An Open-and-Shut Case? Recent Insights into the Activation of EGF/ErbB Receptors

Burgess, Antony W.; Cho, Hyun Soo; Eigenbrot, Charles; Ferguson, Kathryn M.; Garrett, T.P.J.; Leahy, Daniel J.; Lemmon, Mark A.; Sliwkowski, Mark X.; Ward, Colin W.; Yokoyama, Shigeyuki

doi:10.1016/s1097-2765(03)00350-2

Cited by 801 publications

(764 citation statements)

References 86 publications

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“…The first is a 35° rotation of the L2-CR-L1 domains with respect to the linker connecting the L2 and FnIII-1 domains (residues Ala466- E469); the second is a 55° swing of the CR-L1 pair (as a rigid body) around the Gly306-Lys310 linker between the CR and L2 domains (not resolved in the current structure). These domain movements are similar to the rotation and translation observed for the related EGFR family upon ligand binding 27 . Based on the comparison between unbound and bound receptor, it appears that the α-CT helix moves between ~55 Å (if we consider the helix from the same monomer) and ~70 Å (if we consider the α-CT coming from the other monomer).…”

supporting

confidence: 72%

Structure of the insulin receptor–insulin complex by single-particle cryo-EM analysis

Scapin

Dandey

Zhang

et al. 2018

Nature

204

243

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Summary The insulin receptor (IR) is a dimeric protein that plays a crucial role in controlling glucose homeostasis, regulating lipid, protein and carbohydrate metabolism, and modulating brain neurotransmitter levels1,2. IR dysfunctions have been associated with many diseases, including diabetes, cancer, and Alzheimer’s1,3,4. The primary sequence has been known since the 1980s5, and is composed of an extracellular portion (ectodomain, ECD), a single transmembrane helix and an intracellular tyrosine kinase domain. Insulin binding to the dimeric ECD triggers kinase domain auto-phosphorylation and subsequent activation of downstream signaling molecules. Biochemical and mutagenesis data have identified two putative insulin binding sites (S1 and S2)6. While insulin bound to an ECD fragment containing S1 and the apo ectodomain have been characterized structurally7,8, details of insulin binding to the full receptor and the signal propagation mechanism are still not understood. Here we report single particle cryoEM reconstructions for the 1:2 (4.3 Å) and 1:1 (7.4 Å) IR ECD dimer:Insulin complexes. The symmetric 4.3 Å structure shows two insulin molecules per dimer, each bound between the Leucine-rich sub domain L1 of one monomer and the first fibronectin-like domain (FnIII-1) of the other monomer, and making extensive interactions with the α subunit C-terminal helix (α-CT helix). The 7.4 Å structure has only one similarly bound insulin per receptor dimer. The structures confirm the S1 binding interactions and define the full S2 binding site. These insulin receptor states suggest that recruitment of the α-CT helix upon binding of the first insulin changes the relative sub domain orientations and triggers downstream signal propagation.

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supporting

confidence: 72%

Structure of the insulin receptor–insulin complex by single-particle cryo-EM analysis

Scapin

Dandey

Zhang

et al. 2018

Nature

204

243

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“…By contrast, the prognostic significance of EGFR overexpression varies across studies, and responses to EGFR-targeted therapeutic agents do not correlate with levels of EGFR (Arteaga, 2002). Structural studies of ErbB receptors (Burgess et al, 2003) provide one explanation for this difference. Whereas EGFR dimerization is 'autoinhibited' in the absence of EGF, ErbB2 adopts an active-like conformation even without bound ligand (Burgess et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…Structural studies of ErbB receptors (Burgess et al, 2003) provide one explanation for this difference. Whereas EGFR dimerization is 'autoinhibited' in the absence of EGF, ErbB2 adopts an active-like conformation even without bound ligand (Burgess et al, 2003). Accordingly, simply overexpressing ErbB2 transforms NIH3T3 cells (Hudziak et al, 1987;Di Fiore et al, 1987b), whereas EGFR can only transform NIH3T3 cells in the presence of EGF (Di Fiore et al, 1987a).…”

