Abstract

The epidermal growth factor receptor (EGFR) plays vital roles in cellular processes including cell proliferation, survival, motility, and differentiation. The dysregulated activation of the receptor is often implicated in human cancers. EGFR is synthesized as a single-pass transmembrane protein, which consists of an extracellular ligand-binding domain and an intracellular kinase domain separated by a single transmembrane domain. The receptor is activated by a variety of polypeptide ligands such as epidermal growth factor and transforming growth factor α. It has long been thought that EGFR is activated by ligand-induced dimerization of the receptor monomer, which brings intracellular kinase domains into close proximity for trans-autophosphorylation. An increasing number of diverse studies, however, demonstrate that EGFR is present as a pre-formed, yet inactive, dimer prior to ligand binding. Furthermore, recent progress in structural studies has provided insight into conformational changes during the activation of a pre-formed EGFR dimer. Upon ligand binding to the extracellular domain of EGFR, its transmembrane domains rotate or twist parallel to the plane of the cell membrane, resulting in the reorientation of the intracellular kinase domain dimer from a symmetric inactive configuration to an asymmetric active form (the “rotation model”). This model is also able to explain how oncogenic mutations activate the receptor in the absence of the ligand, without assuming that the mutations induce receptor dimerization. In this review, we discuss the mechanisms underlying the ligand-induced activation of the preformed EGFR dimer, as well as how oncogenic mutations constitutively activate the receptor dimer, based on the rotation model.

Highlights

  • The epidermal growth factor receptor (EGFR) is a member of the ErbB receptor family, which is a member of the receptor tyrosine kinase superfamily

  • T678 by protein kinase C leads to the complete loss of cooperativity [77]. These results suggest that the JM-A segment plays a role in negative cooperativity in ligand binding to the EGFR dimer

  • How is the EGFR dimer activated by ligand binding? It is known that the EGFR dimer is formed through an interaction of the intracellular domain [38,48], the transmembrane domain [83,84], and the extracellular C-terminal region of Subdomain IV [58,62]

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Summary

Introduction

The epidermal growth factor receptor (EGFR) is a member of the ErbB receptor family, which is a member of the receptor tyrosine kinase superfamily. According to the “rotation model”, ligand binding to the extracellular domain of the EGFR dimer induces rotation of the transmembrane domains parallel to the plane of the cell membrane, which leads to the reorientation of the intracellular kinase domain dimer from a symmetric inactive configuration to an asymmetric active form. This model is able to explain how oncogenic mutations activate the receptor in the absence of the ligand, without assuming that the mutations induce receptor dimerization. Excellent reviews have recently been published on the mechanism of activation of EGFR based on the ligand-induced dimerization model [25,26,27,28,29]

EGFR Has a Dimeric Structure
Structures of Inactive and Active EGFR Dimers
Negative Cooperativity in Ligand Binding to EGFR
Mechanism of Activation of EGFR Dimers by Ligand Binding
EGFR and Cancer
EGFR Overproduction
Mutations that Constitutively Activate EGFR
Mutations in the Extracellular Domain
Mutations in the Intracellular JM Region
Mutations in the Kinase Domain
Mutations in the C-Terminal Tail Region
Findings
Conclusions
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