PKD phosphorylation and COP9/Signalosome modulate intracellular Spry2 protein stability

Martínez, Natalia; Gragera, Teresa; Lucas, María Pilar de; Cámara, Ana Belén; Ballester, Alicia; Anta, Berta; Fernández-Medarde, Alberto; López-Briones, T.; Ortega, Judith; Peña Jiménez, Daniel; Barbáchano, Antonio; Montero-Calle, Ana; Cordero, Víctor; Barderas, Rodrigo; Iglesias, Teresa; Yunta, M.; Oliva, José Luis; Muñoz, Alberto; Santos de Dios, Eugenio; Zarich, Natasha; Rojas-Cabañeros, José M.

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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Detalles Bibliográficos
Autores:	Martínez, Natalia, Gragera, Teresa, Lucas, María Pilar de, Cámara, Ana Belén, Ballester, Alicia, Anta, Berta, Fernández-Medarde, Alberto, López-Briones, T., Ortega, Judith, Peña Jiménez, Daniel, Barbáchano, Antonio, Montero-Calle, Ana, Cordero, Víctor, Barderas, Rodrigo, Iglesias, Teresa, Yunta, M., Oliva, José Luis, Muñoz, Alberto, Santos de Dios, Eugenio, Zarich, Natasha, Rojas-Cabañeros, José M.
Tipo de recurso:	artículo
Estado:	Versión publicada
Fecha de publicación:	2023
País:	España
Institución:	Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:	DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:	oai:digital.csic.es:10261/348308
Acceso en línea:	http://hdl.handle.net/10261/348308
Access Level:	acceso abierto
Palabra clave:	Checkpoint signalling Targeted therapies Ubiquitylation

