ERK1/2 mitogen-activated protein kinase dimerization is essential for the regulation of cell motility

ERK1/2 mitogen-activated protein kinases (ERK) are key regulators of basic cellular processes, including proliferation, survival, and migration. Upon phosphorylation, ERK becomes activated and a portion of it dimerizes. The importance of ERK activation in specific cellular events is generally well d...

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Autores: De la Fuente Vivas, Dalia, Cappitelli, Vincenzo, García Gómez, Rocío, Valero Díaz, Sara, Amato, Camilla, Rodríguez, Javier, Duro-Sánchez, Santiago, Kriegsheim, Alexander von, Grusch, Michael, Lozano, José, Arribas, Joaquín, Casar Martínez, Berta, Crespo, Piero
Tipo de recurso: artículo
Fecha de publicación:2025
País:España
Institución:Universidad de Cantabria (UC)
Repositorio:UCrea Repositorio Abierto de la Universidad de Cantabria
Idioma:inglés
OAI Identifier:oai:repositorio.unican.es:10902/36664
Acceso en línea:https://hdl.handle.net/10902/36664
Access Level:acceso abierto
Palabra clave:Cell motility
ERK
KSR
MAP kinases
Scaffold proteins
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spelling ERK1/2 mitogen-activated protein kinase dimerization is essential for the regulation of cell motilityDe la Fuente Vivas, DaliaCappitelli, VincenzoGarcía Gómez, RocíoValero Díaz, SaraAmato, CamillaRodríguez, JavierDuro-Sánchez, SantiagoKriegsheim, Alexander vonGrusch, MichaelLozano, JoséArribas, JoaquínCasar Martínez, BertaCrespo, PieroCell motilityERKKSRMAP kinasesScaffold proteinsERK1/2 mitogen-activated protein kinases (ERK) are key regulators of basic cellular processes, including proliferation, survival, and migration. Upon phosphorylation, ERK becomes activated and a portion of it dimerizes. The importance of ERK activation in specific cellular events is generally well documented, but the role played by dimerization is largely unknown. Here, we demonstrate that impeding ERK dimerization precludes cellular movement by interfering with the molecular machinery that executes the rearrangements of the actin cytoskeleton. We also show that a constitutively dimeric ERK mutant can drive cell motility per se, demonstrating that ERK dimerization is both necessary and sufficient for inducing cellular migration. Importantly, we unveil that the scaffold protein kinase suppressor of Ras 1 (KSR1) is a critical element for endowing external agonists, acting through tyrosine kinase receptors, with the capacity to induce ERK dimerization and, subsequently, to unleash cellular motion. In agreement, clinical data disclose that high KSR1 expression levels correlate with greater metastatic potential and adverse evolution of mammary tumors. Overall, our results portray both ERK dimerization and KSR1 as essential factors for the regulation of cell motility and mammary tumor dissemination.We are indebted to Dr D. Engelberg for providing reagents. PC lab is supported by grant PID2021- 126288OB-I00 and PDC2022-133569-I00 from the Spanish Ministry of Science (MICIU/AEI/FEDER, UE); CIBERONC (CB16/12/00436) from the Instituto de Salud Carlos III (ISCIII); and a grant from ASPLA S.A “Encintalo en Rosa” Initiative. BC is funded by grants from Ministerio de Innovación, Ciencia y Universidades, MICIU PID2020/112760RB-100 and La Fundació d’Estudis i Recerca Oncológica (FERO, BFERO2021.03). JA is supported by CIBERONC; Breast Cancer Research Foundation (BCRF-23-008) and Instituto de Salud Carlos III (ISCIII) (PI22/ 00001). AK is supported by the Wellcome Trust (Multiuser Equipment Grant, 208402/Z/17/Z). DF-V is a CIBERONC predoctoral fellow (JCSTF2105526).John Wiley & SonsUniversidad de Cantabria20252025-01-01journal articlehttp://purl.org/coar/resource_type/c_6501NAhttp://purl.org/coar/version/c_be7fb7dd8ff6fe43info:eu-repo/semantics/articlehttps://hdl.handle.net/10902/36664Molecular Oncology, 2025, 19(2), 452-473reponame:UCrea Repositorio Abierto de la Universidad de Cantabriainstname:Universidad de Cantabria (UC)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repositorio.unican.es:10902/366642026-06-02T12:39:31Z
