PKD phosphorylation and COP9/Signalosome modulate intracellular Spry2 protein stability

Spry2 is a molecular modulator of tyrosine kinase receptor signaling pathways that has cancer-type-specific effects. Mammalian Spry2 protein undergoes tyrosine and serine phosphorylation in response to growth factor stimulation. Spry2 expression is distinctly altered in various cancer types. Inhibit...

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Autores: Martinez, Natalia, Gragera, Teresa, de Lucas, Maria Pilar, Camara, Ana Belen, Ballester, Alicia, Anta-Felez, Berta, Fernández-Medarde, Alberto, López-Briones, Tania, Ortega, Judith, Peña-Jimenez, Daniel, Barbáchano, Antonio, Montero-Calle, Ana Maria, Cordero, Víctor, Barderas Manchado, Rodrigo, Iglesias, Teresa, Yunta, Mónica, Oliva-Martinez, Jose Luis, Muñoz, Alberto, Santos, Eugenio, Zarich-Dimitrievich, Natasha, Rojas-Cabañeros, Jose Maria
Formato: artículo
Fecha de publicación:2023
País:España
Recursos:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/16052
Acesso em linha:http://hdl.handle.net/20.500.12105/16052
Access Level:acceso abierto
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spelling PKD phosphorylation and COP9/Signalosome modulate intracellular Spry2 protein stabilityMartinez, NataliaGragera, Teresade Lucas, Maria PilarCamara, Ana BelenBallester, AliciaAnta-Felez, BertaFernández-Medarde, AlbertoLópez-Briones, TaniaOrtega, JudithPeña-Jimenez, DanielBarbáchano, AntonioMontero-Calle, Ana MariaCordero, VíctorBarderas Manchado, RodrigoIglesias, TeresaYunta, MónicaOliva-Martinez, Jose LuisMuñoz, AlbertoSantos, EugenioZarich-Dimitrievich, NatashaRojas-Cabañeros, Jose MariaSpry2 is a molecular modulator of tyrosine kinase receptor signaling pathways that has cancer-type-specific effects. Mammalian Spry2 protein undergoes tyrosine and serine phosphorylation in response to growth factor stimulation. Spry2 expression is distinctly altered in various cancer types. Inhibition of the proteasome functionality results in reduced intracellular Spry2 degradation. Using in vitro and in vivo assays, we show that protein kinase D (PKD) phosphorylates Spry2 at serine 112 and interacts in vivo with the C-terminal half of this protein. Importantly, missense mutation of Ser112 decreases the rate of Spry2 intracellular protein degradation. Either knocking down the expression of all three mammalian PKD isoforms or blocking their kinase activity with a specific inhibitor contributes to the stabilization of Spry2 wild-type protein. Downregulation of CSN3, a component of the COP9/Signalosome that binds PKD, significantly increases the half-life of Spry2 wild-type protein but does not affect the stability of a Spry2 after mutating Ser112 to the non-phosphorylatable residue alanine. Our data demonstrate that both PKD and the COP9/Signalosome play a significant role in control of Spry2 intracellular stability and support the consideration of the PKD/COP9 complex as a potential therapeutic target in tumors where Spry2 expression is reduced.Nature Publishing GroupInstituto de Salud Carlos IIIUnión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)Ministerio de Asuntos Económicos y Transformación Digital (España)Asociación Española Contra el CáncerMinisterio de Ciencia e Innovación (España)Fundación Ramón ArecesCentro de Investigación Biomédica en Red - CIBERONC (Cáncer)Agencia Estatal de Investigación (España)Centro de Investigación Biomédica en Red - CIBERNED (Enfermedades Neurodegenerativas)Fundación Universidad Alfonso X el SabioJunta de Castilla y León (España)Solorzano-Barruso Foundation20232023-05-1120232023-04-1220232023-04-12research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/20.500.12105/16052reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Atribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/160522026-06-12T12:43:37Z
dc.title.none.fl_str_mv PKD phosphorylation and COP9/Signalosome modulate intracellular Spry2 protein stability
title PKD phosphorylation and COP9/Signalosome modulate intracellular Spry2 protein stability
spellingShingle PKD phosphorylation and COP9/Signalosome modulate intracellular Spry2 protein stability
Martinez, Natalia
title_short PKD phosphorylation and COP9/Signalosome modulate intracellular Spry2 protein stability
title_full PKD phosphorylation and COP9/Signalosome modulate intracellular Spry2 protein stability
