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ERK1/2 inhibitors act as monovalent degraders inducing ubiquitylation and proteasome-dependent turnover of ERK2, but not ERK1

Innate or acquired resistance to small molecule BRAF or MEK1/2 inhibitors (BRAFi or MEKi) typically arises through mechanisms that sustain or reinstate ERK1/2 activation. This has led to the development of a range of ERK1/2 inhibitors (ERKi) that either inhibit kinase catalytic activity (catERKi) or...

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Autores principales: Balmanno, Kathryn, Kidger, Andrew M., Byrne, Dominic P., Sale, Matthew J., Nassman, Nejma, Eyers, Patrick A., Cook, Simon J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Portland Press Ltd. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10212521/
https://www.ncbi.nlm.nih.gov/pubmed/37018014
http://dx.doi.org/10.1042/BCJ20220598
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author Balmanno, Kathryn
Kidger, Andrew M.
Byrne, Dominic P.
Sale, Matthew J.
Nassman, Nejma
Eyers, Patrick A.
Cook, Simon J.
author_facet Balmanno, Kathryn
Kidger, Andrew M.
Byrne, Dominic P.
Sale, Matthew J.
Nassman, Nejma
Eyers, Patrick A.
Cook, Simon J.
author_sort Balmanno, Kathryn
collection PubMed
description Innate or acquired resistance to small molecule BRAF or MEK1/2 inhibitors (BRAFi or MEKi) typically arises through mechanisms that sustain or reinstate ERK1/2 activation. This has led to the development of a range of ERK1/2 inhibitors (ERKi) that either inhibit kinase catalytic activity (catERKi) or additionally prevent the activating pT-E-pY dual phosphorylation of ERK1/2 by MEK1/2 (dual-mechanism or dmERKi). Here, we show that eight different ERKi (both catERKi or dmERKi) drive the turnover of ERK2, the most abundant ERK isoform, with little or no effect on ERK1. Thermal stability assays show that ERKi do not destabilise ERK2 (or ERK1) in vitro, suggesting that ERK2 turnover is a cellular consequence of ERKi binding. ERK2 turnover is not observed upon treatment with MEKi alone, suggesting it is ERKi binding to ERK2 that drives ERK2 turnover. However, MEKi pre-treatment, which blocks ERK2 pT-E-pY phosphorylation and dissociation from MEK1/2, prevents ERK2 turnover. ERKi treatment of cells drives the poly-ubiquitylation and proteasome-dependent turnover of ERK2 and pharmacological or genetic inhibition of Cullin-RING E3 ligases prevents this. Our results suggest that ERKi, including current clinical candidates, act as ‘kinase degraders’, driving the proteasome-dependent turnover of their major target, ERK2. This may be relevant to the suggestion of kinase-independent effects of ERK1/2 and the therapeutic use of ERKi.
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spelling pubmed-102125212023-05-26 ERK1/2 inhibitors act as monovalent degraders inducing ubiquitylation and proteasome-dependent turnover of ERK2, but not ERK1 Balmanno, Kathryn Kidger, Andrew M. Byrne, Dominic P. Sale, Matthew J. Nassman, Nejma Eyers, Patrick A. Cook, Simon J. Biochem J Cancer Innate or acquired resistance to small molecule BRAF or MEK1/2 inhibitors (BRAFi or MEKi) typically arises through mechanisms that sustain or reinstate ERK1/2 activation. This has led to the development of a range of ERK1/2 inhibitors (ERKi) that either inhibit kinase catalytic activity (catERKi) or additionally prevent the activating pT-E-pY dual phosphorylation of ERK1/2 by MEK1/2 (dual-mechanism or dmERKi). Here, we show that eight different ERKi (both catERKi or dmERKi) drive the turnover of ERK2, the most abundant ERK isoform, with little or no effect on ERK1. Thermal stability assays show that ERKi do not destabilise ERK2 (or ERK1) in vitro, suggesting that ERK2 turnover is a cellular consequence of ERKi binding. ERK2 turnover is not observed upon treatment with MEKi alone, suggesting it is ERKi binding to ERK2 that drives ERK2 turnover. However, MEKi pre-treatment, which blocks ERK2 pT-E-pY phosphorylation and dissociation from MEK1/2, prevents ERK2 turnover. ERKi treatment of cells drives the poly-ubiquitylation and proteasome-dependent turnover of ERK2 and pharmacological or genetic inhibition of Cullin-RING E3 ligases prevents this. Our results suggest that ERKi, including current clinical candidates, act as ‘kinase degraders’, driving the proteasome-dependent turnover of their major target, ERK2. This may be relevant to the suggestion of kinase-independent effects of ERK1/2 and the therapeutic use of ERKi. Portland Press Ltd. 2023-05-04 /pmc/articles/PMC10212521/ /pubmed/37018014 http://dx.doi.org/10.1042/BCJ20220598 Text en © 2023 The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Cancer
Balmanno, Kathryn
Kidger, Andrew M.
Byrne, Dominic P.
Sale, Matthew J.
Nassman, Nejma
Eyers, Patrick A.
Cook, Simon J.
ERK1/2 inhibitors act as monovalent degraders inducing ubiquitylation and proteasome-dependent turnover of ERK2, but not ERK1
title ERK1/2 inhibitors act as monovalent degraders inducing ubiquitylation and proteasome-dependent turnover of ERK2, but not ERK1
title_full ERK1/2 inhibitors act as monovalent degraders inducing ubiquitylation and proteasome-dependent turnover of ERK2, but not ERK1
title_fullStr ERK1/2 inhibitors act as monovalent degraders inducing ubiquitylation and proteasome-dependent turnover of ERK2, but not ERK1
title_full_unstemmed ERK1/2 inhibitors act as monovalent degraders inducing ubiquitylation and proteasome-dependent turnover of ERK2, but not ERK1
title_short ERK1/2 inhibitors act as monovalent degraders inducing ubiquitylation and proteasome-dependent turnover of ERK2, but not ERK1
title_sort erk1/2 inhibitors act as monovalent degraders inducing ubiquitylation and proteasome-dependent turnover of erk2, but not erk1
topic Cancer
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10212521/
https://www.ncbi.nlm.nih.gov/pubmed/37018014
http://dx.doi.org/10.1042/BCJ20220598
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