p38γ promotes breast cancer cell motility and metastasis through regulation of RhoC GTPase, cytoskeletal architecture, and a novel leading edge behavior

Autores
Rosenthal, Devin T.; Iyer, Harish; Escudero, Silvia; Bao, Liwei; Wu, Zhifen; Ventura, Alejandra; Kleer, Celina G.; Arruda, Ellen M.; Garikipati, Krishna; Merajver, Sofia D.
Año de publicación
2011
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Understanding the molecular alterations that confer cancer cells with motile, metastatic properties is needed to improve patient survival. Here, we report that p38γ motogen-activated protein kinase regulates breast cancer cell motility and metastasis, in part, by controlling expression of the metastasis-associated small GTPase RhoC. This p38γ-RhoC regulatory connection was mediated by a novel mechanism of modulating RhoC ubiquitination. This relationship persisted across multiple cell lines and in clinical breast cancer specimens. Using a computational mechanical model based on the finite element method, we showed that p38γ-mediated cytoskeletal changes are sufficient to control cell motility. This model predicted novel dynamics of leading edge actin protrusions, which were experimentally verified and established to be closely related to cell shape and cytoskeletal morphology. Clinical relevance was supported by evidence that elevated expression of p38γ is associated with lower overall survival of patients with breast cancer. Taken together, our results offer a detailed characterization of how p38γ contributes to breast cancer progression. Herein we present a new mechanics-based analysis of cell motility, and report on the discovery of a leading edge behavior in motile cells to accommodate modified cytoskeletal architecture. In summary, these findings not only identify a novel mechanism for regulating RhoC expression but also advance p38γ as a candidate therapeutic target.
Fil: Rosenthal, Devin T.. University of Michigan; Estados Unidos
Fil: Iyer, Harish. University of Michigan; Estados Unidos
Fil: Escudero, Silvia. Harvard Medical School; Estados Unidos
Fil: Bao, Liwei. University of Michigan; Estados Unidos
Fil: Wu, Zhifen. University of Michigan; Estados Unidos
Fil: Ventura, Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular. Laboratorio de Fisiología y Biología Molecular; Argentina
Fil: Kleer, Celina G.. University of Michigan; Estados Unidos
Fil: Arruda, Ellen M.. University of Michigan; Estados Unidos
Fil: Garikipati, Krishna. University of Michigan; Estados Unidos
Fil: Merajver, Sofia D.. University of Michigan; Estados Unidos
Materia
MATHEMATICAL ONCOLOGY
CELL MOTILITY
METASTASIS
CYTOSKELETAL ARCHITECTURE
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/88181
Acceder
id CONICETDig_2e4c61176f261ab333f46e90ce0978d0
oai_identifier_str oai:ri.conicet.gov.ar:11336/88181
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling p38γ promotes breast cancer cell motility and metastasis through regulation of RhoC GTPase, cytoskeletal architecture, and a novel leading edge behaviorRosenthal, Devin T.Iyer, HarishEscudero, SilviaBao, LiweiWu, ZhifenVentura, AlejandraKleer, Celina G.Arruda, Ellen M.Garikipati, KrishnaMerajver, Sofia D.MATHEMATICAL ONCOLOGYCELL MOTILITYMETASTASISCYTOSKELETAL ARCHITECTUREhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Understanding the molecular alterations that confer cancer cells with motile, metastatic properties is needed to improve patient survival. Here, we report that p38γ motogen-activated protein kinase regulates breast cancer cell motility and metastasis, in part, by controlling expression of the metastasis-associated small GTPase RhoC. This p38γ-RhoC regulatory connection was mediated by a novel mechanism of modulating RhoC ubiquitination. This relationship persisted across multiple cell lines and in clinical breast cancer specimens. Using a computational mechanical model based on the finite element method, we showed that p38γ-mediated cytoskeletal changes are sufficient to control cell motility. This model predicted novel dynamics of leading edge actin protrusions, which were experimentally verified and established to be