A Paradoxical Tumor-Suppressor Role for the Rac1 Exchange Factor Vav1 in T Cell Acute Lymphoblastic Leukemia

Autores
Robles Valero, Javier; Lorenzo Martín, L. Francisco; Menacho Márquez, Mauricio Ariel; Fernández Pisonero, Isabel; Abad, Antonio; Camós, Mireia; Toribio, María Luisa; Espinosa, Lluis; Bigas, Anna; Bustelo, Xosé R.
Año de publicación
2017
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Rho guanine exchange factors (GEFs), the enzymes that stimulate Rho GTPases, are deemed as potential therapeutic targets owing to their protumorigenic functions. However, the understanding of the spectrum of their pathobiological roles in tumors is still very limited. We report here that the GEF Vav1 unexpectedly possesses tumor-suppressor functions in immature T cells. This function entails the noncatalytic nucleation of complexes between the ubiquitin ligase Cbl-b and the intracellular domain of Notch1 (ICN1) that favors ICN1 ubiquitinylation and degradation. Ablation of Vav1 promotes ICN1 signaling and the development of T cell acute lymphoblastic leukemia (T-ALL). The downregulation of Vav1 is essential for the pathogenesis of human T-ALL of the TLX+ clinical subtype, further underscoring the suppressor role of this pathway. Robles-Valero et al. find that Vav1 facilitates binding of Cbl-b to the intracellular domain of Notch1 (ICN1) and promotes ICN1 degradation. Loss of Vav1 induces T cell acute lymphoblastic leukemia (T-ALL) by increasing ICN1 signaling, and TLX inhibits Vav1 expression to stimulate ICN1 signaling in TLX+ T-ALL.
Fil: Robles Valero, Javier. Universidad de Salamanca; España. Consejo Superior de Investigaciones Científicas; España
Fil: Lorenzo Martín, L. Francisco. Universidad de Salamanca; España
Fil: Menacho Márquez, Mauricio Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario. Universidad Nacional de Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario; Argentina. Universidad de Salamanca; España. Consejo Superior de Investigaciones Científicas; España
Fil: Fernández Pisonero, Isabel. Universidad de Salamanca; España. Consejo Superior de Investigaciones Científicas; España
Fil: Abad, Antonio. Universidad de Salamanca; España. Consejo Superior de Investigaciones Científicas; España
Fil: Camós, Mireia. Hospital Sant Joan de Déu; España
Fil: Toribio, María Luisa. Universidad Autónoma de Madrid; España. Consejo Superior de Investigaciones Científicas; España
Fil: Espinosa, Lluis. Universidad de Salamanca; España. Institut Hospital del Mar d’Investigacions Mèdiques; España
Fil: Bigas, Anna. Universidad de Salamanca; España. Institut Hospital del Mar d’Investigacions Mèdiques; España
Fil: Bustelo, Xosé R.. Universidad de Salamanca; España. Consejo Superior de Investigaciones Científicas; España
Materia
ANIMAL MODELS
CBL-B
GENE EXPRESSION PROFILING
LYMPHOMA
NOTCH1
RHO GTPASES
TLX
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/66588
Acceder
id CONICETDig_ff680e13317af1250b725382f479b1ca
oai_identifier_str oai:ri.conicet.gov.ar:11336/66588
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling A Paradoxical Tumor-Suppressor Role for the Rac1 Exchange Factor Vav1 in T Cell Acute Lymphoblastic LeukemiaRobles Valero, JavierLorenzo Martín, L. FranciscoMenacho Márquez, Mauricio ArielFernández Pisonero, IsabelAbad, AntonioCamós, MireiaToribio, María LuisaEspinosa, LluisBigas, AnnaBustelo, Xosé R.ANIMAL MODELSCBL-BGENE EXPRESSION PROFILINGLYMPHOMANOTCH1RHO GTPASESTLXhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Rho guanine exchange factors (GEFs), the enzymes that stimulate Rho GTPases, are deemed as potential therapeutic targets owing to their protumorigenic functions. However, the understanding of the spectrum of their pathobiological roles in tumors is still very limited. We report here that the GEF Vav1 unexpectedly possesses tumor-suppressor functions in immature T cells. This function entails the noncatalytic nucleation of complexes between the ubiquitin ligase Cbl-b and the intracellular domain of Notch1 (ICN1) that favors ICN1 ubiquitinylation and degradation. Ablation of Vav1 promotes ICN1 signaling and the development of T cell acute lymphoblastic leukemia (T-ALL). The downregulation of Vav1 is essential for the pathogenesis