ArticleThe Journal of biological chemistry2014
Point mutations in dimerization motifs of the transmembrane domain stabilize active or inactive state of the EphA2 receptor tyrosine kinase.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 41 citations in OpenAlex.
- Mechanisms and Manifestations of Ligand Bias in Signaling: Focus on Receptor Tyrosine Kinases.Chemical reviews · 2026Review
- Cholesterol-dependent dimerization and conformational dynamics of EphA2 receptors from coarse-grained and all-atom simulations.Structure (London, England : 1993) · 2025Article
- Cholesterol inhibits assembly and oncogenic activation of the EphA2 receptor.Communications biology · 2025Article
- Transmembrane helix interactions regulate oligomerization of the receptor tyrosine kinase EphA2.The Journal of biological chemistry · 2024Article
- Cholesterol inhibits assembly and activation of the EphA2 receptor.bioRxiv : the preprint server for biology · 2024Article
- Transmembrane dimers of type 1 receptors sample alternate configurations: MD simulations using coarse grain Martini 3 versus AlphaFold2 Multimer.Structure (London, England : 1993) · 2023Article
- Direct quantification of ligand-induced lipid and protein microdomains with distinctive signaling properties.ChemSystemsChem · 2022Article
- Bioengineered System for High Throughput Screening of Kv1 Ion Channel Blockers.Bioengineering (Basel, Switzerland) · 2021Article
- Conformational Clamping by a Membrane Ligand Activates the EphA2 Receptor.Journal of molecular biology · 2021Article
- Single-molecule fluorescence vistas of how lipids regulate membrane proteins.Biochemical Society transactions · 2021Review
- Structure of the EphB6 receptor ectodomain.PloS one · 2021Article
- Approaches to Manipulate Ephrin-A:EphA Forward Signaling Pathway.Pharmaceuticals (Basel, Switzerland) · 2020Review
- Membrane receptor activation mechanisms and transmembrane peptide tools to elucidate them.The Journal of biological chemistry · 2020Review
- Disruption of Sema3A/Plexin-A1 inhibitory signalling in oligodendrocytes as a therapeutic strategy to promote remyelination.EMBO molecular medicine · 2019Article
- EphA2 Transmembrane Domain Is Uniquely Required for Keratinocyte Migration by Regulating Ephrin-A1 Levels.The Journal of investigative dermatology · 2018Article
- Article
- A small peptide promotes EphA2 kinase-dependent signaling by stabilizing EphA2 dimers.Biochimica et biophysica acta · 2016Article
- Activation of transmembrane cell-surface receptors via a common mechanism? The "rotation model".BioEssays : news and reviews in molecular, cellular and developmental biology · 2015Review
- Dimerization of the EphA1 receptor tyrosine kinase transmembrane domain: Insights into the mechanism of receptor activation.Biochemistry · 2014Article
- Eph receptor and ephrin function in breast, gut, and skin epithelia.Cell adhesion & migration · 2014Review
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The EphA2 receptor tyrosine kinase plays a central role in the regulation of cell adhesion and guidance in many human tissues. The activation of EphA2 occurs after proper dimerization/oligomerization in the plasma membrane, which occurs with the participation of extracellular and cytoplasmic domains. Our study revealed that the isolated transmembrane domain (TMD) of EphA2 embedded into the lipid bicelle dimerized via the heptad repeat motif L(535)X3G(539)X2A(542)X3V(546)X2L(549) rather than through the alternative glycine zipper motif A(536)X3G(540)X3G(544) (typical for TMD dimerization in many proteins). To evaluate the significance of TMD interactions for full-length EphA2, we substituted key residues in the heptad repeat motif (HR variant: G539I, A542I, G553I) or in the glycine zipper motif (GZ variant: G540I, G544I) and expressed YFP-tagged EphA2 (WT, HR, and GZ variants) in HEK293T cells. Confocal microscopy revealed a similar distribution of all EphA2-YFP variants in cells. The expression of EphA2-YFP variants and their kinase activity (phosphorylation of Tyr(588) and/or Tyr(594)) and ephrin-A3 binding were analyzed with flow cytometry on a single cell basis. Activation of any EphA2 variant is found to occur even without ephrin stimulation when the EphA2 content in cells is sufficiently high. Ephrin-A3 binding is not affected in mutant variants. Mutations in the TMD have a significant effect on EphA2 activity. Both ligand-dependent and ligand-independent activities are enhanced for the HR variant and reduced for the GZ variant compared with the WT. These findings allow us to suggest TMD dimerization switching between the heptad repeat and glycine zipper motifs, corresponding to inactive and active receptor states, respectively, as a mechanism underlying EphA2 signal transduction.
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