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EGFR Regulates the Hippo pathway by promoting the tyrosine phosphorylation of MOB1
The Hippo pathway is frequently dysregulated in cancer, leading to the unrestrained activity of its downstream targets, YAP/TAZ, and aberrant tumor growth. However, the precise mechanisms leading to YAP/TAZ activation in most cancers is still poorly understood. Analysis of large tissue collections r...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8560880/ https://www.ncbi.nlm.nih.gov/pubmed/34725466 http://dx.doi.org/10.1038/s42003-021-02744-4 |
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author | Ando, Toshinori Arang, Nadia Wang, Zhiyong Costea, Daniela Elena Feng, Xiaodong Goto, Yusuke Izumi, Hiroki Gilardi, Mara Ando, Kazuyo Gutkind, J. Silvio |
author_facet | Ando, Toshinori Arang, Nadia Wang, Zhiyong Costea, Daniela Elena Feng, Xiaodong Goto, Yusuke Izumi, Hiroki Gilardi, Mara Ando, Kazuyo Gutkind, J. Silvio |
author_sort | Ando, Toshinori |
collection | PubMed |
description | The Hippo pathway is frequently dysregulated in cancer, leading to the unrestrained activity of its downstream targets, YAP/TAZ, and aberrant tumor growth. However, the precise mechanisms leading to YAP/TAZ activation in most cancers is still poorly understood. Analysis of large tissue collections revealed YAP activation in most head and neck squamous cell carcinoma (HNSCC), but only 29.8% of HNSCC cases present genetic alterations in the FAT1 tumor suppressor gene that may underlie persistent YAP signaling. EGFR is overexpressed in HNSCC and many other cancers, but whether EGFR controls YAP activation is still poorly understood. Here, we discover that EGFR activates YAP/TAZ in HNSCC cells, but independently of its typical signaling targets, including PI3K. Mechanistically, we find that EGFR promotes the phosphorylation of MOB1, a core Hippo pathway component, and the inactivation of LATS1/2 independently of MST1/2. Transcriptomic analysis reveals that erlotinib, a clinical EGFR inhibitor, inactivates YAP/TAZ. Remarkably, loss of LATS1/2, resulting in aberrant YAP/TAZ activity, confers erlotinib resistance on HNSCC and lung cancer cells. Our findings suggest that EGFR-YAP/TAZ signaling plays a growth-promoting role in cancers harboring EGFR alterations, and that inhibition of YAP/TAZ in combination with EGFR might be beneficial to prevent treatment resistance and cancer recurrence. |
format | Online Article Text |
id | pubmed-8560880 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-85608802021-11-15 EGFR Regulates the Hippo pathway by promoting the tyrosine phosphorylation of MOB1 Ando, Toshinori Arang, Nadia Wang, Zhiyong Costea, Daniela Elena Feng, Xiaodong Goto, Yusuke Izumi, Hiroki Gilardi, Mara Ando, Kazuyo Gutkind, J. Silvio Commun Biol Article The Hippo pathway is frequently dysregulated in cancer, leading to the unrestrained activity of its downstream targets, YAP/TAZ, and aberrant tumor growth. However, the precise mechanisms leading to YAP/TAZ activation in most cancers is still poorly understood. Analysis of large tissue collections revealed YAP activation in most head and neck squamous cell carcinoma (HNSCC), but only 29.8% of HNSCC cases present genetic alterations in the FAT1 tumor suppressor gene that may underlie persistent YAP signaling. EGFR is overexpressed in HNSCC and many other cancers, but whether EGFR controls YAP activation is still poorly understood. Here, we discover that EGFR activates YAP/TAZ in HNSCC cells, but independently of its typical signaling targets, including PI3K. Mechanistically, we find that EGFR promotes the phosphorylation of MOB1, a core Hippo pathway component, and the inactivation of LATS1/2 independently of MST1/2. Transcriptomic analysis reveals that erlotinib, a clinical EGFR inhibitor, inactivates YAP/TAZ. Remarkably, loss of LATS1/2, resulting in aberrant YAP/TAZ activity, confers erlotinib resistance on HNSCC and lung cancer cells. Our findings suggest that EGFR-YAP/TAZ signaling plays a growth-promoting role in cancers harboring EGFR alterations, and that inhibition of YAP/TAZ in combination with EGFR might be beneficial to prevent treatment resistance and cancer recurrence. Nature Publishing Group UK 2021-11-01 /pmc/articles/PMC8560880/ /pubmed/34725466 http://dx.doi.org/10.1038/s42003-021-02744-4 Text en © The Author(s) 2021 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 Ando, Toshinori Arang, Nadia Wang, Zhiyong Costea, Daniela Elena Feng, Xiaodong Goto, Yusuke Izumi, Hiroki Gilardi, Mara Ando, Kazuyo Gutkind, J. Silvio EGFR Regulates the Hippo pathway by promoting the tyrosine phosphorylation of MOB1 |
title | EGFR Regulates the Hippo pathway by promoting the tyrosine phosphorylation of MOB1 |
title_full | EGFR Regulates the Hippo pathway by promoting the tyrosine phosphorylation of MOB1 |
title_fullStr | EGFR Regulates the Hippo pathway by promoting the tyrosine phosphorylation of MOB1 |
title_full_unstemmed | EGFR Regulates the Hippo pathway by promoting the tyrosine phosphorylation of MOB1 |
title_short | EGFR Regulates the Hippo pathway by promoting the tyrosine phosphorylation of MOB1 |
title_sort | egfr regulates the hippo pathway by promoting the tyrosine phosphorylation of mob1 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8560880/ https://www.ncbi.nlm.nih.gov/pubmed/34725466 http://dx.doi.org/10.1038/s42003-021-02744-4 |
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