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Review
. 2017 Jun 2;6(2):13.
doi: 10.3390/cells6020013.

Activation of the EGF Receptor by Ligand Binding and Oncogenic Mutations: The "Rotation Model"

Endang R Purba  1 , Ei-Ichiro Saita  2 , Ichiro N Maruyama  3
Affiliations
Review

Activation of the EGF Receptor by Ligand Binding and Oncogenic Mutations: The "Rotation Model"

Endang R Purba et al. Cells. .

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.

Keywords: EGFR; cancer; cell-surface receptor; molecular mechanism; phosphorylation; receptor tyrosine kinase; transmembrane signal transduction.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic diagrams of the domains of EGFR and oncogenic mutation sites. (a) Exons encoding the human EGFR protein (EMBL/GenBank Accession No. AF288738; NCBI Accession No. NM_005228.4). Nucleotide sequence numbers of exon boundaries are shown above the exon diagram; (b) Domain structure of EGFR. Oncogenic mutation sites are also shown below the structure. Amino acid residue numbers (a.a. residue #), including the signal peptide sequences, are also shown below the domain diagram. Mutation sites are shown using a.a. residue numbers, including the signal peptide sequences.
Figure 2
Figure 2
Model for the activation of EGFR by ligand binding. EGFR exists in dimeric form, stabilized through the interaction of the intracellular domains, the transmembrane domains, and the extracellular C-terminal regions of Subdomain IV. The intracelluar kinase domains with a symmetric configuration are further stabilized through interactions with the AP-2 helix. The extracellular domain of the receptor dimer adopts flexible configurations between “tethered” and “extended” forms through the interaction of Subdomains II and IV. The ligand has high affinity for the “extended” structure, and stabilizes the extracellular ligand binding domain for exposure of the “β-hairpin.” Interaction between the two “β-hairpins” in the dimer induces rotation of the transmembrane domains, which dissociates the intracellular symmetric inactive kinase dimer, resulting in an asymmetric active kinase dimer. In this asymmetric active configuration, the C-lobe of the “activator” kinase domain interacts with the N-lobe of the “receiver” kinase for the activation of the latter. Note that structures (a) and (b) indicate a tethered inactive dimer and an extended active dimer, respectively.
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