Regulation of the catalytic activity of the EGF receptor

The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase involved in cell growth that is often misregulated in cancer. Several recent studies highlight the unique structural mechanisms involved in its regulation. Some elucidate the important role that the juxtamembrane segment and the transmembrane helix play in stabilizing the activating asymmetric kinase dimer, and suggest that its activation mechanism is likely to be conserved among the other human EGFR-related receptors. Other studies provide new explanations for two long observed, but poorly understood phenomena, the apparent heterogeneity in ligand binding and the formation of ligand-independent dimers. New insights into the allosteric mechanisms utilized by intracellular regulators of EGFR provide hope that allosteric sites could be used as targets for drug development.

► Review of structural mechanisms regulating EGFR activation.
► New structures show juxtamembrane segment stabilizes activating asymmetric kinase dimer.
► Studies suggest kinase activation mechanism conserved throughout EGFR family.
► New structures suggest mechanism for negative cooperativity in ligand binding.
► New insights into role of ligand-independent dimerization in receptor function.
► Recent findings suggest intracellular regulators use allosteric mechanisms.