Molecular basis of p38a MAPK signaling

[eng] Cells often need to respond to damaging internal and external stimuli. One of the pathways that is frequently activated by stress stimuli involves activation of the kinase p38alpha, which can phosphorylate different substrates, including MK2. Experiments using purified proteins have shown that...

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Detalles Bibliográficos
Autor: Gutierrez Prat, Núria
Tipo de recurso: tesis doctoral
Estado:Versión publicada
Fecha de publicación:2018
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/125684
Acceso en línea:https://hdl.handle.net/2445/125684
http://hdl.handle.net/10803/663438
Access Level:acceso abierto
Palabra clave:Oncologia
Proteínas quinasas
Oncology
Protein kinases
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spelling Molecular basis of p38a MAPK signalingGutierrez Prat, NúriaOncologiaProteínas quinasasOncologyProtein kinases[eng] Cells often need to respond to damaging internal and external stimuli. One of the pathways that is frequently activated by stress stimuli involves activation of the kinase p38alpha, which can phosphorylate different substrates, including MK2. Experiments using purified proteins have shown that non-phosphorylated p38alpha and MK2 can form a tight complex, in which structural constraints impede the interaction of both kinases with effectors and regulators. It is therefore critical to understand how the interaction between p38alpha and MK2 is regulated to ensure that they can release from each other and phosphorylate the required substrates that mediate their functions. Here, we show that in cells under homeostatic conditions, endogenous p38alpha and MK2 form a stable complex that is disrupted upon phosphorylation of both proteins. The separation of the two kinases causes MK2 destabilization and degradation by the proteasome in a MDM2-dependent manner. Depending on the intensity of the stimuli, p38alpha and MK2 undergo different fates. Transient stimulation leads to complex separation and MK2 degradation followed by increased MK2 expression, and the eventual reassembly of the p38alpha:MK2 complex. On the contrary, in cells exposed to strong stimuli that lead to sustained p38alpha activation, as it is often the case with stress, both kinases remain phosphorylated, cannot bind to each other and eventually become destabilized, being unable to recover the steady state. Taken together, our results illustrate a new mechanism of p38alpha signaling regulation based on the p38alpha:MK2 complex dynamics, which may have implications for different processes regulated by p38alpha and MK2 signaling.Universitat de BarcelonaRodríguez Nebreda, ÁngelUniversitat de Barcelona. Facultat de Farmàcia i Ciències de l'Alimentació2018info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/125684http://hdl.handle.net/10803/663438Tesis Doctorals - Facultat - Farmàcia i Ciències de l'Alimentacióreponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglés(c) Gutierrez, 2018info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1256842026-05-27T06:46:51Z
dc.title.none.fl_str_mv Molecular basis of p38a MAPK signaling
title Molecular basis of p38a MAPK signaling
spellingShingle Molecular basis of p38a MAPK signaling
Gutierrez Prat, Núria
Oncologia
Proteínas quinasas
Oncology
Protein kinases
title_short Molecular basis of p38a MAPK signaling
title_full Molecular basis of p38a MAPK signaling
title_fullStr Molecular basis of p38a MAPK signaling
title_full_unstemmed Molecular basis of p38a MAPK signaling
title_sort Molecular basis of p38a MAPK signaling
dc.creator.none.fl_str_mv Gutierrez Prat, Núria
author Gutierrez Prat, Núria
author_facet Gutierrez Prat, Núria
author_role author
dc.contributor.none.fl_str_mv Rodríguez Nebreda, Ángel
Universitat de Barcelona. Facultat de Farmàcia i Ciències de l'Alimentació
dc.subject.none.fl_str_mv Oncologia
Proteínas quinasas
Oncology
Protein kinases
topic Oncologia
Proteínas quinasas
Oncology
Protein kinases
description [eng] Cells often need to respond to damaging internal and external stimuli. One of the pathways that is frequently activated by stress stimuli involves activation of the kinase p38alpha, which can phosphorylate different substrates, including MK2. Experiments using purified proteins have shown that non-phosphorylated p38alpha and MK2 can form a tight complex, in which structural constraints impede the interaction of both kinases with effectors and regulators. It is therefore critical to understand how the interaction between p38alpha and MK2 is regulated to ensure that they can release from each other and phosphorylate the required substrates that mediate their functions. Here, we show that in cells under homeostatic conditions, endogenous p38alpha and MK2 form a stable complex that is disrupted upon phosphorylation of both proteins. The separation of the two kinases causes MK2 destabilization and degradation by the proteasome in a MDM2-dependent manner. Depending on the intensity of the stimuli, p38alpha and MK2 undergo different fates. Transient stimulation leads to complex separation and MK2 degradation followed by increased MK2 expression, and the eventual reassembly of the p38alpha:MK2 complex. On the contrary, in cells exposed to strong stimuli that lead to sustained p38alpha activation, as it is often the case with stress, both kinases remain phosphorylated, cannot bind to each other and eventually become destabilized, being unable to recover the steady state. Taken together, our results illustrate a new mechanism of p38alpha signaling regulation based on the p38alpha:MK2 complex dynamics, which may have implications for different processes regulated by p38alpha and MK2 signaling.
publishDate 2018
dc.date.none.fl_str_mv 2018
dc.type.none.fl_str_mv info:eu-repo/semantics/doctoralThesis
info:eu-repo/semantics/publishedVersion
format doctoralThesis
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/125684
http://hdl.handle.net/10803/663438
url https://hdl.handle.net/2445/125684
http://hdl.handle.net/10803/663438
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv (c) Gutierrez, 2018
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) Gutierrez, 2018
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Universitat de Barcelona
publisher.none.fl_str_mv Universitat de Barcelona
dc.source.none.fl_str_mv Tesis Doctorals - Facultat - Farmàcia i Ciències de l'Alimentació
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,301629

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