title_fullStr PKD phosphorylation and COP9/Signalosome modulate intracellular Spry2 protein stability
title_full_unstemmed PKD phosphorylation and COP9/Signalosome modulate intracellular Spry2 protein stability
title_sort PKD phosphorylation and COP9/Signalosome modulate intracellular Spry2 protein stability
dc.creator.none.fl_str_mv Martinez, Natalia
Gragera, Teresa
de Lucas, Maria Pilar
Camara, Ana Belen
Ballester, Alicia
Anta-Felez, Berta
Fernández-Medarde, Alberto
López-Briones, Tania
Ortega, Judith
Peña-Jimenez, Daniel
Barbáchano, Antonio
Montero-Calle, Ana Maria
Cordero, Víctor
Barderas Manchado, Rodrigo
Iglesias, Teresa
Yunta, Mónica
Oliva-Martinez, Jose Luis
Muñoz, Alberto
Santos, Eugenio
Zarich-Dimitrievich, Natasha
Rojas-Cabañeros, Jose Maria
author Martinez, Natalia
author_facet Martinez, Natalia
Gragera, Teresa
de Lucas, Maria Pilar
Camara, Ana Belen
Ballester, Alicia
Anta-Felez, Berta
Fernández-Medarde, Alberto
López-Briones, Tania
Ortega, Judith
Peña-Jimenez, Daniel
Barbáchano, Antonio
Montero-Calle, Ana Maria
Cordero, Víctor
Barderas Manchado, Rodrigo
Iglesias, Teresa
Yunta, Mónica
Oliva-Martinez, Jose Luis
Muñoz, Alberto
Santos, Eugenio
Zarich-Dimitrievich, Natasha
Rojas-Cabañeros, Jose Maria
author_role author
author2 Gragera, Teresa
de Lucas, Maria Pilar
Camara, Ana Belen
Ballester, Alicia
Anta-Felez, Berta
Fernández-Medarde, Alberto
López-Briones, Tania
Ortega, Judith
Peña-Jimenez, Daniel
Barbáchano, Antonio
Montero-Calle, Ana Maria
Cordero, Víctor
Barderas Manchado, Rodrigo
Iglesias, Teresa
Yunta, Mónica
Oliva-Martinez, Jose Luis
Muñoz, Alberto
Santos, Eugenio
Zarich-Dimitrievich, Natasha
Rojas-Cabañeros, Jose Maria
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Instituto de Salud Carlos III
Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
Ministerio de Asuntos Económicos y Transformación Digital (España)
Asociación Española Contra el Cáncer
Ministerio de Ciencia e Innovación (España)
Fundación Ramón Areces
Centro de Investigación Biomédica en Red - CIBERONC (Cáncer)
Agencia Estatal de Investigación (España)
Centro de Investigación Biomédica en Red - CIBERNED (Enfermedades Neurodegenerativas)
Fundación Universidad Alfonso X el Sabio
Junta de Castilla y León (España)
Solorzano-Barruso Foundation
description Spry2 is a molecular modulator of tyrosine kinase receptor signaling pathways that has cancer-type-specific effects. Mammalian Spry2 protein undergoes tyrosine and serine phosphorylation in response to growth factor stimulation. Spry2 expression is distinctly altered in various cancer types. Inhibition of the proteasome functionality results in reduced intracellular Spry2 degradation. Using in vitro and in vivo assays, we show that protein kinase D (PKD) phosphorylates Spry2 at serine 112 and interacts in vivo with the C-terminal half of this protein. Importantly, missense mutation of Ser112 decreases the rate of Spry2 intracellular protein degradation. Either knocking down the expression of all three mammalian PKD isoforms or blocking their kinase activity with a specific inhibitor contributes to the stabilization of Spry2 wild-type protein. Downregulation of CSN3, a component of the COP9/Signalosome that binds PKD, significantly increases the half-life of Spry2 wild-type protein but does not affect the stability of a Spry2 after mutating Ser112 to the non-phosphorylatable residue alanine. Our data demonstrate that both PKD and the COP9/Signalosome play a significant role in control of Spry2 intracellular stability and support the consideration of the PKD/COP9 complex as a potential therapeutic target in tumors where Spry2 expression is reduced.
publishDate 2023
dc.date.none.fl_str_mv 2023
2023-05-11
2023
2023-04-12
2023
2023-04-12
dc.type.none.fl_str_mv research article
http://purl.org/coar/resource_type/c_2df8fbb1
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/20.500.12105/16052
url http://hdl.handle.net/20.500.12105/16052
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
Atribución 4.0 Internacional
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
Atribución 4.0 Internacional
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv reponame:Repisalud
instname:Instituto de Salud Carlos III (ISCIII)
instname_str Instituto de Salud Carlos III (ISCIII)
reponame_str Repisalud
collection Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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