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Spatio-temporal regulation of EGFR signaling by the Eps15 homology domain-containing protein 3 (EHD3)
The epidermal growth factor (EGF) receptor EGFR is a major receptor tyrosine kinase whose role in gliomagenesis is well established. We have recently identified EHD3 [Eps15 homology (EH) domain-containing protein 3], an endocytic trafficking regulatory protein, as a putative brain tumor suppressor....
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5346708/ https://www.ncbi.nlm.nih.gov/pubmed/27811356 http://dx.doi.org/10.18632/oncotarget.13008 |
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author | Amessou, Mohamed Ebrahim, Abdul Shukkur Dilly, Ashok Joseph, Melvin Tabolina, Marina Chukkapalli, Sahiti Meroueh, Louay Syed, Joseph T. Liddane, Allison Lang, Siera Lanae Al-Katib, Ayad Kandouz, Mustapha |
author_facet | Amessou, Mohamed Ebrahim, Abdul Shukkur Dilly, Ashok Joseph, Melvin Tabolina, Marina Chukkapalli, Sahiti Meroueh, Louay Syed, Joseph T. Liddane, Allison Lang, Siera Lanae Al-Katib, Ayad Kandouz, Mustapha |
author_sort | Amessou, Mohamed |
collection | PubMed |
description | The epidermal growth factor (EGF) receptor EGFR is a major receptor tyrosine kinase whose role in gliomagenesis is well established. We have recently identified EHD3 [Eps15 homology (EH) domain-containing protein 3], an endocytic trafficking regulatory protein, as a putative brain tumor suppressor. Here, we investigate the underlying mechanisms, by establishing a novel mechanistic and functional connection between EHD3 and the EGFR signaling pathway. We show that, in response to stimulation with the EGF ligand, EHD3 accelerates the rate of EGFR degradation by dramatically increasing its ubiquitination. As part of this process, EHD3 also regulates EGFR endosomal trafficking by diverting it away from the recycling route into the degradative pathway. Moreover, we found that upon EGF activation, rather than affecting the total MAPK and AKT downstream signaling, EHD3 decreases endosome-based signaling of these two pathways, thus suggesting the contribution of EHD3 in the spatial regulation of EGFR signaling. This function explains the higher sensitivity of EHD3-expressing cells to the growth-inhibitory effects of EGF. In summary, this is the first report supporting a mechanism of EHD3-mediated tumor suppression that involves the attenuation of endosomal signaling of the EGFR oncogene. |
format | Online Article Text |
id | pubmed-5346708 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-53467082017-03-30 Spatio-temporal regulation of EGFR signaling by the Eps15 homology domain-containing protein 3 (EHD3) Amessou, Mohamed Ebrahim, Abdul Shukkur Dilly, Ashok Joseph, Melvin Tabolina, Marina Chukkapalli, Sahiti Meroueh, Louay Syed, Joseph T. Liddane, Allison Lang, Siera Lanae Al-Katib, Ayad Kandouz, Mustapha Oncotarget Research Paper The epidermal growth factor (EGF) receptor EGFR is a major receptor tyrosine kinase whose role in gliomagenesis is well established. We have recently identified EHD3 [Eps15 homology (EH) domain-containing protein 3], an endocytic trafficking regulatory protein, as a putative brain tumor suppressor. Here, we investigate the underlying mechanisms, by establishing a novel mechanistic and functional connection between EHD3 and the EGFR signaling pathway. We show that, in response to stimulation with the EGF ligand, EHD3 accelerates the rate of EGFR degradation by dramatically increasing its ubiquitination. As part of this process, EHD3 also regulates EGFR endosomal trafficking by diverting it away from the recycling route into the degradative pathway. Moreover, we found that upon EGF activation, rather than affecting the total MAPK and AKT downstream signaling, EHD3 decreases endosome-based signaling of these two pathways, thus suggesting the contribution of EHD3 in the spatial regulation of EGFR signaling. This function explains the higher sensitivity of EHD3-expressing cells to the growth-inhibitory effects of EGF. In summary, this is the first report supporting a mechanism of EHD3-mediated tumor suppression that involves the attenuation of endosomal signaling of the EGFR oncogene. Impact Journals LLC 2016-11-01 /pmc/articles/PMC5346708/ /pubmed/27811356 http://dx.doi.org/10.18632/oncotarget.13008 Text en Copyright: © 2016 Amessou et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Amessou, Mohamed Ebrahim, Abdul Shukkur Dilly, Ashok Joseph, Melvin Tabolina, Marina Chukkapalli, Sahiti Meroueh, Louay Syed, Joseph T. Liddane, Allison Lang, Siera Lanae Al-Katib, Ayad Kandouz, Mustapha Spatio-temporal regulation of EGFR signaling by the Eps15 homology domain-containing protein 3 (EHD3) |
title | Spatio-temporal regulation of EGFR signaling by the Eps15 homology domain-containing protein 3 (EHD3) |
title_full | Spatio-temporal regulation of EGFR signaling by the Eps15 homology domain-containing protein 3 (EHD3) |
title_fullStr | Spatio-temporal regulation of EGFR signaling by the Eps15 homology domain-containing protein 3 (EHD3) |
title_full_unstemmed | Spatio-temporal regulation of EGFR signaling by the Eps15 homology domain-containing protein 3 (EHD3) |
title_short | Spatio-temporal regulation of EGFR signaling by the Eps15 homology domain-containing protein 3 (EHD3) |
title_sort | spatio-temporal regulation of egfr signaling by the eps15 homology domain-containing protein 3 (ehd3) |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5346708/ https://www.ncbi.nlm.nih.gov/pubmed/27811356 http://dx.doi.org/10.18632/oncotarget.13008 |
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