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Confinement of unliganded EGFR by tetraspanin nanodomains gates EGFR ligand binding and signaling
The epidermal growth factor receptor (EGFR) is a central regulator of cell physiology. EGFR is activated by ligand binding, triggering receptor dimerization, activation of kinase activity, and intracellular signaling. EGFR is transiently confined within various plasma membrane nanodomains, yet how t...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10170156/ https://www.ncbi.nlm.nih.gov/pubmed/37160944 http://dx.doi.org/10.1038/s41467-023-38390-z |
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author | Sugiyama, Michael G. Brown, Aidan I. Vega-Lugo, Jesus Borges, Jazlyn P. Scott, Andrew M. Jaqaman, Khuloud Fairn, Gregory D. Antonescu, Costin N. |
author_facet | Sugiyama, Michael G. Brown, Aidan I. Vega-Lugo, Jesus Borges, Jazlyn P. Scott, Andrew M. Jaqaman, Khuloud Fairn, Gregory D. Antonescu, Costin N. |
author_sort | Sugiyama, Michael G. |
collection | PubMed |
description | The epidermal growth factor receptor (EGFR) is a central regulator of cell physiology. EGFR is activated by ligand binding, triggering receptor dimerization, activation of kinase activity, and intracellular signaling. EGFR is transiently confined within various plasma membrane nanodomains, yet how this may contribute to regulation of EGFR ligand binding is poorly understood. To resolve how EGFR nanoscale compartmentalization gates ligand binding, we developed single-particle tracking methods to track the mobility of ligand-bound and total EGFR, in combination with modeling of EGFR ligand binding. In comparison to unliganded EGFR, ligand-bound EGFR is more confined and distinctly regulated by clathrin and tetraspanin nanodomains. Ligand binding to unliganded EGFR occurs preferentially in tetraspanin nanodomains, and disruption of tetraspanin nanodomains impairs EGFR ligand binding and alters the conformation of the receptor’s ectodomain. We thus reveal a mechanism by which EGFR confinement within tetraspanin nanodomains regulates receptor signaling at the level of ligand binding. |
format | Online Article Text |
id | pubmed-10170156 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-101701562023-05-11 Confinement of unliganded EGFR by tetraspanin nanodomains gates EGFR ligand binding and signaling Sugiyama, Michael G. Brown, Aidan I. Vega-Lugo, Jesus Borges, Jazlyn P. Scott, Andrew M. Jaqaman, Khuloud Fairn, Gregory D. Antonescu, Costin N. Nat Commun Article The epidermal growth factor receptor (EGFR) is a central regulator of cell physiology. EGFR is activated by ligand binding, triggering receptor dimerization, activation of kinase activity, and intracellular signaling. EGFR is transiently confined within various plasma membrane nanodomains, yet how this may contribute to regulation of EGFR ligand binding is poorly understood. To resolve how EGFR nanoscale compartmentalization gates ligand binding, we developed single-particle tracking methods to track the mobility of ligand-bound and total EGFR, in combination with modeling of EGFR ligand binding. In comparison to unliganded EGFR, ligand-bound EGFR is more confined and distinctly regulated by clathrin and tetraspanin nanodomains. Ligand binding to unliganded EGFR occurs preferentially in tetraspanin nanodomains, and disruption of tetraspanin nanodomains impairs EGFR ligand binding and alters the conformation of the receptor’s ectodomain. We thus reveal a mechanism by which EGFR confinement within tetraspanin nanodomains regulates receptor signaling at the level of ligand binding. Nature Publishing Group UK 2023-05-09 /pmc/articles/PMC10170156/ /pubmed/37160944 http://dx.doi.org/10.1038/s41467-023-38390-z Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Sugiyama, Michael G. Brown, Aidan I. Vega-Lugo, Jesus Borges, Jazlyn P. Scott, Andrew M. Jaqaman, Khuloud Fairn, Gregory D. Antonescu, Costin N. Confinement of unliganded EGFR by tetraspanin nanodomains gates EGFR ligand binding and signaling |
title | Confinement of unliganded EGFR by tetraspanin nanodomains gates EGFR ligand binding and signaling |
title_full | Confinement of unliganded EGFR by tetraspanin nanodomains gates EGFR ligand binding and signaling |
title_fullStr | Confinement of unliganded EGFR by tetraspanin nanodomains gates EGFR ligand binding and signaling |
title_full_unstemmed | Confinement of unliganded EGFR by tetraspanin nanodomains gates EGFR ligand binding and signaling |
title_short | Confinement of unliganded EGFR by tetraspanin nanodomains gates EGFR ligand binding and signaling |
title_sort | confinement of unliganded egfr by tetraspanin nanodomains gates egfr ligand binding and signaling |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10170156/ https://www.ncbi.nlm.nih.gov/pubmed/37160944 http://dx.doi.org/10.1038/s41467-023-38390-z |
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