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

Authors
  • Alves, Daiane S1
  • Westerfield, Justin M1
  • Shi, Xiaojun2, 3, 4, 5
  • Nguyen, Vanessa P1
  • Stefanski, Katherine M6
  • Booth, Kristen R1
  • Kim, Soyeon2
  • Morrell-Falvey, Jennifer1, 7
  • Wang, Bing-Cheng3, 4, 5
  • Abel, Steven M8, 9
  • Smith, Adam W2
  • Barrera, Francisco N1
  • 1 Department of Biochemistry & Cellular and Molecular Biology, University of Tennessee, Knoxville, United States. , (United States)
  • 2 Department of Chemistry, University of Akron, Akron, United States. , (United States)
  • 3 Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, United States. , (United States)
  • 4 Pharmacology, Case Western Reserve University, Cleveland, United States. , (United States)
  • 5 Rammelkamp Center for Research, MetroHealth Medical Center, Cleveland, United States. , (United States)
  • 6 Graduate School of Genome Science and Technology, University of Tennessee, Knoxville, United States. , (United States)
  • 7 Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, United States. , (United States)
  • 8 Department of Chemical and Biomolecular Engineering, University of Tennessee, Knoxville, United States. , (United States)
  • 9 National Institute for Mathematical and Biological Synthesis, University of Tennessee, Knoxville, United States. , (United States)
Type
Published Article
Journal
eLife
Publisher
"eLife Sciences Organisation, Ltd."
Publication Date
Sep 17, 2018
Volume
7
Identifiers
DOI: 10.7554/eLife.36645
PMID: 30222105
Source
Medline
Keywords
Language
English
License
Unknown

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 comparing 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. © 2018, Alves et al.

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