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Protein kinase A can block EphA2 receptor–mediated cell repulsion by increasing EphA2 S897 phosphorylation
The EphA2 receptor tyrosine kinase plays key roles in tissue homeostasis and disease processes such as cancer, pathological angiogenesis, and inflammation through two distinct signaling mechanisms. EphA2 “canonical” signaling involves ephrin-A ligand binding, tyrosine autophosphorylation, and kinase...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society for Cell Biology
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5007095/ https://www.ncbi.nlm.nih.gov/pubmed/27385333 http://dx.doi.org/10.1091/mbc.E16-01-0048 |
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author | Barquilla, Antonio Lamberto, Ilaria Noberini, Roberta Heynen-Genel, Susanne Brill, Laurence M. Pasquale, Elena B. |
author_facet | Barquilla, Antonio Lamberto, Ilaria Noberini, Roberta Heynen-Genel, Susanne Brill, Laurence M. Pasquale, Elena B. |
author_sort | Barquilla, Antonio |
collection | PubMed |
description | The EphA2 receptor tyrosine kinase plays key roles in tissue homeostasis and disease processes such as cancer, pathological angiogenesis, and inflammation through two distinct signaling mechanisms. EphA2 “canonical” signaling involves ephrin-A ligand binding, tyrosine autophosphorylation, and kinase activity; EphA2 “noncanonical” signaling involves phosphorylation of serine 897 (S897) by AKT and RSK kinases. To identify small molecules counteracting EphA2 canonical signaling, we developed a high-content screening platform measuring inhibition of ephrin-A1–induced PC3 prostate cancer cell retraction. Surprisingly, most hits from a screened collection of pharmacologically active compounds are agents that elevate intracellular cAMP by activating G protein–coupled receptors such as the β2-adrenoceptor. We found that cAMP promotes phosphorylation of S897 by protein kinase A (PKA) as well as increases the phosphorylation of several nearby serine/threonine residues, which constitute a phosphorylation hotspot. Whereas EphA2 canonical and noncanonical signaling have been viewed as mutually exclusive, we show that S897 phosphorylation by PKA can coexist with EphA2 tyrosine phosphorylation and block cell retraction induced by EphA2 kinase activity. Our findings reveal a novel paradigm in EphA2 function involving the interplay of canonical and noncanonical signaling and highlight the ability of the β2-adrenoceptor/cAMP/PKA axis to rewire EphA2 signaling in a subset of cancer cells. |
format | Online Article Text |
id | pubmed-5007095 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-50070952016-11-16 Protein kinase A can block EphA2 receptor–mediated cell repulsion by increasing EphA2 S897 phosphorylation Barquilla, Antonio Lamberto, Ilaria Noberini, Roberta Heynen-Genel, Susanne Brill, Laurence M. Pasquale, Elena B. Mol Biol Cell Articles The EphA2 receptor tyrosine kinase plays key roles in tissue homeostasis and disease processes such as cancer, pathological angiogenesis, and inflammation through two distinct signaling mechanisms. EphA2 “canonical” signaling involves ephrin-A ligand binding, tyrosine autophosphorylation, and kinase activity; EphA2 “noncanonical” signaling involves phosphorylation of serine 897 (S897) by AKT and RSK kinases. To identify small molecules counteracting EphA2 canonical signaling, we developed a high-content screening platform measuring inhibition of ephrin-A1–induced PC3 prostate cancer cell retraction. Surprisingly, most hits from a screened collection of pharmacologically active compounds are agents that elevate intracellular cAMP by activating G protein–coupled receptors such as the β2-adrenoceptor. We found that cAMP promotes phosphorylation of S897 by protein kinase A (PKA) as well as increases the phosphorylation of several nearby serine/threonine residues, which constitute a phosphorylation hotspot. Whereas EphA2 canonical and noncanonical signaling have been viewed as mutually exclusive, we show that S897 phosphorylation by PKA can coexist with EphA2 tyrosine phosphorylation and block cell retraction induced by EphA2 kinase activity. Our findings reveal a novel paradigm in EphA2 function involving the interplay of canonical and noncanonical signaling and highlight the ability of the β2-adrenoceptor/cAMP/PKA axis to rewire EphA2 signaling in a subset of cancer cells. The American Society for Cell Biology 2016-09-01 /pmc/articles/PMC5007095/ /pubmed/27385333 http://dx.doi.org/10.1091/mbc.E16-01-0048 Text en © 2016 Barquilla et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology. |
spellingShingle | Articles Barquilla, Antonio Lamberto, Ilaria Noberini, Roberta Heynen-Genel, Susanne Brill, Laurence M. Pasquale, Elena B. Protein kinase A can block EphA2 receptor–mediated cell repulsion by increasing EphA2 S897 phosphorylation |
title | Protein kinase A can block EphA2 receptor–mediated cell repulsion by increasing EphA2 S897 phosphorylation |
title_full | Protein kinase A can block EphA2 receptor–mediated cell repulsion by increasing EphA2 S897 phosphorylation |
title_fullStr | Protein kinase A can block EphA2 receptor–mediated cell repulsion by increasing EphA2 S897 phosphorylation |
title_full_unstemmed | Protein kinase A can block EphA2 receptor–mediated cell repulsion by increasing EphA2 S897 phosphorylation |
title_short | Protein kinase A can block EphA2 receptor–mediated cell repulsion by increasing EphA2 S897 phosphorylation |
title_sort | protein kinase a can block epha2 receptor–mediated cell repulsion by increasing epha2 s897 phosphorylation |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5007095/ https://www.ncbi.nlm.nih.gov/pubmed/27385333 http://dx.doi.org/10.1091/mbc.E16-01-0048 |
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