Asymmetric dimerization and allosteric control in the epidermal growth factor receptor.

The human epidermal growth factor receptor (EGFR or HER1) and its three close relatives, HER2, HER3 and HER4, are receptor tyrosine kinases (RTKs) that regulate critical cellular processes and are frequently dysregulated in cancer. In contrast to RTKs that are activated primarily by trans-autophosphorylation, HER family receptors switch on through a fundamentally different mechanism based on asymmetric interactions between two kinase domains within a dimer. This distinctive mode of allosteric activation arose early in evolution and remains unique to the HER family. This review describes how ligand binding promotes asymmetric dimerization of the EGFR kinase domains, whereby one kinase (the 'activator') allosterically stabilizes the active conformation of its partner (the 'receiver') without requiring activation loop phosphorylation. Structural elements that enable this process include a hydrophobic activator/receiver interface, a membrane-proximal juxtamembrane 'latch' that stabilizes the dimer and an autoinhibitory element in the C-terminal tail that favours the inactive state. We discuss how oncogenic alterations, including the L858R mutation, exon 19 deletions and kinase domain duplications, drive ligand-independent asymmetric dimerization and how the action of the endogenous inhibitor MIG-6 and new allosteric inhibitors can be understood in the context of activator/receiver asymmetric dimerization. This article is part of the discussion meeting issue 'Epidermal growth factor receptor after 40 years'.