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 de...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2018-09-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/36645 |
| _version_ | 1797997583951462400 |
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| author | Daiane S Alves Justin M Westerfield Xiaojun Shi Vanessa P Nguyen Katherine M Stefanski Kristen R Booth Soyeon Kim Jennifer Morrell-Falvey Bing-Cheng Wang Steven M Abel Adam W Smith Francisco N Barrera |
| author_facet | Daiane S Alves Justin M Westerfield Xiaojun Shi Vanessa P Nguyen Katherine M Stefanski Kristen R Booth Soyeon Kim Jennifer Morrell-Falvey Bing-Cheng Wang Steven M Abel Adam W Smith Francisco N Barrera |
| author_sort | Daiane S Alves |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T10:34:55Z |
| format | Article |
| id | doaj.art-c5d8558633184388971353fd6c908488 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T10:34:55Z |
| publishDate | 2018-09-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-c5d8558633184388971353fd6c9084882022-12-22T04:29:20ZengeLife Sciences Publications LtdeLife2050-084X2018-09-01710.7554/eLife.36645A novel pH-dependent membrane peptide that binds to EphA2 and inhibits cell migrationDaiane S Alves0https://orcid.org/0000-0001-9154-4748Justin M Westerfield1https://orcid.org/0000-0002-3937-5833Xiaojun Shi2https://orcid.org/0000-0002-8060-5880Vanessa P Nguyen3https://orcid.org/0000-0002-7650-0138Katherine M Stefanski4https://orcid.org/0000-0003-3007-0598Kristen R Booth5Soyeon Kim6Jennifer Morrell-Falvey7https://orcid.org/0000-0002-9362-7528Bing-Cheng Wang8Steven M Abel9https://orcid.org/0000-0003-0491-8647Adam W Smith10https://orcid.org/0000-0001-5216-9017Francisco N Barrera11https://orcid.org/0000-0002-5200-7891Department of Biochemistry & Cellular and Molecular Biology, University of Tennessee, Knoxville, United StatesDepartment of Biochemistry & Cellular and Molecular Biology, University of Tennessee, Knoxville, United StatesDepartment of Chemistry, University of Akron, Akron, United States; Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, United States; Pharmacology, Case Western Reserve University, Cleveland, United States; Rammelkamp Center for Research, MetroHealth Medical Center, Cleveland, United StatesDepartment of Biochemistry & Cellular and Molecular Biology, University of Tennessee, Knoxville, United StatesGraduate School of Genome Science and Technology, University of Tennessee, Knoxville, United StatesDepartment of Biochemistry & Cellular and Molecular Biology, University of Tennessee, Knoxville, United StatesDepartment of Chemistry, University of Akron, Akron, United StatesDepartment of Biochemistry & Cellular and Molecular Biology, University of Tennessee, Knoxville, United States; Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, United StatesDepartment of Physiology and Biophysics, Case Western Reserve University, Cleveland, United States; Pharmacology, Case Western Reserve University, Cleveland, United States; Rammelkamp Center for Research, MetroHealth Medical Center, Cleveland, United StatesDepartment of Chemical and Biomolecular Engineering, University of Tennessee, Knoxville, United States; National Institute for Mathematical and Biological Synthesis, University of Tennessee, Knoxville, United StatesDepartment of Chemistry, University of Akron, Akron, United StatesDepartment of Biochemistry & Cellular and Molecular Biology, University of Tennessee, Knoxville, United StatesMisregulation 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.https://elifesciences.org/articles/36645EphA2 activationreceptor tyrosine kinasemembrane active peptidepH responsive |
| spellingShingle | Daiane S Alves Justin M Westerfield Xiaojun Shi Vanessa P Nguyen Katherine M Stefanski Kristen R Booth Soyeon Kim Jennifer Morrell-Falvey Bing-Cheng Wang Steven M Abel Adam W Smith Francisco N Barrera A novel pH-dependent membrane peptide that binds to EphA2 and inhibits cell migration eLife EphA2 activation receptor tyrosine kinase membrane active peptide pH responsive |
| title | A novel pH-dependent membrane peptide that binds to EphA2 and inhibits cell migration |
| title_full | A novel pH-dependent membrane peptide that binds to EphA2 and inhibits cell migration |
| title_fullStr | A novel pH-dependent membrane peptide that binds to EphA2 and inhibits cell migration |
| title_full_unstemmed | A novel pH-dependent membrane peptide that binds to EphA2 and inhibits cell migration |
| title_short | A novel pH-dependent membrane peptide that binds to EphA2 and inhibits cell migration |
| title_sort | novel ph dependent membrane peptide that binds to epha2 and inhibits cell migration |
| topic | EphA2 activation receptor tyrosine kinase membrane active peptide pH responsive |
| url | https://elifesciences.org/articles/36645 |
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