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

Purba, Endang R.; Saita, Ei-ichiro; Maruyama, Ichiro

doi:10.3390/cells6020013

Cited by 143 publications

(138 citation statements)

References 154 publications

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“…Understanding the role of ligand-independent EGFR oligomers in regulating ErbB activity remains the topic of much investigation (18,19,41,(55)(56)(57). To estimate the oligomeric fraction of unliganded EGFR and HER2 in physiological membranes using the two-dimensional dissociation constants reported here, the concentration of ERBBs in cell membranes must be known.…”

Section: Discussionmentioning

confidence: 99%

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

Byrne

Hristova²,

Leahy

2020

Preprint

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The human Epidermal Growth Factor Receptor (EGFR/ERBB1) is a Receptor Tyrosine Kinase (RTK) that forms active oligomers in response to ligand. Much evidence indicates that EGFR/ERBB1 forms oligomers in the absence of ligand, but the structure and physiological role of these ligandindependent dimers remain unclear. We use fluorescence microscopy to measure the oligomer stability and FRET efficiency for homo-and hetero-oligomers of fluorescent-protein labeled forms of EGFR and its paralog, Human Epidermal Growth Factor Receptor 2 (HER2/ERBB2) in vesicles derived from native cell membranes. Both receptors form ligand-independent oligomers at physiological plasma membrane concentrations. Mutations introduced in the EGFR kinase region at a key interface within the active state dimer alter the FRET efficiency within ligand-independent EGFR oligomers but do not affect their stability. These results indicate that ligand-independent EGFR oligomers do not require this interface and that the inactive state ensemble is distinct from the EGFR active state ensemble.

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Section: Discussionmentioning

confidence: 99%

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

Byrne

Hristova²,

Leahy

2020

Preprint

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“…We have shown that Fzd9b is present in the membrane in proximity to its co-receptor EGFR, which has previously been shown to be membrane localized in an inactive conformation in the absence of a ligand (Purba et al, 2017). Once Wnt9a is present, EGFR phosphorylates tyrosine residues on the CTT of Fzd9b and leads to the recruitment of internalization machinery such as the AP-2 complex and clathrin.…”

Section: A Model For Wnt-fzd Signaling Specificitymentioning

confidence: 89%

EGFR confers exquisite specificity of Wnt9a-Fzd9b signaling in hematopoietic stem cell development

Grainger

Nguyen

Richter

et al. 2018

Preprint

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SummaryThe mechanisms of Wnt-Frizzled (Fzd) signaling selectivity and their biological implications remain unclear. We demonstrate for the first time that the epidermal growth factor receptor (EGFR) is required as a co-factor for Wnt signaling. Using genetic studies in zebrafish, paired with in vitro cell biology and biochemistry, we have determined that Fzd9b signals specifically with Wnt9a in vivo and in vitro to elicit β-catenin dependent Wnt signals that regulate hematopoietic stem and progenitor cell (HSPC) development in the dorsal aorta. This requirement is conserved in the derivation of HSPCs from human embryonic stem cells. Wnt9a-Fzd9b specificity requires two intracellular domains in Fzd9b, which interact with EGFR as a required co-factor to promote signal transduction. EGFR phosphorylates one tyrosine residue on Fzd9b, a requirement for the Wnt signal. These findings indicate that Wnt signaling interactions can be exquisitely specific and inform protocols for derivation of HSPCs in vitro.HighlightsAn in vitro signaling screen identifies Fzd9b as a Wnt9a-specific receptor.Fzd9b and Wnt9a regulate hematopoietic stem cell development as a cognate pair.WNT9A and FZD9 are required for HSPC derivation from human pluripotent cells in vitro.EGFR confers specificity to Wnt9a-Fzd9b signaling in zebrafish and human cells.

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“…Regarding the EGF‐R, its intracellular domain contains 20 tyrosine residues, of which 12 are known to be phosphorylated, thereby leading to EGF‐R activation . This activation can be optionally induced through ligand binding, or in cooperation with integrin‐mediated cell adhesion .…”

Section: Discussionmentioning

confidence: 99%

“…Regarding the EGF-R, its intracellular domain contains 20 tyrosine residues, of which 12 are known to be phosphorylated, thereby leading to EGF-R activation. 37 This activation can be optionally induced through ligand binding, or in cooperation with integrin-mediated cell adhesion. 12 Since integrin-mediated cell adhesion is indispensable for epithelial development, we focused on the tyrosine residue 845 in the present study, known to be phosphorylated by integrins, containing β subunits, like for instance β1.…”

Section: Discussionmentioning

confidence: 99%

Gelatin nonwovens‐based epithelial morphogenesis involves a signaling axis comprising EGF‐receptor, MAP kinases ERK 1/2, and β1 integrin

Jedrusik

Steinberg

Husari

et al. 2018

J Biomedical Materials Res

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In biomaterials research, biomechanics which support tissue regeneration steadily gains of importance. Hence, we have previously shown that gelatin‐based electrospun nonwoven mats (NWMs) with a distinct modulus of elasticity (3.2 kPa) promotes epithelial morphogenesis. Since molecular mechanisms of this morphogenesis are still unknown, the present study aims at identifying molecules, involved herein. Epithelia established on the NMWs showed persistence of the activated state of the epidermal growth factor receptor (EGF‐R), phosphorylated at the src‐specific tyrosine 845 (EGF‐RT845) throughout the observation period of 10 days. To elucidate whether the observed morphogenesis mechanistically involves EGF‐R signaling, we inhibited EGF‐R, by employing the EGF‐RT845 specific inhibitor Gefitinib (IRESSA®). Gefitinib administration yielded a reduced expression of the β1 integrin subunit, a well‐known cell–matrix interaction receptor, concomitant with downregulation of p42/44 ERK1/2 MAP‐kinase activity. To elucidate whether the observed downregulation of β1 is EGF‐RT845‐dependent or emerging from ERK1/2 signaling, we exposed epithelia, grown on the NWMs, with the ERK1/2‐directed inhibitor U0126. In the absence of Gefitinib, inhibition of p42/44 MAP‐kinase activity resulted in decreased β1 integrin protein levels, thus indicating that β1 expression is dependent on ERK1/2 and not EGF‐RT845. Our results showed the first time that an EGF‐R‐β1 integrin‐signaling axis, including ERK1/2, promotes NWM‐elasticity‐based epithelial morphogenesis. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 663–677, 2019.

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

Cited by 143 publications

References 154 publications

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

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

EGFR confers exquisite specificity of Wnt9a-Fzd9b signaling in hematopoietic stem cell development

Gelatin nonwovens‐based epithelial morphogenesis involves a signaling axis comprising EGF‐receptor, MAP kinases ERK 1/2, and β1 integrin

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