The E3 ubiquitin ligase HERC1 controls the ERK signaling pathway targeting C-RAF for degradation

The RAF/MEK/ERK cascade is a conserved intracellular signaling pathway that controls fundamental cellular processes including growth, proliferation, differentiation, survival and migration. Aberrant regulation of this signaling pathway has long been associated with human cancers. A major point of re...

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Autores: Schneider, Taiane, Martinez-Martinez, Arturo, Cubillos Rojas, Mónica, Bartrons Bach, Ramon, Ventura Pujol, Francesc, Rosa López, José Luis
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2018
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/125949
Acceso en línea:https://hdl.handle.net/2445/125949
Access Level:acceso abierto
Palabra clave:Ubiqüitina
Proteïnes de membrana
Transducció de senyal cel·lular
Regulació cel·lular
Ubiquitin
Membrane proteins
Cellular signal transduction
Cellular control mechanisms
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spelling The E3 ubiquitin ligase HERC1 controls the ERK signaling pathway targeting C-RAF for degradationSchneider, TaianeMartinez-Martinez, ArturoCubillos Rojas, MónicaBartrons Bach, RamonVentura Pujol, FrancescRosa López, José LuisUbiqüitinaProteïnes de membranaTransducció de senyal cel·lularRegulació cel·lularUbiquitinMembrane proteinsCellular signal transductionCellular control mechanismsThe RAF/MEK/ERK cascade is a conserved intracellular signaling pathway that controls fundamental cellular processes including growth, proliferation, differentiation, survival and migration. Aberrant regulation of this signaling pathway has long been associated with human cancers. A major point of regulation of this pathway occurs at the level of the serine/threonine protein kinase C-RAF. Here, we show how the E3 ubiquitin ligase HERC1 regulates ERK signaling. HERC1 knockdown induced cellular proliferation, which is associated with an increase in ERK phosphorylation and in C-RAF protein levels. We demonstrate that overexpression of wild-type C-RAF is sufficient to increase ERK phosphorylation. Experiments with pharmacological inhibitors of RAF activity, or with interference RNA, show that the regulation of ERK phosphorylation by HERC1 is RAF-dependent. Immunoprecipitation, pull-down and confocal fluorescence microscopy experiments demonstrate an interaction between HERC1 and C-RAF proteins. Mechanistically, HERC1 controls C-RAF stability by regulating its polyubiquitylation in a lysine 48-linked chain. In vitro ubiquitylation assays indicate that C-RAF is a substrate of the E3 ubiquitin ligase HERC1. Altogether, we show how HERC1 can regulate cell proliferation through the activation of ERK signaling by a mechanism that affects C-RAF's stability.Impact Journals2018201820182018info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion18 p.application/pdfhttps://hdl.handle.net/2445/125949Articles publicats en revistes (Ciències Fisiològiques)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.18632/oncotarget.25847Oncotarget, 2018, vol. 9, num. 59, p. 31531-31548https://doi.org/10.18632/oncotarget.25847cc-by (c) Schneider, Taiane et al., 2018http://creativecommons.org/licenses/by/3.0/esinfo:eu-repo/semantics/openAccessoai:recercat.cat:2445/1259492026-05-29T05:05:01Z
dc.title.none.fl_str_mv The E3 ubiquitin ligase HERC1 controls the ERK signaling pathway targeting C-RAF for degradation
title The E3 ubiquitin ligase HERC1 controls the ERK signaling pathway targeting C-RAF for degradation
spellingShingle The E3 ubiquitin ligase HERC1 controls the ERK signaling pathway targeting C-RAF for degradation
Schneider, Taiane
Ubiqüitina
Proteïnes de membrana
Transducció de senyal cel·lular
Regulació cel·lular
Ubiquitin
Membrane proteins
Cellular signal transduction
Cellular control mechanisms
title_short The E3 ubiquitin ligase HERC1 controls the ERK signaling pathway targeting C-RAF for degradation
title_full The E3 ubiquitin ligase HERC1 controls the ERK signaling pathway targeting C-RAF for degradation
title_fullStr The E3 ubiquitin ligase HERC1 controls the ERK signaling pathway targeting C-RAF for degradation
title_full_unstemmed The E3 ubiquitin ligase HERC1 controls the ERK signaling pathway targeting C-RAF for degradation
title_sort The E3 ubiquitin ligase HERC1 controls the ERK signaling pathway targeting C-RAF for degradation
dc.creator.none.fl_str_mv Schneider, Taiane
Martinez-Martinez, Arturo
Cubillos Rojas, Mónica
Bartrons Bach, Ramon
Ventura Pujol, Francesc
Rosa López, José Luis
author Schneider, Taiane
author_facet Schneider, Taiane
Martinez-Martinez, Arturo
Cubillos Rojas, Mónica
Bartrons Bach, Ramon
Ventura Pujol, Francesc
Rosa López, José Luis
author_role author
author2 Martinez-Martinez, Arturo
Cubillos Rojas, Mónica
Bartrons Bach, Ramon
Ventura Pujol, Francesc
Rosa López, José Luis
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv Ubiqüitina
Proteïnes de membrana
Transducció de senyal cel·lular
Regulació cel·lular
Ubiquitin
Membrane proteins
Cellular signal transduction
Cellular control mechanisms
topic Ubiqüitina
Proteïnes de membrana
Transducció de senyal cel·lular
Regulació cel·lular
Ubiquitin
Membrane proteins
Cellular signal transduction
Cellular control mechanisms
description The RAF/MEK/ERK cascade is a conserved intracellular signaling pathway that controls fundamental cellular processes including growth, proliferation, differentiation, survival and migration. Aberrant regulation of this signaling pathway has long been associated with human cancers. A major point of regulation of this pathway occurs at the level of the serine/threonine protein kinase C-RAF. Here, we show how the E3 ubiquitin ligase HERC1 regulates ERK signaling. HERC1 knockdown induced cellular proliferation, which is associated with an increase in ERK phosphorylation and in C-RAF protein levels. We demonstrate that overexpression of wild-type C-RAF is sufficient to increase ERK phosphorylation. Experiments with pharmacological inhibitors of RAF activity, or with interference RNA, show that the regulation of ERK phosphorylation by HERC1 is RAF-dependent. Immunoprecipitation, pull-down and confocal fluorescence microscopy experiments demonstrate an interaction between HERC1 and C-RAF proteins. Mechanistically, HERC1 controls C-RAF stability by regulating its polyubiquitylation in a lysine 48-linked chain. In vitro ubiquitylation assays indicate that C-RAF is a substrate of the E3 ubiquitin ligase HERC1. Altogether, we show how HERC1 can regulate cell proliferation through the activation of ERK signaling by a mechanism that affects C-RAF's stability.
publishDate 2018
dc.date.none.fl_str_mv 2018
2018
2018
2018
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/125949
url https://hdl.handle.net/2445/125949
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.18632/oncotarget.25847
Oncotarget, 2018, vol. 9, num. 59, p. 31531-31548
https://doi.org/10.18632/oncotarget.25847
dc.rights.none.fl_str_mv cc-by (c) Schneider, Taiane et al., 2018
http://creativecommons.org/licenses/by/3.0/es
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Schneider, Taiane et al., 2018
http://creativecommons.org/licenses/by/3.0/es
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 18 p.
application/pdf
dc.publisher.none.fl_str_mv Impact Journals
publisher.none.fl_str_mv Impact Journals
dc.source.none.fl_str_mv Articles publicats en revistes (Ciències Fisiològiques)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.81155

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