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Extensive conformational and physical plasticity protects HER2-HER3 tumorigenic signaling
Surface-targeting biotherapeutic agents have been successful in treating HER2-amplified cancers through immunostimulation or chemodelivery but have failed to produce effective inhibitors of constitutive HER2-HER3 signaling. We report an extensive structure-function analysis of this tumor driver, rev...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8865943/ https://www.ncbi.nlm.nih.gov/pubmed/35108526 http://dx.doi.org/10.1016/j.celrep.2021.110285 |
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author | Campbell, Marcia R. Ruiz-Saenz, Ana Zhang, Yuntian Peterson, Elliott Steri, Veronica Oeffinger, Julie Sampang, Maryjo Jura, Natalia Moasser, Mark M. |
author_facet | Campbell, Marcia R. Ruiz-Saenz, Ana Zhang, Yuntian Peterson, Elliott Steri, Veronica Oeffinger, Julie Sampang, Maryjo Jura, Natalia Moasser, Mark M. |
author_sort | Campbell, Marcia R. |
collection | PubMed |
description | Surface-targeting biotherapeutic agents have been successful in treating HER2-amplified cancers through immunostimulation or chemodelivery but have failed to produce effective inhibitors of constitutive HER2-HER3 signaling. We report an extensive structure-function analysis of this tumor driver, revealing complete uncoupling of intracellular signaling and tumorigenic function from regulation or constraints from their extracellular domains (ECDs). The canonical HER3 ECD conformational changes and exposure of the dimerization interface are nonessential, and the entire ECDs of HER2 and HER3 are redundant for tumorigenic signaling. Restricting the proximation of partner ECDs with bulk and steric clash through extremely disruptive receptor engineering leaves tumorigenic signaling unperturbed. This is likely due to considerable conformational flexibilities across the span of these receptor molecules and substantial undulations in the plane of the plasma membrane, none of which had been foreseen as impediments to targeting strategies. The massive overexpression of HER2 functionally and physically uncouples intracellular signaling from extracellular constraints. |
format | Online Article Text |
id | pubmed-8865943 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
record_format | MEDLINE/PubMed |
spelling | pubmed-88659432022-02-23 Extensive conformational and physical plasticity protects HER2-HER3 tumorigenic signaling Campbell, Marcia R. Ruiz-Saenz, Ana Zhang, Yuntian Peterson, Elliott Steri, Veronica Oeffinger, Julie Sampang, Maryjo Jura, Natalia Moasser, Mark M. Cell Rep Article Surface-targeting biotherapeutic agents have been successful in treating HER2-amplified cancers through immunostimulation or chemodelivery but have failed to produce effective inhibitors of constitutive HER2-HER3 signaling. We report an extensive structure-function analysis of this tumor driver, revealing complete uncoupling of intracellular signaling and tumorigenic function from regulation or constraints from their extracellular domains (ECDs). The canonical HER3 ECD conformational changes and exposure of the dimerization interface are nonessential, and the entire ECDs of HER2 and HER3 are redundant for tumorigenic signaling. Restricting the proximation of partner ECDs with bulk and steric clash through extremely disruptive receptor engineering leaves tumorigenic signaling unperturbed. This is likely due to considerable conformational flexibilities across the span of these receptor molecules and substantial undulations in the plane of the plasma membrane, none of which had been foreseen as impediments to targeting strategies. The massive overexpression of HER2 functionally and physically uncouples intracellular signaling from extracellular constraints. 2022-02-01 /pmc/articles/PMC8865943/ /pubmed/35108526 http://dx.doi.org/10.1016/j.celrep.2021.110285 Text en https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ). |
spellingShingle | Article Campbell, Marcia R. Ruiz-Saenz, Ana Zhang, Yuntian Peterson, Elliott Steri, Veronica Oeffinger, Julie Sampang, Maryjo Jura, Natalia Moasser, Mark M. Extensive conformational and physical plasticity protects HER2-HER3 tumorigenic signaling |
title | Extensive conformational and physical plasticity protects HER2-HER3 tumorigenic signaling |
title_full | Extensive conformational and physical plasticity protects HER2-HER3 tumorigenic signaling |
title_fullStr | Extensive conformational and physical plasticity protects HER2-HER3 tumorigenic signaling |
title_full_unstemmed | Extensive conformational and physical plasticity protects HER2-HER3 tumorigenic signaling |
title_short | Extensive conformational and physical plasticity protects HER2-HER3 tumorigenic signaling |
title_sort | extensive conformational and physical plasticity protects her2-her3 tumorigenic signaling |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8865943/ https://www.ncbi.nlm.nih.gov/pubmed/35108526 http://dx.doi.org/10.1016/j.celrep.2021.110285 |
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