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network_acronym_str	ES
network_name_str	España
repository_id_str
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 Martínez, Natalia Checkpoint signalling Targeted therapies Ubiquitylation
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	Martínez, Natalia Gragera, Teresa Lucas, María Pilar de Cámara, Ana Belén Ballester, Alicia Anta, Berta Fernández-Medarde, Alberto López-Briones, T. Ortega, Judith Peña Jiménez, Daniel Barbáchano, Antonio Montero-Calle, Ana Cordero, Víctor Barderas, Rodrigo Iglesias, Teresa Yunta, M. Oliva, José Luis Muñoz, Alberto Santos de Dios, Eugenio Zarich, Natasha Rojas-Cabañeros, José M.
author	Martínez, Natalia
author_facet	Martínez, Natalia Gragera, Teresa Lucas, María Pilar de Cámara, Ana Belén Ballester, Alicia Anta, Berta Fernández-Medarde, Alberto López-Briones, T. Ortega, Judith Peña Jiménez, Daniel Barbáchano, Antonio Montero-Calle, Ana Cordero, Víctor Barderas, Rodrigo Iglesias, Teresa Yunta, M. Oliva, José Luis Muñoz, Alberto Santos de Dios, Eugenio Zarich, Natasha Rojas-Cabañeros, José M.
author_role	author
author2	Gragera, Teresa Lucas, María Pilar de Cámara, Ana Belén Ballester, Alicia Anta, Berta Fernández-Medarde, Alberto López-Briones, T. Ortega, Judith Peña Jiménez, Daniel Barbáchano, Antonio Montero-Calle, Ana Cordero, Víctor Barderas, Rodrigo Iglesias, Teresa Yunta, M. Oliva, José Luis Muñoz, Alberto Santos de Dios, Eugenio Zarich, Natasha Rojas-Cabañeros, José M.
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	Ministerio de Economía y Competitividad (España) Instituto de Salud Carlos III Junta de Castilla y León Fundación Ramón Areces Fundación Memoria de D. Samuel Solorzano Barruso Ministerio de Ciencia, Innovación y Universidades (España) Agencia Estatal de Investigación (España) Universidad Alfonso X El Sabio European Commission Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv	Checkpoint signalling Targeted therapies Ubiquitylation
topic	Checkpoint signalling Targeted therapies Ubiquitylation
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 2024 2024
dc.type.none.fl_str_mv	info:eu-repo/semantics/article http://purl.org/coar/resource_type/c_6501 Publisher's version info:eu-repo/semantics/publishedVersion
format	article
status_str	publishedVersion
dc.identifier.none.fl_str_mv	http://hdl.handle.net/10261/348308
url	http://hdl.handle.net/10261/348308
dc.language.none.fl_str_mv	Inglés
language_invalid_str_mv	Inglés
dc.relation.none.fl_str_mv	#PLACEHOLDER_PARENT_METADATA_VALUE# #PLACEHOLDER_PARENT_METADATA_VALUE# #PLACEHOLDER_PARENT_METADATA_VALUE# info:eu-repo/grantAgreement/AEI//SAF2016-78852-R info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-104867RB-I00 info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-115218RB-I00 https://doi.org/10.1038/s41389-023-00465-3 Sí
dc.rights.none.fl_str_mv	info:eu-repo/semantics/openAccess
eu_rights_str_mv	openAccess
dc.format.none.fl_str_mv	application/pdf
dc.publisher.none.fl_str_mv	Springer Nature
publisher.none.fl_str_mv	Springer Nature
dc.source.none.fl_str_mv	reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str	Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str	DIGITAL.CSIC. Repositorio Institucional del CSIC
collection	DIGITAL.CSIC. Repositorio Institucional del CSIC
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repository.mail.fl_str_mv
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spelling	PKD phosphorylation and COP9/Signalosome modulate intracellular Spry2 protein stabilityMartínez, NataliaGragera, TeresaLucas, María Pilar deCámara, Ana BelénBallester, AliciaAnta, BertaFernández-Medarde, AlbertoLópez-Briones, T.Ortega, JudithPeña Jiménez, DanielBarbáchano, AntonioMontero-Calle, AnaCordero, VíctorBarderas, RodrigoIglesias, TeresaYunta, M.Oliva, José LuisMuñoz, AlbertoSantos de Dios, EugenioZarich, NatashaRojas-Cabañeros, José M.Checkpoint signallingTargeted therapiesUbiquitylationSpry2 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.JMR-C received grant support from MINECO-FEDER (SAF2016-78852-R), AESI-ISCIII (PI20CIII/00029) and Spanish Association against Cancer (AECC, CGB14143035THOM). ES group was supported by grants from ISCIII-MCUI (FIS PI19/00934), JCyL (SA264P18-UIC 076), Areces Foundation (CIVP19A5942), Solorzano-Barruso Foundation (FS/32–2020) and by ISCIII-CIBERONC (group CB16/12/00352). Funding to AM group was provided by the Agencia Estatal de Investigación (PID2019-104867RB-I00/AEI/10.13039/501100011033) and by ISCIII-CIBERONC (group CB16/12/00273). TI was supported by grant PID2020-115218RB-I00 funded by MCIN/AEI/ 10.13039/501100011033 and by “ERDF A way of making Europe” and by ISCIII-CIBERNED. RB received grant support from AESI-ISCIII (PI20CIII/00019). Finally, DP-J and MY groups were supported by grants 1.012.022 (to DP-J), 1.010.929 and 1.400.002 (both to MY) from Fundación Universidad Alfonso X el Sabio (FUAX). All research co-financed by FEDER funds.Peer reviewedSpringer NatureMinisterio de Economía y Competitividad (España)Instituto de Salud Carlos IIIJunta de Castilla y LeónFundación Ramón ArecesFundación Memoria de D. Samuel Solorzano BarrusoMinisterio de Ciencia, Innovación y Universidades (España)Agencia Estatal de Investigación (España)Universidad Alfonso X El SabioEuropean CommissionConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202420242023info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/348308reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI//SAF2016-78852-Rinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-104867RB-I00info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-115218RB-I00https://doi.org/10.1038/s41389-023-00465-3Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3483082026-05-22T06:33:51Z
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PKD phosphorylation and COP9/Signalosome modulate intracellular Spry2 protein stability

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