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
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/18220
Acceder
id CONICETDig_ba19111c85edd6c2a5cf5960c1f8607a
oai_identifier_str oai:ri.conicet.gov.ar:11336/18220
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling 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 Técnicas2025-10-22T11:46:50Zoai: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:34982025-10-22 11:46:50.498CONICET 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
_version_ 1846782171440742400
score 12.982451

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