of human T-ALL of the TLX+ clinical subtype, further underscoring the suppressor role of this pathway. Robles-Valero et al. find that Vav1 facilitates binding of Cbl-b to the intracellular domain of Notch1 (ICN1) and promotes ICN1 degradation. Loss of Vav1 induces T cell acute lymphoblastic leukemia (T-ALL) by increasing ICN1 signaling, and TLX inhibits Vav1 expression to stimulate ICN1 signaling in TLX+ T-ALL.Fil: Robles Valero, Javier. Universidad de Salamanca; España. Consejo Superior de Investigaciones Científicas; EspañaFil: Lorenzo Martín, L. Francisco. Universidad de Salamanca; EspañaFil: Menacho Márquez, Mauricio Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario. Universidad Nacional de Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario; Argentina. Universidad de Salamanca; España. Consejo Superior de Investigaciones Científicas; EspañaFil: Fernández Pisonero, Isabel. Universidad de Salamanca; España. Consejo Superior de Investigaciones Científicas; EspañaFil: Abad, Antonio. Universidad de Salamanca; España. Consejo Superior de Investigaciones Científicas; EspañaFil: Camós, Mireia. Hospital Sant Joan de Déu; EspañaFil: Toribio, María Luisa. Universidad Autónoma de Madrid; España. Consejo Superior de Investigaciones Científicas; EspañaFil: Espinosa, Lluis. Universidad de Salamanca; España. Institut Hospital del Mar d’Investigacions Mèdiques; EspañaFil: Bigas, Anna. Universidad de Salamanca; España. Institut Hospital del Mar d’Investigacions Mèdiques; EspañaFil: Bustelo, Xosé R.. Universidad de Salamanca; España. Consejo Superior de Investigaciones Científicas; EspañaCell Press2017-11info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/66588Robles Valero, Javier; Lorenzo Martín, L. Francisco; Menacho Márquez, Mauricio Ariel; Fernández Pisonero, Isabel; Abad, Antonio; et al.; A Paradoxical Tumor-Suppressor Role for the Rac1 Exchange Factor Vav1 in T Cell Acute Lymphoblastic Leukemia; Cell Press; Cancer Cell; 32; 5; 11-2017; 608-623; e91535-6108CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.ccell.2017.10.004info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S1535610817304579info:eu-repo/semantics/altIdentifier/url/https://www.cell.com/cancer-cell/fulltext/S1535-6108(17)30457-9info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T12:00:36Zoai:ri.conicet.gov.ar:11336/66588instacron: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:34982025-10-22 12:00:36.414CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv A Paradoxical Tumor-Suppressor Role for the Rac1 Exchange Factor Vav1 in T Cell Acute Lymphoblastic Leukemia
title A Paradoxical Tumor-Suppressor Role for the Rac1 Exchange Factor Vav1 in T Cell Acute Lymphoblastic Leukemia
spellingShingle A Paradoxical Tumor-Suppressor Role for the Rac1 Exchange Factor Vav1 in T Cell Acute Lymphoblastic Leukemia
Robles Valero, Javier
ANIMAL MODELS
CBL-B
GENE EXPRESSION PROFILING
LYMPHOMA
NOTCH1
RHO GTPASES
TLX
title_short A Paradoxical Tumor-Suppressor Role for the Rac1 Exchange Factor Vav1 in T Cell Acute Lymphoblastic Leukemia
title_full A Paradoxical Tumor-Suppressor Role for the Rac1 Exchange Factor Vav1 in T Cell Acute Lymphoblastic Leukemia
title_fullStr A Paradoxical Tumor-Suppressor Role for the Rac1 Exchange Factor Vav1 in T Cell Acute Lymphoblastic Leukemia
title_full_unstemmed A Paradoxical Tumor-Suppressor Role for the Rac1 Exchange Factor Vav1 in T Cell Acute Lymphoblastic Leukemia
title_sort A Paradoxical Tumor-Suppressor Role for the Rac1 Exchange Factor Vav1 in T Cell Acute Lymphoblastic Leukemia
dc.creator.none.fl_str_mv Robles Valero, Javier
Lorenzo Martín, L. Francisco
Menacho Márquez, Mauricio Ariel
Fernández Pisonero, Isabel
Abad, Antonio
Camós, Mireia
Toribio, María Luisa
Espinosa, Lluis
Bigas, Anna
Bustelo, Xosé R.
author Robles Valero, Javier
author_facet Robles Valero, Javier
Lorenzo Martín, L. Francisco
Menacho Márquez, Mauricio Ariel
Fernández Pisonero, Isabel
Abad, Antonio
Camós, Mireia
Toribio, María Luisa
Espinosa, Lluis
Bigas, Anna
Bustelo, Xosé R.
author_role author
author2 Lorenzo Martín, L. Francisco
Menacho Márquez, Mauricio Ariel
Fernández Pisonero, Isabel
Abad, Antonio
Camós, Mireia
Toribio, María Luisa
Espinosa, Lluis
Bigas, Anna
Bustelo, Xosé R.
