Cargando…

Disruption of the Keap1-mTORC2 axis by cancer-derived Keap1/mLST8 mutations leads to oncogenic mTORC2-AKT activation

The mechanistic target of the rapamycin (mTOR) pathway, which participates in the regulation of cellular growth and metabolism, is aberrantly regulated in various cancer types. The mTOR complex 2 (mTORC2), which consists of the core components mTOR, Rictor, mSin1, and mLST8, primarily responds to gr...

Descripción completa

Detalles Bibliográficos
Autores principales: Chen, Yingji, Jiao, Dongyue, He, Huiying, Sun, Huiru, Liu, Yajuan, Shi, Qing, Zhang, Pingzhao, Li, Yao, Mo, Ren, Gao, Kun, Wang, Chenji
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10498434/
https://www.ncbi.nlm.nih.gov/pubmed/37688978
http://dx.doi.org/10.1016/j.redox.2023.102872
_version_ 1785105519004876800
author Chen, Yingji
Jiao, Dongyue
He, Huiying
Sun, Huiru
Liu, Yajuan
Shi, Qing
Zhang, Pingzhao
Li, Yao
Mo, Ren
Gao, Kun
Wang, Chenji
author_facet Chen, Yingji
Jiao, Dongyue
He, Huiying
Sun, Huiru
Liu, Yajuan
Shi, Qing
Zhang, Pingzhao
Li, Yao
Mo, Ren
Gao, Kun
Wang, Chenji
author_sort Chen, Yingji
collection PubMed
description The mechanistic target of the rapamycin (mTOR) pathway, which participates in the regulation of cellular growth and metabolism, is aberrantly regulated in various cancer types. The mTOR complex 2 (mTORC2), which consists of the core components mTOR, Rictor, mSin1, and mLST8, primarily responds to growth signals. However, the coordination between mTORC2 assembly and activity remains poorly understood. Keap1, a major sensor of oxidative stress in cells, functions as a substrate adaptor for Cullin 3-RING E3 ubiquitin ligase (CRL3) to promote proteasomal degradation of NF-E2-related factor 2 (NRF2), which is a transcription factor that protects cells against oxidative and electrophilic stress. In the present study, we demonstrate that Keap1 binds to mLST8 via a conserved ETGE motif. The CRL3(Keap1) ubiquitin ligase complex promotes non-degradative ubiquitination of mLST8, thus reducing mTORC2 complex integrity and mTORC2-AKT activation. However, this effect can be prevented by oxidative/electrophilic stresses and growth factor signaling-induced reactive oxygen species (ROS) burst. Cancer-derived Keap1 or mLST8 mutations disrupt the Keap1-mLST8 interaction and allow mLST8 to evade Keap1-mediated ubiquitination, thereby enhancing mTORC2-AKT activation and promoting cell malignancy and remodeling cell metabolism. Our findings provide new insights into the molecular mechanisms of Keap1/mLST8 mutation-driven tumorigenesis by promoting mTORC2-AKT activation, which is independent of the canonical NRF2 pathway.
format Online
Article
Text
id pubmed-10498434
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Elsevier
record_format MEDLINE/PubMed
spelling pubmed-104984342023-09-14 Disruption of the Keap1-mTORC2 axis by cancer-derived Keap1/mLST8 mutations leads to oncogenic mTORC2-AKT activation Chen, Yingji Jiao, Dongyue He, Huiying Sun, Huiru Liu, Yajuan Shi, Qing Zhang, Pingzhao Li, Yao Mo, Ren Gao, Kun Wang, Chenji Redox Biol Research Paper The mechanistic target of the rapamycin (mTOR) pathway, which participates in the regulation of cellular growth and metabolism, is aberrantly regulated in various cancer types. The mTOR complex 2 (mTORC2), which consists of the core components mTOR, Rictor, mSin1, and mLST8, primarily responds to growth signals. However, the coordination between mTORC2 assembly and activity remains poorly understood. Keap1, a major sensor of oxidative stress in cells, functions as a substrate adaptor for Cullin 3-RING E3 