dc.title.none.fl_str_mv ERK1/2 mitogen-activated protein kinase dimerization is essential for the regulation of cell motility
title ERK1/2 mitogen-activated protein kinase dimerization is essential for the regulation of cell motility
spellingShingle ERK1/2 mitogen-activated protein kinase dimerization is essential for the regulation of cell motility
De la Fuente Vivas, Dalia
Cell motility
ERK
KSR
MAP kinases
Scaffold proteins
title_short ERK1/2 mitogen-activated protein kinase dimerization is essential for the regulation of cell motility
title_full ERK1/2 mitogen-activated protein kinase dimerization is essential for the regulation of cell motility
title_fullStr ERK1/2 mitogen-activated protein kinase dimerization is essential for the regulation of cell motility
title_full_unstemmed ERK1/2 mitogen-activated protein kinase dimerization is essential for the regulation of cell motility
title_sort ERK1/2 mitogen-activated protein kinase dimerization is essential for the regulation of cell motility
dc.creator.none.fl_str_mv De la Fuente Vivas, Dalia
Cappitelli, Vincenzo
García Gómez, Rocío
Valero Díaz, Sara
Amato, Camilla
Rodríguez, Javier
Duro-Sánchez, Santiago
Kriegsheim, Alexander von
Grusch, Michael
Lozano, José
Arribas, Joaquín
Casar Martínez, Berta
Crespo, Piero
author De la Fuente Vivas, Dalia
author_facet De la Fuente Vivas, Dalia
Cappitelli, Vincenzo
García Gómez, Rocío
Valero Díaz, Sara
Amato, Camilla
Rodríguez, Javier
Duro-Sánchez, Santiago
Kriegsheim, Alexander von
Grusch, Michael
Lozano, José
Arribas, Joaquín
Casar Martínez, Berta
Crespo, Piero
author_role author
author2 Cappitelli, Vincenzo
García Gómez, Rocío
Valero Díaz, Sara
Amato, Camilla
Rodríguez, Javier
Duro-Sánchez, Santiago
Kriegsheim, Alexander von
Grusch, Michael
Lozano, José
Arribas, Joaquín
Casar Martínez, Berta
Crespo, Piero
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universidad de Cantabria
dc.subject.none.fl_str_mv Cell motility
ERK
KSR
MAP kinases
Scaffold proteins
topic Cell motility
ERK
KSR
MAP kinases
Scaffold proteins
description ERK1/2 mitogen-activated protein kinases (ERK) are key regulators of basic cellular processes, including proliferation, survival, and migration. Upon phosphorylation, ERK becomes activated and a portion of it dimerizes. The importance of ERK activation in specific cellular events is generally well documented, but the role played by dimerization is largely unknown. Here, we demonstrate that impeding ERK dimerization precludes cellular movement by interfering with the molecular machinery that executes the rearrangements of the actin cytoskeleton. We also show that a constitutively dimeric ERK mutant can drive cell motility per se, demonstrating that ERK dimerization is both necessary and sufficient for inducing cellular migration. Importantly, we unveil that the scaffold protein kinase suppressor of Ras 1 (KSR1) is a critical element for endowing external agonists, acting through tyrosine kinase receptors, with the capacity to induce ERK dimerization and, subsequently, to unleash cellular motion. In agreement, clinical data disclose that high KSR1 expression levels correlate with greater metastatic potential and adverse evolution of mammary tumors. Overall, our results portray both ERK dimerization and KSR1 as essential factors for the regulation of cell motility and mammary tumor dissemination.
publishDate 2025
dc.date.none.fl_str_mv 2025
2025-01-01
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
NA
http://purl.org/coar/version/c_be7fb7dd8ff6fe43
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/10902/36664
url https://hdl.handle.net/10902/36664
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv John Wiley & Sons
publisher.none.fl_str_mv John Wiley & Sons
dc.source.none.fl_str_mv Molecular Oncology, 2025, 19(2), 452-473
reponame:UCrea Repositorio Abierto de la Universidad de Cantabria
instname:Universidad de Cantabria (UC)
instname_str Universidad de Cantabria (UC)
reponame_str UCrea Repositorio Abierto de la Universidad de Cantabria
collection UCrea Repositorio Abierto de la Universidad de Cantabria
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.811543

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