Ligand-independent EGFR oligomers do not rely on the active state asymmetric kinase dimer

Byrne, Patrick O.; Hristova, Kalina; Leahy, Daniel J.

doi:10.1101/2020.04.24.056077

Cited by 2 publications

(2 citation statements)

References 67 publications

(91 reference statements)

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“…Our model calculations show that such constitutive dimers harbor receptors with symmetric, inactive kinase dimers. This conclusion is in agreement with a recent study showing that mutations introduced into the active, asymmetric kinase dimer interface do not significantly affect the stability of ligand-independent, preformed dimers ( Byrne et al, 2020 ). Due to the very low affinity of these dimeric species for binding of the first ligand, they hardly bind EGF at low ligand concentrations, i.e., the fraction of these preformed dimers is constant in this concentration range of EGF.…”

Section: Discussionsupporting

confidence: 93%

“…A possible explanation for the assignment of different EGF affinities to dimers with symmetric and asymmetric KD dimers invoking higher order clusters is provided below. Preformed, unliganded EGFR dimers harbor inactive, symmetric kinase dimers as revealed by the fitting and also supported by literature data ( Byrne et al, 2020 ). Such preformed dimers have been found to form chains or polymers of dimers ( Zanetti-Domingues et al, 2018 ).…”

Section: Discussionsupporting

confidence: 88%

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Comprehensive Model for Epidermal Growth Factor Receptor Ligand Binding Involving Conformational States of the Extracellular and the Kinase Domains

Hajdu

Váradi

Rebenku

et al. 2020

Front. Cell Dev. Biol.

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The epidermal growth factor (EGF) receptor (EGFR) undergoes ligand-dependent dimerization to initiate transmembrane signaling. Although crystallographic structures of the extracellular and kinase domains are available, ligand binding has not been quantitatively analyzed taking the influence of both domains into account. Here, we developed a model explicitly accounting for conformational changes of the kinase and extracellular domains, their dimerizations and ligand binding to monomeric and dimeric receptor species. The model was fitted to ligand binding data of suspended cells expressing receptors with active or inactive kinase conformations. Receptor dimers with inactive, symmetric configuration of the kinase domains exhibit positive cooperativity and very weak binding affinity for the first ligand, whereas dimers with active, asymmetric kinase dimers are characterized by negative cooperativity and subnanomolar binding affinity for the first ligand. The homodimerization propensity of EGFR monomers with active kinase domains is ∼100-times higher than that of dimers with inactive kinase domains. Despite this fact, constitutive, ligand-independent dimers are mainly generated from monomers with inactive kinase domains due to the excess of such monomers in the membrane. The experimental finding of increased positive cooperativity at high expression levels of EGFR was recapitulated by the model. Quantitative prediction of ligand binding to different receptor species revealed that EGF binds to receptor monomers and dimers in an expression-level dependent manner without significant recruitment of monomers to dimers upon EGF stimulation below the phase transition temperature of the membrane. Results of the fitting offer unique insight into the workings of the EGFR.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 88%

Comprehensive Model for Epidermal Growth Factor Receptor Ligand Binding Involving Conformational States of the Extracellular and the Kinase Domains

Hajdu

Váradi

Rebenku

et al. 2020

Front. Cell Dev. Biol.

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Conserved Roles for Receptor Tyrosine Kinase Extracellular Regions in Regulating Receptor and Pathway Activity

Gonzalez-Magaldi

McCabe

Cartwright

et al. 2020

Preprint

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38Receptor Tyrosine Kinases (RTKs) comprise a diverse group of cell-surface receptors that 39 mediate key signaling events during animal development and are frequently activated in 40 cancer. Ligand-induced dimerization is the canonical mechanism by which RTKs are thought 41 to be activated. We show here that deletion of the extracellular regions of 10 RTKs representing 42 7 RTK classes or their substitution with the dimeric immunoglobulin Fc region results in 43 constitutive receptor phosphorylation but fails to result in phosphorylation of downstream 44 signaling effectors Erk or Akt. Conversely, substitution of RTK extracellular regions with the 45 extracellular region of the Epidermal Growth Factor Receptor (EGFR) results in increases in 46 Erk and/or Akt phosphorylation in response to EGF. These results indicate that the activation 47 signal generated by the EGFR extracellular region is capable of activating at least 7 different 48 RTK classes. Failure of phosphorylated Fc-RTK chimeras to stimulate phosphorylation of 49 downstream effectors indicates that either dimerization and receptor phosphorylation per se 50 are insufficient to activate signaling or constitutive dimerization leads to pathway inhibition. 51 52 53 54 55 56 57 58 59

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Ligand-independent EGFR oligomers do not rely on the active state asymmetric kinase dimer

Cited by 2 publications

References 67 publications

Comprehensive Model for Epidermal Growth Factor Receptor Ligand Binding Involving Conformational States of the Extracellular and the Kinase Domains

Comprehensive Model for Epidermal Growth Factor Receptor Ligand Binding Involving Conformational States of the Extracellular and the Kinase Domains

Conserved Roles for Receptor Tyrosine Kinase Extracellular Regions in Regulating Receptor and Pathway Activity

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