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Structure-Based View of Epidermal Growth Factor Receptor Regulation

2008; Annual Reviews; Volume: 37; Issue: 1 Linguagem: Inglês

10.1146/annurev.biophys.37.032807.125829

1936-1238

Kathryn M. Ferguson,

Monoclonal and Polyclonal Antibodies Research

High-resolution X-ray crystal structures determined in the past six years dramatically influence our view of ligand-induced activation of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases. Ligand binding to the extracellular region of EGFR promotes a major domain reorganization, plus local conformational changes, that are required to generate an entirely receptor-mediated dimer. In this activated complex the intracellular kinase domains associate to form an asymmetric dimer that supports the allosteric activation of one kinase. These models are discussed with emphasis on recent studies that add details or bolster the generality of this view of activation of this family of receptors. The EGFR family is implicated in several disease states, perhaps most notably in cancers. Activating tumor mutations have been identified in the intracellular and extracellular regions of EGFR. The impact of these tumor mutations on the understanding of EGFR activation and of its inhibition is discussed.