closely related to cell shape and cytoskeletal morphology. Clinical relevance was supported by evidence that elevated expression of p38γ is associated with lower overall survival of patients with breast cancer. Taken together, our results offer a detailed characterization of how p38γ contributes to breast cancer progression. Herein we present a new mechanics-based analysis of cell motility, and report on the discovery of a leading edge behavior in motile cells to accommodate modified cytoskeletal architecture. In summary, these findings not only identify a novel mechanism for regulating RhoC expression but also advance p38γ as a candidate therapeutic target.Fil: Rosenthal, Devin T.. University of Michigan; Estados UnidosFil: Iyer, Harish. University of Michigan; Estados UnidosFil: Escudero, Silvia. Harvard Medical School; Estados UnidosFil: Bao, Liwei. University of Michigan; Estados UnidosFil: Wu, Zhifen. University of Michigan; Estados UnidosFil: Ventura, Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular. Laboratorio de Fisiología y Biología Molecular; ArgentinaFil: Kleer, Celina G.. University of Michigan; Estados UnidosFil: Arruda, Ellen M.. University of Michigan; Estados UnidosFil: Garikipati, Krishna. University of Michigan; Estados UnidosFil: Merajver, Sofia D.. University of Michigan; Estados UnidosAmerican Association for Cancer Research2011-10info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/88181Rosenthal, Devin T.; Iyer, Harish; Escudero, Silvia; Bao, Liwei; Wu, Zhifen; et al.; p38γ promotes breast cancer cell motility and metastasis through regulation of RhoC GTPase, cytoskeletal architecture, and a novel leading edge behavior; American Association for Cancer Research; Cancer Research; 71; 20; 10-2011; 6338-63490008-5472CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1158/0008-5472.CAN-11-1291info:eu-repo/semantics/altIdentifier/url/https://cancerres.aacrjournals.org/content/71/20/6338info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-10T13:06:38Zoai:ri.conicet.gov.ar:11336/88181instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-10 13:06:38.517CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv p38γ promotes breast cancer cell motility and metastasis through regulation of RhoC GTPase, cytoskeletal architecture, and a novel leading edge behavior
title p38γ promotes breast cancer cell motility and metastasis through regulation of RhoC GTPase, cytoskeletal architecture, and a novel leading edge behavior
spellingShingle p38γ promotes breast cancer cell motility and metastasis through regulation of RhoC GTPase, cytoskeletal architecture, and a novel leading edge behavior
Rosenthal, Devin T.
MATHEMATICAL ONCOLOGY
CELL MOTILITY
METASTASIS
CYTOSKELETAL ARCHITECTURE
title_short p38γ promotes breast cancer cell motility and metastasis through regulation of RhoC GTPase, cytoskeletal architecture, and a novel leading edge behavior
title_full p38γ promotes breast cancer cell motility and metastasis through regulation of RhoC GTPase, cytoskeletal architecture, and a novel leading edge behavior
title_fullStr p38γ promotes breast cancer cell motility and metastasis through regulation of RhoC GTPase, cytoskeletal architecture, and a novel leading edge behavior
title_full_unstemmed p38γ promotes breast cancer cell motility and metastasis through regulation of RhoC GTPase, cytoskeletal architecture, and a novel leading edge behavior
title_sort p38γ promotes breast cancer cell motility and metastasis through regulation of RhoC GTPase, cytoskeletal architecture, and a novel leading edge behavior
dc.creator.none.fl_str_mv Rosenthal, Devin T.
Iyer, Harish
Escudero, Silvia
Bao, Liwei
Wu, Zhifen
Ventura, Alejandra
Kleer, Celina G.
Arruda, Ellen M.
Garikipati, Krishna
Merajver, Sofia D.
author Rosenthal, Devin T.
author_facet Rosenthal, Devin T.
Iyer, Harish
Escudero, Silvia
Bao, Liwei
Wu, Zhifen
Ventura, Alejandra
Kleer, Celina G.
Arruda, Ellen M.
Garikipati, Krishna
Merajver, Sofia D.
author_role author
author2 Iyer, Harish
Escudero, Silvia
Bao, Liwei
Wu, Zhifen
Ventura, Alejandra
Kleer, Celina G.
Arruda, Ellen M.
Garikipati, Krishna
Merajver, Sofia D.
