Platelet C3G: a key player in vesicle exocytosis, spreading and clot retraction

C3G is a Rap1 GEF that plays a pivotal role in platelet-mediated processes such as angiogenesis, tumor growth, and metastasis by modulating the platelet secretome. Here, we explore the mechanisms through which C3G governs platelet secretion. For this, we utilized animal models featuring either overe...

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Autores: Fernández-Infante, Cristina, Hernández-Cano, Luis, Herranz, Óscar, Berrocal, Pablo, Sicilia-Navarro, Carmen, González-Porras, José R., Bastida, José María, Porras, Almudena, Guerrero Arroyo, María del Carmen
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2024
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/367209
Acceso en línea:http://hdl.handle.net/10261/367209
Access Level:acceso abierto
Palabra clave:RapGEF1
Granule secretion
Platelet spreading
Compound exocytosis
Actin polymerization
Secretome
Coagulation
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network_name_str España
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dc.title.none.fl_str_mv Platelet C3G: a key player in vesicle exocytosis, spreading and clot retraction
title Platelet C3G: a key player in vesicle exocytosis, spreading and clot retraction
spellingShingle Platelet C3G: a key player in vesicle exocytosis, spreading and clot retraction
Fernández-Infante, Cristina
RapGEF1
Granule secretion
Platelet spreading
Compound exocytosis
Actin polymerization
Secretome
Coagulation
title_short Platelet C3G: a key player in vesicle exocytosis, spreading and clot retraction
title_full Platelet C3G: a key player in vesicle exocytosis, spreading and clot retraction
title_fullStr Platelet C3G: a key player in vesicle exocytosis, spreading and clot retraction
title_full_unstemmed Platelet C3G: a key player in vesicle exocytosis, spreading and clot retraction
title_sort Platelet C3G: a key player in vesicle exocytosis, spreading and clot retraction
dc.creator.none.fl_str_mv Fernández-Infante, Cristina
Hernández-Cano, Luis
Herranz, Óscar
Berrocal, Pablo
Sicilia-Navarro, Carmen
González-Porras, José R.
Bastida, José María
Porras, Almudena
Guerrero Arroyo, María del Carmen
author Fernández-Infante, Cristina
author_facet Fernández-Infante, Cristina
Hernández-Cano, Luis
Herranz, Óscar
Berrocal, Pablo
Sicilia-Navarro, Carmen
González-Porras, José R.
Bastida, José María
Porras, Almudena
Guerrero Arroyo, María del Carmen
author_role author
author2 Hernández-Cano, Luis
Herranz, Óscar
Berrocal, Pablo
Sicilia-Navarro, Carmen
González-Porras, José R.
Bastida, José María
Porras, Almudena
Guerrero Arroyo, María del Carmen
author2_role author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Economía y Competitividad (España)
Ministerio de Ciencia, Innovación y Universidades (España)
Agencia Estatal de Investigación (España)
European Commission
Junta de Castilla y León
Fundación Científica Asociación Española Contra el Cáncer
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv RapGEF1
Granule secretion
Platelet spreading
Compound exocytosis
Actin polymerization
Secretome
Coagulation
topic RapGEF1
Granule secretion
Platelet spreading
Compound exocytosis
Actin polymerization
Secretome
Coagulation
description C3G is a Rap1 GEF that plays a pivotal role in platelet-mediated processes such as angiogenesis, tumor growth, and metastasis by modulating the platelet secretome. Here, we explore the mechanisms through which C3G governs platelet secretion. For this, we utilized animal models featuring either overexpression or deletion of C3G in platelets, as well as PC12 cell clones expressing C3G mutants. We found that C3G specifically regulates α-granule secretion via PKCδ, but it does not affect δ-granules or lysosomes. C3G activated RalA through a GEF-dependent mechanism, facilitating vesicle docking, while interfering with the formation of the trans-SNARE complex, thereby restricting vesicle fusion. Furthermore, C3G promotes the formation of lamellipodia during platelet spreading on specific substrates by enhancing actin polymerization via Src and Rac1-Arp2/3 pathways, but not Rap1. Consequently, C3G deletion in platelets favored kiss-and-run exocytosis. C3G also controlled granule secretion in PC12 cells, including pore formation. Additionally, C3G-deficient platelets exhibited reduced phosphatidylserine exposure, resulting in decreased thrombin generation, which along with defective actin polymerization and spreading, led to impaired clot retraction. In summary, platelet C3G plays a dual role by facilitating platelet spreading and clot retraction through the promotion of outside-in signaling while concurrently downregulating α-granule secretion by restricting granule fusion.
