A non-catalytic function of the Src family tyrosine kinases controls prolactin-induced Jak2 signaling
- Autores
- García Martínez, José Manuel; Calcabrini, Annarica; Gonzalez, Lorena; Martín Forero, Esther; Agulló Ortuño, María Teresa; Simon, Valérie; Watkin, Harriet; Anderson, Steve M.; Roche, Serge; Martin Pérez, Jorge
- Año de publicación
- 2010
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- The cytokine prolactin (PRL) plays important roles in the proliferation and differentiation of the mammary gland and it has been implicated in tumorigenesis. The prolactin receptor (PRLR) is devoid of catalytic activity and its mitogenic response is controlled by cytoplasmic tyrosine kinases of the Src (SFK) and Jak families. How PRLR uses these kinases for signaling is not well understood. Previous studies indicated that PRLR-induced Jak2 activation does not require SFK catalytic activity in favor of separate signaling operating on this cellular response. Here we show that, nevertheless, PRLR requires Src-SH2 and -SH3 domains for Jak2 signaling. In W53 lymphoid cells, conditional expression of two c-Src non-catalytic mutants, either SrcK295M/Y527F or Src∆K, whose SH3 and SH2 domains are exposed, controls Jak2/Stat5 activation by recruiting Jak2, avoiding its activation by endogenous active SFK. In contrast, the kinase inactive SrcK295M mutant, with inaccessible SH3 and SH2 domains, does not. Furthermore, all three mutants attenuate PRLR-induced Akt and p70S6K activation. Accordingly, PRLR-induced Jak2/Stat5 signaling is inhibited in MCF7 breast cancer cells by Src depletion, expression of SrcK295M/Y527F or active Src harboring an inactive SH2 (SrcR175L) or SH3 domain (SrcW118A). Finally, Jak2/Stat5 pathway is also reduced in Src−/− mice mammary glands. We thus conclude that, in addition to Akt and p70S6K, SFK regulate PRLR-induced Jak2 signaling through a kinase-independent mechanism.
Fil: García Martínez, José Manuel. Universidad Autónoma de Madrid; España. Consejo Superior de Investigaciones Cientificas; España
Fil: Calcabrini, Annarica. Universidad Autónoma de Madrid; España. Consejo Superior de Investigaciones Cientificas; España
Fil: Gonzalez, Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Autónoma de Madrid; España
Fil: Martín Forero, Esther. Universidad Autónoma de Madrid; España. Consejo Superior de Investigaciones Cientificas; España
Fil: Agulló Ortuño, María Teresa. Universidad Autónoma de Madrid; España. Consejo Superior de Investigaciones Cientificas; España
Fil: Simon, Valérie. Centre de Recherche de Biochimie Macromoléculaire; Francia. Centre National de la Recherche Scientifique; Francia
Fil: Watkin, Harriet. University of Colorado Health Sciences Center; Estados Unidos
Fil: Anderson, Steve M.. University of Colorado Health Sciences Center; Estados Unidos
Fil: Roche, Serge. Centre de Recherche de Biochimie Macromoléculaire; Francia. Centre National de la Recherche Scientifique; Francia
Fil: Martin Pérez, Jorge. Universidad Autónoma de Madrid; España. Consejo Superior de Investigaciones Cientificas; España - Materia
-
Prolactin
Src Family Kinases
Src Scaffold Functions
Jak2
Sta5
Akt
Erk1/2
Cell Proliferation - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
- Repositorio
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/18220
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network_name_str |
