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Internalization Mechanisms of the Epidermal Growth Factor Receptor after Activation with Different Ligands
The epidermal growth factor receptor (EGFR) regulates normal growth and differentiation, but dysregulation of the receptor or one of the EGFR ligands is involved in the pathogenesis of many cancers. There are eight ligands for EGFR, however most of the research into trafficking of the receptor after...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3589378/ https://www.ncbi.nlm.nih.gov/pubmed/23472148 http://dx.doi.org/10.1371/journal.pone.0058148 |
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author | Henriksen, Lasse Grandal, Michael Vibo Knudsen, Stine Louise Jeppe van Deurs, Bo Grøvdal, Lene Melsæther |
author_facet | Henriksen, Lasse Grandal, Michael Vibo Knudsen, Stine Louise Jeppe van Deurs, Bo Grøvdal, Lene Melsæther |
author_sort | Henriksen, Lasse |
collection | PubMed |
description | The epidermal growth factor receptor (EGFR) regulates normal growth and differentiation, but dysregulation of the receptor or one of the EGFR ligands is involved in the pathogenesis of many cancers. There are eight ligands for EGFR, however most of the research into trafficking of the receptor after ligand activation focuses on the effect of epidermal growth factor (EGF) and transforming growth factor-α (TGF-α). For a long time it was believed that clathrin-mediated endocytosis was the major pathway for internalization of the receptor, but recent work suggests that different pathways exist. Here we show that clathrin ablation completely inhibits internalization of EGF- and TGF-α-stimulated receptor, however the inhibition of receptor internalization in cells treated with heparin-binding EGF-like growth factor (HB-EGF) or betacellulin (BTC) was only partial. In contrast, clathrin knockdown fully inhibits EGFR degradation after all ligands tested. Furthermore, inhibition of dynamin function blocked EGFR internalization after stimulation with all ligands. Knocking out a number of clathrin-independent dynamin-dependent pathways of internalization had no effect on the ligand-induced endocytosis of the EGFR. We suggest that EGF and TGF-α lead to EGFR endocytosis mainly via the clathrin-mediated pathway. Furthermore, we suggest that HB-EGF and BTC also lead to EGFR endocytosis via a clathrin-mediated pathway, but can additionally use an unidentified internalization pathway or better recruit the small amount of clathrin remaining after clathrin knockdown. |
format | Online Article Text |
id | pubmed-3589378 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-35893782013-03-07 Internalization Mechanisms of the Epidermal Growth Factor Receptor after Activation with Different Ligands Henriksen, Lasse Grandal, Michael Vibo Knudsen, Stine Louise Jeppe van Deurs, Bo Grøvdal, Lene Melsæther PLoS One Research Article The epidermal growth factor receptor (EGFR) regulates normal growth and differentiation, but dysregulation of the receptor or one of the EGFR ligands is involved in the pathogenesis of many cancers. There are eight ligands for EGFR, however most of the research into trafficking of the receptor after ligand activation focuses on the effect of epidermal growth factor (EGF) and transforming growth factor-α (TGF-α). For a long time it was believed that clathrin-mediated endocytosis was the major pathway for internalization of the receptor, but recent work suggests that different pathways exist. Here we show that clathrin ablation completely inhibits internalization of EGF- and TGF-α-stimulated receptor, however the inhibition of receptor internalization in cells treated with heparin-binding EGF-like growth factor (HB-EGF) or betacellulin (BTC) was only partial. In contrast, clathrin knockdown fully inhibits EGFR degradation after all ligands tested. Furthermore, inhibition of dynamin function blocked EGFR internalization after stimulation with all ligands. Knocking out a number of clathrin-independent dynamin-dependent pathways of internalization had no effect on the ligand-induced endocytosis of the EGFR. We suggest that EGF and TGF-α lead to EGFR endocytosis mainly via the clathrin-mediated pathway. Furthermore, we suggest that HB-EGF and BTC also lead to EGFR endocytosis via a clathrin-mediated pathway, but can additionally use an unidentified internalization pathway or better recruit the small amount of clathrin remaining after clathrin knockdown. Public Library of Science 2013-03-05 /pmc/articles/PMC3589378/ /pubmed/23472148 http://dx.doi.org/10.1371/journal.pone.0058148 Text en © 2013 Henriksen et al http://creativecommons.org/licenses/by/4.0/ 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 properly credited. |
spellingShingle | Research Article Henriksen, Lasse Grandal, Michael Vibo Knudsen, Stine Louise Jeppe van Deurs, Bo Grøvdal, Lene Melsæther Internalization Mechanisms of the Epidermal Growth Factor Receptor after Activation with Different Ligands |
title | Internalization Mechanisms of the Epidermal Growth Factor Receptor after Activation with Different Ligands |
title_full | Internalization Mechanisms of the Epidermal Growth Factor Receptor after Activation with Different Ligands |
title_fullStr | Internalization Mechanisms of the Epidermal Growth Factor Receptor after Activation with Different Ligands |
title_full_unstemmed | Internalization Mechanisms of the Epidermal Growth Factor Receptor after Activation with Different Ligands |
title_short | Internalization Mechanisms of the Epidermal Growth Factor Receptor after Activation with Different Ligands |
title_sort | internalization mechanisms of the epidermal growth factor receptor after activation with different ligands |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3589378/ https://www.ncbi.nlm.nih.gov/pubmed/23472148 http://dx.doi.org/10.1371/journal.pone.0058148 |
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