A novel pH-dependent membrane peptide that binds to EphA2 and inhibits cell migration

  1. Daiane Santana Alves
  2. Justin M Westerfield
  3. Xiaojun Shi
  4. Vanessa P Nguyen
  5. Katherine M Stefanski
  6. Kristen R Booth
  7. Soyeon Kim
  8. Jennifer Morrell-Falvey
  9. Bing-Cheng Wang
  10. Steven M Abel
  11. Adam W Smith
  12. Francisco N Barrera  Is a corresponding author
  1. University of Tennessee, United States
  2. University of Akron, United States
  3. 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

  1. Daiane Santana Alves

    Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoville, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Justin M Westerfield

    Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3937-5833
  3. Xiaojun Shi

    Department of Chemistry, University of Akron, Akron, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8060-5880
  4. Vanessa P Nguyen

    Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Katherine M Stefanski

    Graduate School of Genome Science and Technology, University of Tennessee, Knoxville, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Kristen R Booth

    Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Soyeon Kim

    Department of Chemistry, University of Akron, Akron, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Jennifer Morrell-Falvey

    Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9362-7528
  9. Bing-Cheng Wang

    Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Steven M Abel

    Department of Chemical and Biomolecular Engineering, University of Tennessee, Knoxville, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0491-8647
  11. Adam W Smith

    Department of Chemistry, University of Akron, Akron, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5216-9017
  12. Francisco N Barrera

    Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, United States
    For correspondence
    fbarrera@utk.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5200-7891

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

  1. Patricia Bassereau, Institut Curie, France

Publication history

  1. Received: March 13, 2018
  2. Accepted: September 16, 2018
  3. Accepted Manuscript published: September 17, 2018 (version 1)
  4. Version of Record published: October 17, 2018 (version 2)
  5. 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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  1. Daiane Santana Alves
  2. Justin M Westerfield
  3. Xiaojun Shi
  4. Vanessa P Nguyen
  5. Katherine M Stefanski
  6. Kristen R Booth
  7. Soyeon Kim
  8. Jennifer Morrell-Falvey
  9. Bing-Cheng Wang
  10. Steven M Abel
  11. Adam W Smith
  12. Francisco N Barrera
(2018)
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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