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

Abstract

Abstract:The epidermal growth factor receptor (EGFR) plays vital roles in cellular processes including cell proliferation, survival, motility and differentiation. 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 preformed 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 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 ligand without assuming that the mutations induce receptor dimerization. In this review, we discuss mechanisms underlying 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: cancer; cell-surface receptor; EGFR; molecular mechanism; phosphorylation; receptor tyrosine kinase; transmembrane signal transduction Peer-reviewed version available at Cells 2017, 6, , 13; doi:10.3390/cells60200132 of 24 IntroductionThe epidermal growth factor receptor (EGFR) is a member of the ErbB receptor family, which is a member of the receptor tyrosine kinase superfamily. The ErbB receptor family consists of EGFR (also known as ErbB1 or HER1), ErbB2 (Neu or HER2), ErbB3 (HER3) and ErbB4 (HER4). EGFR is involved in a variety of cellular processes including cell proliferation, motility, survival and differentiation, and is essential for normal animal development [1][2][3][4]. Aberrant activation of EGFR is implicated in a variety of human cancers [5]. The receptor is activated by binding of various ligands including epidermal growth factor (EGF), transforming growth factor α (TGFα), amphiregulin (AREG), epigen, β-cellulin, heparin-binding EGF (HB-EGF) and epiregulin [6,7]. EGFR is a singlepass transmembrane protein, consisting of an extracellular domain, a transmembrane domain, a juxtamembrane (JM) segment, a kinase domain, and a C-terminal regulatory tail ( Figure 1) [8,9]. Upon ligand binding, the C-terminal tail becomes tyrosinephosphorylated, and mediates interactions between the re...

Investigating underlying molecular mechanisms, signaling pathways, emerging therapeutic approaches in pancreatic cancer

“…Following ligand binding, EGFR undergoes receptor homo or heterodimerization at the cell surface, followed by internalization. Dimerization leads to phosphorylation of the intracytoplasmic EGFR tyrosine kinase domain, which acts as a binding site for signaling molecules such as RAS ( 101 ). Activation of downstream pathways stimulates cellular proliferation, angiogenesis, and metastatic development and inhibits apoptosis ( 102 ).…”