ubiquitin ligase (CRL3) to promote proteasomal degradation of NF-E2-related factor 2 (NRF2), which is a transcription factor that protects cells against oxidative and electrophilic stress. In the present study, we demonstrate that Keap1 binds to mLST8 via a conserved ETGE motif. The CRL3(Keap1) ubiquitin ligase complex promotes non-degradative ubiquitination of mLST8, thus reducing mTORC2 complex integrity and mTORC2-AKT activation. However, this effect can be prevented by oxidative/electrophilic stresses and growth factor signaling-induced reactive oxygen species (ROS) burst. Cancer-derived Keap1 or mLST8 mutations disrupt the Keap1-mLST8 interaction and allow mLST8 to evade Keap1-mediated ubiquitination, thereby enhancing mTORC2-AKT activation and promoting cell malignancy and remodeling cell metabolism. Our findings provide new insights into the molecular mechanisms of Keap1/mLST8 mutation-driven tumorigenesis by promoting mTORC2-AKT activation, which is independent of the canonical NRF2 pathway. Elsevier 2023-09-05 /pmc/articles/PMC10498434/ /pubmed/37688978 http://dx.doi.org/10.1016/j.redox.2023.102872 Text en © 2023 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Paper
Chen, Yingji
Jiao, Dongyue
He, Huiying
Sun, Huiru
Liu, Yajuan
Shi, Qing
Zhang, Pingzhao
Li, Yao
Mo, Ren
Gao, Kun
Wang, Chenji
Disruption of the Keap1-mTORC2 axis by cancer-derived Keap1/mLST8 mutations leads to oncogenic mTORC2-AKT activation
title Disruption of the Keap1-mTORC2 axis by cancer-derived Keap1/mLST8 mutations leads to oncogenic mTORC2-AKT activation
title_full Disruption of the Keap1-mTORC2 axis by cancer-derived Keap1/mLST8 mutations leads to oncogenic mTORC2-AKT activation
title_fullStr Disruption of the Keap1-mTORC2 axis by cancer-derived Keap1/mLST8 mutations leads to oncogenic mTORC2-AKT activation
title_full_unstemmed Disruption of the Keap1-mTORC2 axis by cancer-derived Keap1/mLST8 mutations leads to oncogenic mTORC2-AKT activation
title_short Disruption of the Keap1-mTORC2 axis by cancer-derived Keap1/mLST8 mutations leads to oncogenic mTORC2-AKT activation
title_sort disruption of the keap1-mtorc2 axis by cancer-derived keap1/mlst8 mutations leads to oncogenic mtorc2-akt activation
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10498434/
https://www.ncbi.nlm.nih.gov/pubmed/37688978
http://dx.doi.org/10.1016/j.redox.2023.102872
work_keys_str_mv AT chenyingji disruptionofthekeap1mtorc2axisbycancerderivedkeap1mlst8mutationsleadstooncogenicmtorc2aktactivation
AT jiaodongyue disruptionofthekeap1mtorc2axisbycancerderivedkeap1mlst8mutationsleadstooncogenicmtorc2aktactivation
AT hehuiying disruptionofthekeap1mtorc2axisbycancerderivedkeap1mlst8mutationsleadstooncogenicmtorc2aktactivation
AT sunhuiru disruptionofthekeap1mtorc2axisbycancerderivedkeap1mlst8mutationsleadstooncogenicmtorc2aktactivation
AT liuyajuan disruptionofthekeap1mtorc2axisbycancerderivedkeap1mlst8mutationsleadstooncogenicmtorc2aktactivation
AT shiqing disruptionofthekeap1mtorc2axisbycancerderivedkeap1mlst8mutationsleadstooncogenicmtorc2aktactivation
AT zhangpingzhao disruptionofthekeap1mtorc2axisbycancerderivedkeap1mlst8mutationsleadstooncogenicmtorc2aktactivation
AT liyao disruptionofthekeap1mtorc2axisbycancerderivedkeap1mlst8mutationsleadstooncogenicmtorc2aktactivation
AT moren disruptionofthekeap1mtorc2axisbycancerderivedkeap1mlst8mutationsleadstooncogenicmtorc2aktactivation
AT gaokun disruptionofthekeap1mtorc2axisbycancerderivedkeap1mlst8mutationsleadstooncogenicmtorc2aktactivation
AT wangchenji disruptionofthekeap1mtorc2axisbycancerderivedkeap1mlst8mutationsleadstooncogenicmtorc2aktactivation