Section: Introductionmentioning

confidence: 99%

EGF-independent activation of cell-surface EGF receptors harboring mutations found in gefitinib-sensitive lung cancer

2006

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Several somatic mutations within the tyrosine kinase domain of epidermal growth factor receptor (EGFR) have been identified that predict clinical response of non-smallcell lung carcinoma (NSCLC) patients to gefitinib. To test the hypothesis that these mutations cause constitutive EGF receptor signaling, and to investigate its mechanistic basis, we expressed representative examples in a null background and analysed their biochemical properties. Each mutation caused significant EGF-independent tyrosine phosphorylation of EGFR, and allowed the receptor to promote Ba/F3 cell mitogenesis in the absence of EGF, arguing that these are oncogenic mutations. Active mutated receptors are present at the cell surface and are fully competent to bind EGF. Recent structural studies show that the inactive EGFR tyrosine kinase domain is autoinhibited by intramolecular interactions between its activation loop and aC helix. We find that mutations predicted to disrupt this autoinhibitory interaction (including several that have not been described in NSCLC) elevate EGF-independent tyrosine kinase activity, thus providing new insight into how somatic mutations activate EGFR and other ErbB family members.

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“…The process of ligand-induced dimerization is now quite well understood, based on crystallographic studies. 8,25 Precisely how this ligand-induced dimerization event is coupled to, and leads to, activation of the intracellular tyrosine kinase domain has also emerged from recent crystallographic studies. 75 The crystal structure of the EGFRTK domain was first published in 2002, both alone and in complex with an inhibitor erlotinib, 63 and displayed several unique features.…”

Section: Introductionmentioning

confidence: 99%

A Multiscale Computational Approach to Dissect Early Events in the Erb Family Receptor Mediated Activation, Differential Signaling, and Relevance to Oncogenic Transformations

et al. 2007

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Abstract-We describe a hierarchical multiscale computational approach based on molecular dynamics simulations, free energy-based molecular docking simulations, deterministic network-based kinetic modeling, and hybrid discrete/ continuum stochastic dynamics protocols to study the dimermediated receptor activation characteristics of the Erb family receptors, specifically the epidermal growth factor receptor (EGFR). Through these modeling approaches, we are able to extend the prior modeling of EGF-mediated signal transduction by considering specific EGFR tyrosine kinase (EGFRTK) docking interactions mediated by differential binding and phosphorylation of different C-terminal peptide tyrosines on the RTK tail. By modeling signal flows through branching pathways of the EGFRTK resolved on a molecular basis, we are able to transcribe the effects of molecular alterations in the receptor (e.g., mutant forms of the receptor) to differing kinetic behavior and downstream signaling response. Our molecular dynamics simulations show that the drug sensitizing mutation (L834R) of EGFR stabilizes the active conformation to make the system constitutively active. Docking simulations show preferential characteristics (for wildtype vs. mutant receptors) in inhibitor binding as well as preferential enhancement of phosphorylation of particular substrate tyrosines over others. We find that in comparison to the wildtype system, the L834R mutant RTK preferentially binds the inhibitor erlotinib, as well as preferentially phosphorylates the substrate tyrosine Y1068 but not Y1173. We predict that these molecular level changes result in preferential activation of the Akt signaling pathway in comparison to the Erk signaling pathway for cells with normal EGFR expression. For cells with EGFR over expression, the mutant over activates both Erk and Akt pathways, in comparison to wildtype. These results are consistent with qualitative experimental measurements reported in the literature. We discuss these consequences in light of how the network topology and signaling characteristics of altered (mutant) cell lines are shaped differently in relationship to native cell lines.

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An Open-and-Shut Case? Recent Insights into the Activation of EGF/ErbB Receptors

Cited by 801 publications

References 86 publications

Structure of the insulin receptor–insulin complex by single-particle cryo-EM analysis

Structure of the insulin receptor–insulin complex by single-particle cryo-EM analysis

EGF-independent activation of cell-surface EGF receptors harboring mutations found in gefitinib-sensitive lung cancer

A Multiscale Computational Approach to Dissect Early Events in the Erb Family Receptor Mediated Activation, Differential Signaling, and Relevance to Oncogenic Transformations

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