaling complex.
We also demonstrated that the cytoplasmic module of EGFR is capable of dimerizing and activating on its own, because the juxtamembrane segment of the receptor is able to dimerize the kinase domains (Jura et al., Cell 2009
; this was also shown independently by Mark Lemmon
and colleagues, University of Pennsylvania). Data from our group are consistent with a mechanism in which the extracellular domains prevent the intrinsic ability of the transmembrane and cytoplasmic domains to dimerize and activate, with ligand binding releasing this block. Recently, we used cell-based analyses to work out the nature of the coupling between the extracellular domains of the receptor and the kinase domains, demonstrating that the extracellular binding of ligands to the receptor is transmitted to the intracellular kinase domains through a specific conformational coupling of the transmembrane helices (Endres et al., Cell 2013)