A novel pH-dependent membrane peptide that binds to EphA2 and inhibits cell migration
- University of Tennessee, United States
- University of Akron, United States
- Case Western Reserve University, United States
Abstract
Misregulation of the signaling axis formed by the receptor tyrosine kinase (RTK) EphA2 and its ligand, ephrinA1, causes aberrant cell-cell contacts that contribute to metastasis. Solid tumors are characterized by an acidic extracellular medium. We intend to take advantage of this tumor feature to design new molecules that specifically target tumors. We created a novel pH-dependent transmembrane peptide, TYPE7, by altering the sequence of the transmembrane domain of EphA2. TYPE7 is highly soluble and interacts with the surface of lipid membranes at neutral pH, while acidity triggers transmembrane insertion. TYPE7 binds to endogenous EphA2 and reduces Akt phosphorylation and cell migration as effectively as ephrinA1. Interestingly, we found large differences in juxtamembrane tyrosine phosphorylation and the extent of EphA2 clustering when compared TYPE7 with activation by ephrinA1. This work shows that it is possible to design new pH-triggered membrane peptides to activate RTK and gain insights on its activation mechanism.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Justin M Westerfield
Jennifer Morrell-Falvey
Francisco N Barrera
Funding
National Institute of General Medical Sciences (R01GM120642)
- Francisco N Barrera
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Patricia Bassereau, Institut Curie, France
Publication history
- Received: March 13, 2018
- Accepted: September 16, 2018
- Accepted Manuscript published: September 17, 2018 (version 1)
- Version of Record published: October 17, 2018 (version 2)
- Version of Record updated: August 30, 2019 (version 3)
Copyright
© 2018, Alves et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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A novel pH-dependent membrane peptide that binds to EphA2 and inhibits cell migration
eLife 7:e36645.
https://doi.org/10.7554/eLife.36645
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