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Cells 2017, 6(2), 13; doi:10.3390/cells6020013

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

Information Processing Biology Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa 904-0495
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Received: 21 April 2017 / Revised: 17 May 2017 / Accepted: 31 May 2017 / Published: 2 June 2017
(This article belongs to the Special Issue Receptor Tyrosine Kinases in Health and Disease)
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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. View Full-Text
Keywords: cancer; cell-surface receptor; EGFR; molecular mechanism; phosphorylation; receptor tyrosine kinase; transmembrane signal transduction cancer; cell-surface receptor; EGFR; molecular mechanism; phosphorylation; receptor tyrosine kinase; transmembrane signal transduction
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Purba, E.R.; Saita, E.-I.; Maruyama, I.N. Activation of the EGF Receptor by Ligand Binding and Oncogenic Mutations: The “Rotation Model”. Cells 2017, 6, 13.

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