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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...

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Autores principales: Ando, Toshinori, Arang, Nadia, Wang, Zhiyong, Costea, Daniela Elena, Feng, Xiaodong, Goto, Yusuke, Izumi, Hiroki, Gilardi, Mara, Ando, Kazuyo, Gutkind, J. Silvio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
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.
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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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