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A non-catalytic function of the Src family tyrosine kinases controls prolactin-induced Jak2 signalingGarcía Martínez, José ManuelCalcabrini, AnnaricaGonzalez, LorenaMartín Forero, EstherAgulló Ortuño, María TeresaSimon, ValérieWatkin, HarrietAnderson, Steve M.Roche, SergeMartin Pérez, JorgeProlactinSrc Family KinasesSrc Scaffold FunctionsJak2Sta5AktErk1/2Cell Proliferationhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1The cytokine prolactin (PRL) plays important roles in the proliferation and differentiation of the mammary gland and it has been implicated in tumorigenesis. The prolactin receptor (PRLR) is devoid of catalytic activity and its mitogenic response is controlled by cytoplasmic tyrosine kinases of the Src (SFK) and Jak families. How PRLR uses these kinases for signaling is not well understood. Previous studies indicated that PRLR-induced Jak2 activation does not require SFK catalytic activity in favor of separate signaling operating on this cellular response. Here we show that, nevertheless, PRLR requires Src-SH2 and -SH3 domains for Jak2 signaling. In W53 lymphoid cells, conditional expression of two c-Src non-catalytic mutants, either SrcK295M/Y527F or Src∆K, whose SH3 and SH2 domains are exposed, controls Jak2/Stat5 activation by recruiting Jak2, avoiding its activation by endogenous active SFK. In contrast, the kinase inactive SrcK295M mutant, with inaccessible SH3 and SH2 domains, does not. Furthermore, all three mutants attenuate PRLR-induced Akt and p70S6K activation. Accordingly, PRLR-induced Jak2/Stat5 signaling is inhibited in MCF7 breast cancer cells by Src depletion, expression of SrcK295M/Y527F or active Src harboring an inactive SH2 (SrcR175L) or SH3 domain (SrcW118A). Finally, Jak2/Stat5 pathway is also reduced in Src−/− mice mammary glands. We thus conclude that, in addition to Akt and p70S6K, SFK regulate PRLR-induced Jak2 signaling through a kinase-independent mechanism.Fil: García Martínez, José Manuel. Universidad Autónoma de Madrid; España. Consejo Superior de Investigaciones Cientificas; EspañaFil: Calcabrini, Annarica. Universidad Autónoma de Madrid; España. Consejo Superior de Investigaciones Cientificas; EspañaFil: Gonzalez, Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Autónoma de Madrid; EspañaFil: Martín Forero, Esther. Universidad Autónoma de Madrid; España. Consejo Superior de Investigaciones Cientificas; EspañaFil: Agulló Ortuño, María Teresa. Universidad Autónoma de Madrid; España. Consejo Superior de Investigaciones Cientificas; EspañaFil: Simon, Valérie. Centre de Recherche de Biochimie Macromoléculaire; Francia. Centre National de la Recherche Scientifique; FranciaFil: Watkin, Harriet. University of Colorado Health Sciences Center; Estados UnidosFil: Anderson, Steve M.. University of Colorado Health Sciences Center; Estados UnidosFil: Roche, Serge. Centre de Recherche de Biochimie Macromoléculaire; Francia. Centre National de la Recherche Scientifique; FranciaFil: Martin Pérez, Jorge. Universidad Autónoma de Madrid; España. Consejo Superior de Investigaciones Cientificas; EspañaElsevier Inc2010-03info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/18220García Martínez, José Manuel; Calcabrini, Annarica; Gonzalez, Lorena; Martín Forero, Esther; Agulló Ortuño, María Teresa; et al.; A non-catalytic function of the Src family tyrosine kinases controls prolactin-induced Jak2 signaling; Elsevier Inc; Cellular Signalling; 22; 3; 3-2010; 415-4260898-6568CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S0898656809003301?via%3Dihubinfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.cellsig.2009.10.013info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:16:40Zoai:ri.conicet.gov.ar:11336/18220instacron: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:34982025-09-29 10:16:41.114CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
dc.title.none.fl_str_mv |
A non-catalytic function of the Src family tyrosine kinases controls prolactin-induced Jak2 signaling |
title |
A non-catalytic function of the Src family tyrosine kinases controls prolactin-induced Jak2 signaling |