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv MATHEMATICAL ONCOLOGY
CELL MOTILITY
METASTASIS
CYTOSKELETAL ARCHITECTURE
topic MATHEMATICAL ONCOLOGY
CELL MOTILITY
METASTASIS
CYTOSKELETAL ARCHITECTURE
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Understanding the molecular alterations that confer cancer cells with motile, metastatic properties is needed to improve patient survival. Here, we report that p38γ motogen-activated protein kinase regulates breast cancer cell motility and metastasis, in part, by controlling expression of the metastasis-associated small GTPase RhoC. This p38γ-RhoC regulatory connection was mediated by a novel mechanism of modulating RhoC ubiquitination. This relationship persisted across multiple cell lines and in clinical breast cancer specimens. Using a computational mechanical model based on the finite element method, we showed that p38γ-mediated cytoskeletal changes are sufficient to control cell motility. This model predicted novel dynamics of leading edge actin protrusions, which were experimentally verified and established to be closely related to cell shape and cytoskeletal morphology. Clinical relevance was supported by evidence that elevated expression of p38γ is associated with lower overall survival of patients with breast cancer. Taken together, our results offer a detailed characterization of how p38γ contributes to breast cancer progression. Herein we present a new mechanics-based analysis of cell motility, and report on the discovery of a leading edge behavior in motile cells to accommodate modified cytoskeletal architecture. In summary, these findings not only identify a novel mechanism for regulating RhoC expression but also advance p38γ as a candidate therapeutic target.
Fil: Rosenthal, Devin T.. University of Michigan; Estados Unidos
Fil: Iyer, Harish. University of Michigan; Estados Unidos
Fil: Escudero, Silvia. Harvard Medical School; Estados Unidos
Fil: Bao, Liwei. University of Michigan; Estados Unidos
Fil: Wu, Zhifen. University of Michigan; Estados Unidos
Fil: Ventura, Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular. Laboratorio de Fisiología y Biología Molecular; Argentina
Fil: Kleer, Celina G.. University of Michigan; Estados Unidos
Fil: Arruda, Ellen M.. University of Michigan; Estados Unidos
Fil: Garikipati, Krishna. University of Michigan; Estados Unidos
Fil: Merajver, Sofia D.. University of Michigan; Estados Unidos
description Understanding the molecular alterations that confer cancer cells with motile, metastatic properties is needed to improve patient survival. Here, we report that p38γ motogen-activated protein kinase regulates breast cancer cell motility and metastasis, in part, by controlling expression of the metastasis-associated small GTPase RhoC. This p38γ-RhoC regulatory connection was mediated by a novel mechanism of modulating RhoC ubiquitination. This relationship persisted across multiple cell lines and in clinical breast cancer specimens. Using a computational mechanical model based on the finite element method, we showed that p38γ-mediated cytoskeletal changes are sufficient to control cell motility. This model predicted novel dynamics of leading edge actin protrusions, which were experimentally verified and established to be closely related to cell shape and cytoskeletal morphology. Clinical relevance was supported by evidence that elevated expression of p38γ is associated with lower overall survival of patients with breast cancer. Taken together, our results offer a detailed characterization of how p38γ contributes to breast cancer progression. Herein we present a new mechanics-based analysis of cell motility, and report on the discovery of a leading edge behavior in motile cells to accommodate modified cytoskeletal architecture. In summary, these findings not only identify a novel mechanism for regulating RhoC expression but also advance p38γ as a candidate therapeutic target.
publishDate 2011
dc.date.none.fl_str_mv 2011-10
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/88181
Rosenthal, Devin T.; Iyer, Harish; Escudero, Silvia; Bao, Liwei; Wu, Zhifen; et al.; p38γ promotes breast cancer cell motility and metastasis through regulation of RhoC GTPase, cytoskeletal architecture, and a novel leading edge behavior; American Association for Cancer Research; Cancer Research; 71; 20; 10-2011; 6338-6349
0008-5472
CONICET Digital
CONICET
url http://hdl.handle.net/11336/88181
identifier_str_mv Rosenthal, Devin T.; Iyer, Harish; Escudero, Silvia; Bao, Liwei; Wu, Zhifen; et al.; p38γ promotes breast cancer cell motility and metastasis through regulation of RhoC GTPase, cytoskeletal architecture, and a novel leading edge behavior; American Association for Cancer Research; Cancer Research; 71; 20; 10-2011; 6338-6349
0008-5472
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1158/0008-5472.CAN-11-1291
info:eu-repo/semantics/altIdentifier/url/https://cancerres.aacrjournals.org/content/71/20/6338
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Association for Cancer Research
publisher.none.fl_str_mv American Association for Cancer Research
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 12.993085

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