Emerging concepts in the regulation of the EGF receptor and other receptor tyrosine kinases

• Activation of receptor tyrosine kinases involves both dimerization and allostery.
• Their catalytic domains are flexible and adopt multiple inactive conformations.
• Their extracellular modules hinder ligand-independent activation.
• Their extracellular and intracellular modules are directly conformationally coupled.

The activation of receptor tyrosine kinases in response to extracellular signals is a principal component of metazoan signaling. Structural analysis of the extracellular and intracellular domains of these receptors has shed substantial light on the mechanisms underlying their activation. A remaining challenge is to understand how these domains operate together in the context of the full-length receptors. With a focus on the epidermal growth factor (EGF) receptor, this review highlights recent advances towards this goal. Although receptor tyrosine kinases are divergent in terms of the details of how they operate, these studies reveal common mechanisms that ensure activation in the proper context. Understanding these mechanisms provides insights into the vulnerabilities of these receptors to disease-causing mutations.