spellingShingle |
A non-catalytic function of the Src family tyrosine kinases controls prolactin-induced Jak2 signaling García Martínez, José Manuel Prolactin Src Family Kinases Src Scaffold Functions Jak2 Sta5 Akt Erk1/2 Cell Proliferation |
title_short |
A non-catalytic function of the Src family tyrosine kinases controls prolactin-induced Jak2 signaling |
title_full |
A non-catalytic function of the Src family tyrosine kinases controls prolactin-induced Jak2 signaling |
title_fullStr |
A non-catalytic function of the Src family tyrosine kinases controls prolactin-induced Jak2 signaling |
title_full_unstemmed |
A non-catalytic function of the Src family tyrosine kinases controls prolactin-induced Jak2 signaling |
title_sort |
A non-catalytic function of the Src family tyrosine kinases controls prolactin-induced Jak2 signaling |
dc.creator.none.fl_str_mv |
García Martínez, José Manuel Calcabrini, Annarica Gonzalez, Lorena Martín Forero, Esther Agulló Ortuño, María Teresa Simon, Valérie Watkin, Harriet Anderson, Steve M. Roche, Serge Martin Pérez, Jorge |
author |
García Martínez, José Manuel |
author_facet |
García Martínez, José Manuel Calcabrini, Annarica Gonzalez, Lorena Martín Forero, Esther Agulló Ortuño, María Teresa Simon, Valérie Watkin, Harriet Anderson, Steve M. Roche, Serge Martin Pérez, Jorge |
author_role |
author |
author2 |
Calcabrini, Annarica Gonzalez, Lorena Martín Forero, Esther Agulló Ortuño, María Teresa Simon, Valérie Watkin, Harriet Anderson, Steve M. Roche, Serge Martin Pérez, Jorge |
author2_role |
author author author author author author author author author |
dc.subject.none.fl_str_mv |
Prolactin Src Family Kinases Src Scaffold Functions Jak2 Sta5 Akt Erk1/2 Cell Proliferation |
topic |
Prolactin Src Family Kinases Src Scaffold Functions Jak2 Sta5 Akt Erk1/2 Cell Proliferation |
purl_subject.fl_str_mv |
https://purl.org/becyt/ford/1.6 https://purl.org/becyt/ford/1 |
dc.description.none.fl_txt_mv |
The cytokine prolactin (PRL) plays important roles in the proliferation and differentiation of the mammary gland and it has been implicated in tumorigenesis. The prolactin receptor (PRLR) is devoid of catalytic activity and its mitogenic response is controlled by cytoplasmic tyrosine kinases of the Src (SFK) and Jak families. How PRLR uses these kinases for signaling is not well understood. Previous studies indicated that PRLR-induced Jak2 activation does not require SFK catalytic activity in favor of separate signaling operating on this cellular response. Here we show that, nevertheless, PRLR requires Src-SH2 and -SH3 domains for Jak2 signaling. In W53 lymphoid cells, conditional expression of two c-Src non-catalytic mutants, either SrcK295M/Y527F or Src∆K, whose SH3 and SH2 domains are exposed, controls Jak2/Stat5 activation by recruiting Jak2, avoiding its activation by endogenous active SFK. In contrast, the kinase inactive SrcK295M mutant, with inaccessible SH3 and SH2 domains, does not. Furthermore, all three mutants attenuate PRLR-induced Akt and p70S6K activation. Accordingly, PRLR-induced Jak2/Stat5 signaling is inhibited in MCF7 breast cancer cells by Src depletion, expression of SrcK295M/Y527F or active Src harboring an inactive SH2 (SrcR175L) or SH3 domain (SrcW118A). Finally, Jak2/Stat5 pathway is also reduced in Src−/− mice mammary glands. We thus conclude that, in addition to Akt and p70S6K, SFK regulate PRLR-induced Jak2 signaling through a kinase-independent mechanism. Fil: García Martínez, José Manuel. Universidad Autónoma de Madrid; España. Consejo Superior de Investigaciones Cientificas; España Fil: Calcabrini, Annarica. Universidad Autónoma de Madrid; España. Consejo Superior de Investigaciones Cientificas; España Fil: Gonzalez, Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Autónoma de Madrid; España Fil: Martín Forero, Esther. Universidad Autónoma de Madrid; España. Consejo Superior de Investigaciones Cientificas; España Fil: Agulló Ortuño, María Teresa. Universidad Autónoma de Madrid; España. Consejo Superior de Investigaciones Cientificas; España Fil: Simon, Valérie. Centre de Recherche de Biochimie Macromoléculaire; Francia. Centre National de la Recherche Scientifique; Francia Fil: Watkin, Harriet. University of Colorado Health Sciences Center; Estados Unidos Fil: Anderson, Steve M.. University of Colorado Health Sciences Center; Estados Unidos Fil: Roche, Serge. Centre de Recherche de Biochimie Macromoléculaire; Francia. Centre National de la Recherche Scientifique; Francia Fil: Martin Pérez, Jorge. Universidad Autónoma de Madrid; España. Consejo Superior de Investigaciones Cientificas; España |
description |
The cytokine prolactin (PRL) plays important roles in the proliferation and differentiation of the mammary gland and it has been implicated in tumorigenesis. The prolactin receptor (PRLR) is devoid of catalytic activity and its mitogenic response is controlled by cytoplasmic tyrosine kinases of the Src (SFK) and Jak families. How PRLR uses these kinases for signaling is not well understood. Previous studies indicated that PRLR-induced Jak2 activation does not require SFK catalytic activity in favor of separate signaling operating on this cellular response. Here we show that, nevertheless, PRLR requires Src-SH2 and -SH3 domains for Jak2 signaling. In W53 lymphoid cells, conditional expression of two c-Src non-catalytic mutants, either SrcK295M/Y527F or Src∆K, whose SH3 and SH2 domains are exposed, controls Jak2/Stat5 activation by recruiting Jak2, avoiding its activation by endogenous active SFK. In contrast, the kinase inactive SrcK295M mutant, with inaccessible SH3 and SH2 domains, does not. Furthermore, all three mutants attenuate PRLR-induced Akt and p70S6K activation. Accordingly, PRLR-induced Jak2/Stat5 signaling is inhibited in MCF7 breast cancer cells by Src depletion, expression of SrcK295M/Y527F or active Src harboring an inactive SH2 (SrcR175L) or SH3 domain (SrcW118A). Finally, Jak2/Stat5 pathway is also reduced in Src−/− mice mammary glands. We thus conclude that, in addition to Akt and p70S6K, SFK regulate PRLR-induced Jak2 signaling through a kinase-independent mechanism. |
publishDate |
2010 |
dc.date.none.fl_str_mv |
2010-03 |
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/11336/18220 García Martínez, José Manuel; Calcabrini, Annarica; Gonzalez, Lorena; Martín Forero, Esther; Agulló Ortuño, María Teresa; et al.; A non-catalytic function of the Src family tyrosine kinases controls prolactin-induced Jak2 signaling; Elsevier Inc; Cellular Signalling; 22; 3; 3-2010; 415-426 0898-6568 CONICET Digital CONICET |
url |
http://hdl.handle.net/11336/18220 |
identifier_str_mv |
García Martínez, José Manuel; Calcabrini, Annarica; Gonzalez, Lorena; Martín Forero, Esther; Agulló Ortuño, María Teresa; et al.; A non-catalytic function of the Src family tyrosine kinases controls prolactin-induced Jak2 signaling; Elsevier Inc; Cellular Signalling; 22; 3; 3-2010; 415-426 0898-6568 CONICET Digital CONICET |
dc.language.none.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
info:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S0898656809003301?via%3Dihub info:eu-repo/semantics/altIdentifier/doi/10.1016/j.cellsig.2009.10.013 |
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 |
Elsevier Inc |
publisher.none.fl_str_mv |
Elsevier Inc |
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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1844614112932265984 |
score |
13.070432 |