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv ANIMAL MODELS
CBL-B
GENE EXPRESSION PROFILING
LYMPHOMA
NOTCH1
RHO GTPASES
TLX
topic ANIMAL MODELS
CBL-B
GENE EXPRESSION PROFILING
LYMPHOMA
NOTCH1
RHO GTPASES
TLX
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Rho guanine exchange factors (GEFs), the enzymes that stimulate Rho GTPases, are deemed as potential therapeutic targets owing to their protumorigenic functions. However, the understanding of the spectrum of their pathobiological roles in tumors is still very limited. We report here that the GEF Vav1 unexpectedly possesses tumor-suppressor functions in immature T cells. This function entails the noncatalytic nucleation of complexes between the ubiquitin ligase Cbl-b and the intracellular domain of Notch1 (ICN1) that favors ICN1 ubiquitinylation and degradation. Ablation of Vav1 promotes ICN1 signaling and the development of T cell acute lymphoblastic leukemia (T-ALL). The downregulation of Vav1 is essential for the pathogenesis of human T-ALL of the TLX+ clinical subtype, further underscoring the suppressor role of this pathway. Robles-Valero et al. find that Vav1 facilitates binding of Cbl-b to the intracellular domain of Notch1 (ICN1) and promotes ICN1 degradation. Loss of Vav1 induces T cell acute lymphoblastic leukemia (T-ALL) by increasing ICN1 signaling, and TLX inhibits Vav1 expression to stimulate ICN1 signaling in TLX+ T-ALL.
Fil: Robles Valero, Javier. Universidad de Salamanca; España. Consejo Superior de Investigaciones Científicas; España
Fil: Lorenzo Martín, L. Francisco. Universidad de Salamanca; España
Fil: Menacho Márquez, Mauricio Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario. Universidad Nacional de Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario; Argentina. Universidad de Salamanca; España. Consejo Superior de Investigaciones Científicas; España
Fil: Fernández Pisonero, Isabel. Universidad de Salamanca; España. Consejo Superior de Investigaciones Científicas; España
Fil: Abad, Antonio. Universidad de Salamanca; España. Consejo Superior de Investigaciones Científicas; España
Fil: Camós, Mireia. Hospital Sant Joan de Déu; España
Fil: Toribio, María Luisa. Universidad Autónoma de Madrid; España. Consejo Superior de Investigaciones Científicas; España
Fil: Espinosa, Lluis. Universidad de Salamanca; España. Institut Hospital del Mar d’Investigacions Mèdiques; España
Fil: Bigas, Anna. Universidad de Salamanca; España. Institut Hospital del Mar d’Investigacions Mèdiques; España
Fil: Bustelo, Xosé R.. Universidad de Salamanca; España. Consejo Superior de Investigaciones Científicas; España
description Rho guanine exchange factors (GEFs), the enzymes that stimulate Rho GTPases, are deemed as potential therapeutic targets owing to their protumorigenic functions. However, the understanding of the spectrum of their pathobiological roles in tumors is still very limited. We report here that the GEF Vav1 unexpectedly possesses tumor-suppressor functions in immature T cells. This function entails the noncatalytic nucleation of complexes between the ubiquitin ligase Cbl-b and the intracellular domain of Notch1 (ICN1) that favors ICN1 ubiquitinylation and degradation. Ablation of Vav1 promotes ICN1 signaling and the development of T cell acute lymphoblastic leukemia (T-ALL). The downregulation of Vav1 is essential for the pathogenesis of human T-ALL of the TLX+ clinical subtype, further underscoring the suppressor role of this pathway. Robles-Valero et al. find that Vav1 facilitates binding of Cbl-b to the intracellular domain of Notch1 (ICN1) and promotes ICN1 degradation. Loss of Vav1 induces T cell acute lymphoblastic leukemia (T-ALL) by increasing ICN1 signaling, and TLX inhibits Vav1 expression to stimulate ICN1 signaling in TLX+ T-ALL.
publishDate 2017
dc.date.none.fl_str_mv 2017-11
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/11336/66588
Robles Valero, Javier; Lorenzo Martín, L. Francisco; Menacho Márquez, Mauricio Ariel; Fernández Pisonero, Isabel; Abad, Antonio; et al.; A Paradoxical Tumor-Suppressor Role for the Rac1 Exchange Factor Vav1 in T Cell Acute Lymphoblastic Leukemia; Cell Press; Cancer Cell; 32; 5; 11-2017; 608-623; e9
1535-6108
CONICET Digital
CONICET
url http://hdl.handle.net/11336/66588
identifier_str_mv Robles Valero, Javier; Lorenzo Martín, L. Francisco; Menacho Márquez, Mauricio Ariel; Fernández Pisonero, Isabel; Abad, Antonio; et al.; A Paradoxical Tumor-Suppressor Role for the Rac1 Exchange Factor Vav1 in T Cell Acute Lymphoblastic Leukemia; Cell Press; Cancer Cell; 32; 5; 11-2017; 608-623; e9
1535-6108
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1016/j.ccell.2017.10.004
info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S1535610817304579
info:eu-repo/semantics/altIdentifier/url/https://www.cell.com/cancer-cell/fulltext/S1535-6108(17)30457-9
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Cell Press
publisher.none.fl_str_mv Cell Press
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 12.982451

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