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

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.
Authors:
ORCiD logo [1] ; ORCiD logo [1] ; ORCiD logo [2] ; ORCiD logo [1] ; ORCiD logo [3] ;  [1] ;  [4] ; ORCiD logo [5] ;  [6] ; ORCiD logo [7] ; ORCiD logo [4] ; ORCiD logo [1]
  1. Univ. of Tennessee, Knoxville, TN (United States). Dept. of Biochemistry & Cellular and Molecular Biology
  2. Univ. of Akron, OH (United States). Dept. of Chemistry; Case Western Reserve Univ., Cleveland, OH (United States). Dept. of Physiology and Biophysics. Dept. of Pharmacology; MetroHealth Medical Center, Cleveland, OH (United States). Rammelkamp Center for Research
  3. Univ. of Tennessee, Knoxville, TN (United States). Graduate School of Genome Science and Technology
  4. Univ. of Akron, OH (United States). Dept. of Chemistry
  5. Univ. of Tennessee, Knoxville, TN (United States). Dept. of Biochemistry & Cellular and Molecular Biology; Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Biosciences Division
  6. Case Western Reserve Univ., Cleveland, OH (United States). Dept. of Physiology and Biophysics. Dept. of Pharmacology; MetroHealth Medical Center, Cleveland, OH (United States). Rammelkamp Center for Research
  7. Univ. of Tennessee, Knoxville, TN (United States). Dept. of Chemical and Biomolecular Engineering. National Inst. for Mathematical and Biological Synthesis
Publication Date:
Grant/Contract Number:
AC05-00OR22725; R01GM120642; R01NS096956; R01CA155676
Type:
Accepted Manuscript
Journal Name:
eLife
Additional Journal Information:
Journal Volume: 7; Journal ID: ISSN 2050-084X
Publisher:
eLife Sciences Publications, Ltd.
Research Org:
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Univ. of Tennessee, Knoxville, TN (United States); Case Western Reserve Univ., Cleveland, OH (United States)
Sponsoring Org:
USDOE Office of Science (SC); National Inst. of Health (NIH) (United States)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES
OSTI Identifier:
1479723

Alves, Daiane S., Westerfield, Justin M., Shi, Xiaojun, Nguyen, Vanessa P., Stefanski, Katherine M., Booth, Kristen R., Kim, Soyeon, Morrell-Falvey, Jennifer, Wang, Bing-Cheng, Abel, Steven M., Smith, Adam W., and Barrera, Francisco N.. A novel pH-dependent membrane peptide that binds to EphA2 and inhibits cell migration. United States: N. p., Web. doi:10.7554/eLife.36645.
Alves, Daiane S., Westerfield, Justin M., Shi, Xiaojun, Nguyen, Vanessa P., Stefanski, Katherine M., Booth, Kristen R., Kim, Soyeon, Morrell-Falvey, Jennifer, Wang, Bing-Cheng, Abel, Steven M., Smith, Adam W., & Barrera, Francisco N.. A novel pH-dependent membrane peptide that binds to EphA2 and inhibits cell migration. United States. doi:10.7554/eLife.36645.
Alves, Daiane S., Westerfield, Justin M., Shi, Xiaojun, Nguyen, Vanessa P., Stefanski, Katherine M., Booth, Kristen R., Kim, Soyeon, Morrell-Falvey, Jennifer, Wang, Bing-Cheng, Abel, Steven M., Smith, Adam W., and Barrera, Francisco N.. 2018. "A novel pH-dependent membrane peptide that binds to EphA2 and inhibits cell migration". United States. doi:10.7554/eLife.36645. https://www.osti.gov/servlets/purl/1479723.
@article{osti_1479723,
title = {A novel pH-dependent membrane peptide that binds to EphA2 and inhibits cell migration},
author = {Alves, Daiane S. and Westerfield, Justin M. and Shi, Xiaojun and Nguyen, Vanessa P. and Stefanski, Katherine M. and Booth, Kristen R. and Kim, Soyeon and Morrell-Falvey, Jennifer and Wang, Bing-Cheng and Abel, Steven M. and Smith, Adam W. and Barrera, Francisco N.},
abstractNote = {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.},
doi = {10.7554/eLife.36645},
journal = {eLife},
number = ,
volume = 7,
place = {United States},
year = {2018},
month = {9}
}

Works referenced in this record:

Mechanisms and functions of eph and ephrin signalling
journal, July 2002
  • Kullander, Klas; Klein, R�diger
  • Nature Reviews Molecular Cell Biology, Vol. 3, Issue 7, p. 475-486
  • DOI: 10.1038/nrm856