publishDate 2024
dc.date.none.fl_str_mv 2024
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/10261/367209
url http://hdl.handle.net/10261/367209
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#
#PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/MINECO//SAF2016-76588-C2-2-R
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-104143RB-C21
info:eu-repo/grantAgreement/MINECO//SAF2016-76588-C2-1-R
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-104143RB-C22
The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.1007/s00018-023-05109-8
https://doi.org/10.1007/s00018-023-05109-8
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
publisher.none.fl_str_mv Springer
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
repository.name.fl_str_mv
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spelling Platelet C3G: a key player in vesicle exocytosis, spreading and clot retractionFernández-Infante, CristinaHernández-Cano, LuisHerranz, ÓscarBerrocal, PabloSicilia-Navarro, CarmenGonzález-Porras, José R.Bastida, José MaríaPorras, AlmudenaGuerrero Arroyo, María del CarmenRapGEF1Granule secretionPlatelet spreadingCompound exocytosisActin polymerizationSecretomeCoagulationC3G is a Rap1 GEF that plays a pivotal role in platelet-mediated processes such as angiogenesis, tumor growth, and metastasis by modulating the platelet secretome. Here, we explore the mechanisms through which C3G governs platelet secretion. For this, we utilized animal models featuring either overexpression or deletion of C3G in platelets, as well as PC12 cell clones expressing C3G mutants. We found that C3G specifically regulates α-granule secretion via PKCδ, but it does not affect δ-granules or lysosomes. C3G activated RalA through a GEF-dependent mechanism, facilitating vesicle docking, while interfering with the formation of the trans-SNARE complex, thereby restricting vesicle fusion. Furthermore, C3G promotes the formation of lamellipodia during platelet spreading on specific substrates by enhancing actin polymerization via Src and Rac1-Arp2/3 pathways, but not Rap1. Consequently, C3G deletion in platelets favored kiss-and-run exocytosis. C3G also controlled granule secretion in PC12 cells, including pore formation. Additionally, C3G-deficient platelets exhibited reduced phosphatidylserine exposure, resulting in decreased thrombin generation, which along with defective actin polymerization and spreading, led to impaired clot retraction. In summary, platelet C3G plays a dual role by facilitating platelet spreading and clot retraction through the promotion of outside-in signaling while concurrently downregulating α-granule secretion by restricting granule fusion.his work was supported by Grants SAF2016-76588-C2-2-R and PID2019-104143RB-C21 (CG), SAF2016-76588-C2-1-R and PID2019-104143RB-C22 (AP) funded by MCIN/AEI/https://doi.org/10.13039/501100011033 and ERDF “A way of making Europe”, and by grants SA017U16 and SA078P20 (CG) funded by the Council of Education of Junta de Castilla y León, Spain and ERDF “A way of making Europe”. CF-I, LH-C and PB are recipients of fellowships from the Council of Education of Junta de Castilla y León, Spain, and The Social European Funding. ÓH is recipient of a FPU fellowship from the Spanish Ministry of Education. The authors’ institution is supported by the Programa de Apoyo a Planes Estratégicos de Investigación de Estructuras de Investigación de Excelencia co-funded by Junta de Castilla y León and ERDF (CLC-2017-01) and by the Scientific Foundation of the Spanish Association Against Cancer (Programa Excelencia 2022 EPAEC222641CICS).Peer reviewedSpringerMinisterio de Economía y Competitividad (España)Ministerio de Ciencia, Innovación y Universidades (España)Agencia Estatal de Investigación (España)European CommissionJunta de Castilla y LeónFundación Científica Asociación Española Contra el CáncerConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202420242024info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/367209reponame: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##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/MINECO//SAF2016-76588-C2-2-Rinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-104143RB-C21info:eu-repo/grantAgreement/MINECO//SAF2016-76588-C2-1-Rinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-104143RB-C22The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.1007/s00018-023-05109-8https://doi.org/10.1007/s00018-023-05109-8Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3672092026-05-22T06:33:51Z
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