Modulación de la estabilidad de la quinasa de receptores acoplados a proteínas G (GRK2) por la ligasa Mdm2

Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 12-12-2007

Detalles Bibliográficos
Autor: Salcedo, Alicia
Tipo de recurso: tesis doctoral
Fecha de publicación:2007
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/7956
Acceso en línea:http://hdl.handle.net/10261/7956
Access Level:acceso abierto
Palabra clave:Células proliferación
Proteínas G
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spelling Modulación de la estabilidad de la quinasa de receptores acoplados a proteínas G (GRK2) por la ligasa Mdm2Salcedo, AliciaCélulas proliferaciónProteínas GTesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 12-12-2007G protein-coupled receptor kinases (GRKs) and β-arrestins are key regulators of G protein-coupled receptors (GPCRs), a family of plasma membrane receptors involved in a variety of cellular and physiological processes, including cell migration, proliferation and survival. GRKs and arrestins promote GPCR uncoupling from G proteins upon agonist stimulation (desensitization) and receptor internalization. In addition, GRKs and arrestins can act as scaffold proteins, functionally interacting with a variety of signal transduction proteins, thus linking GPCR to new signalling pathways. GRK2, an ubiquitous member of the GRK family, displays an altered expression in several pathological conditions. However, the molecular mechanisms underlying such changes, and the functional consequences of altering GRK2 levels in different cell types are poorly understood. We had previously reported that GRK2 was rapidly degraded by the proteasome pathway upon GPCR stimulation, in a process dependent on β-arrestin function and involving GRK2 phosphorylation by different kinases. In this work, we report the identifi cation of Mdm2, an E3 ligase involved in the control of cell growth and survival, as a key player in GPCR degradation. Mdm2 and GRK2 associate upon GPCR stimulation in a β-arrestin-dependent manner. Increased Mdm2 expression accelerates GRK2 proteolysis and promotes kinase ubiquitination at defi ned residues, whereas GRK2 turnover is markedly impaired in Mdm2- defi cient cells. In addition, β-arrestin recruitment to the receptor also promotes GRK2 degradation by the proteasome pathway in a Mdm2-independent manner, triggering the phosphorylation of GRK2 by c-Src and the subsequent recognition of the tyrosine-phosphorylated GRK2 by E3 ligases as Hakai. Interestingly, we fi nd that activation of the PI3K/AKT pathway by IGF-1 alters Mdm2-mediated GRK2 degradation, leading to enhanced GRK2 stability and increased kinase levels. Notably, increased GRK2 levels are detected in transformed vs. non-transformed breast cell lines, and in a proportion of breast cancer pacients, particularly those showing increased AKT pathway activity. Finally, we report that GRK2 levels positively modulate the proliferation rate of the MCF-7 breast carcinoma cell line and the migration and invasion of breast cancer and melanoma cell lines towards key chemotactic signals. Overall, our data suggest that GRK2 plays a role in tumor progression and that inhibition of GRK2 expression could represent a novel therapeutic strategy in certain cancer types.Peer reviewedUniversidad Autónoma de MadridMayor Menéndez, FedericoPenela Márquez, Petronila200820082007info:eu-repo/semantics/doctoralThesishttp://purl.org/coar/resource_type/c_db063787208 bytesapplication/pdfhttp://hdl.handle.net/10261/7956reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Españolinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/79562026-05-22T06:33:51Z
dc.title.none.fl_str_mv Modulación de la estabilidad de la quinasa de receptores acoplados a proteínas G (GRK2) por la ligasa Mdm2
title Modulación de la estabilidad de la quinasa de receptores acoplados a proteínas G (GRK2) por la ligasa Mdm2
spellingShingle Modulación de la estabilidad de la quinasa de receptores acoplados a proteínas G (GRK2) por la ligasa Mdm2
Salcedo, Alicia
Células proliferación
Proteínas G
title_short Modulación de la estabilidad de la quinasa de receptores acoplados a proteínas G (GRK2) por la ligasa Mdm2
title_full Modulación de la estabilidad de la quinasa de receptores acoplados a proteínas G (GRK2) por la ligasa Mdm2
title_fullStr Modulación de la estabilidad de la quinasa de receptores acoplados a proteínas G (GRK2) por la ligasa Mdm2
title_full_unstemmed Modulación de la estabilidad de la quinasa de receptores acoplados a proteínas G (GRK2) por la ligasa Mdm2
title_sort Modulación de la estabilidad de la quinasa de receptores acoplados a proteínas G (GRK2) por la ligasa Mdm2
dc.creator.none.fl_str_mv Salcedo, Alicia
author Salcedo, Alicia
author_facet Salcedo, Alicia
author_role author
dc.contributor.none.fl_str_mv Mayor Menéndez, Federico
Penela Márquez, Petronila
dc.subject.none.fl_str_mv Células proliferación
Proteínas G
topic Células proliferación
Proteínas G
description Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 12-12-2007
publishDate 2007
dc.date.none.fl_str_mv 2007
2008
2008
dc.type.none.fl_str_mv info:eu-repo/semantics/doctoralThesis
http://purl.org/coar/resource_type/c_db06
format doctoralThesis
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/7956
url http://hdl.handle.net/10261/7956
dc.language.none.fl_str_mv Español
language_invalid_str_mv Español
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 3787208 bytes
application/pdf
dc.publisher.none.fl_str_mv Universidad Autónoma de Madrid
publisher.none.fl_str_mv Universidad Autónoma de Madrid
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
repository.mail.fl_str_mv
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score 15,81155

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