CDK and MAPK Synergistically Regulate Signaling Dynamics via a Shared Multi-site Phosphorylation Region on the Scaffold Protein Ste5

Autores
Repetto, María Victoria; Winters, Matthew J.; Bush, Alan; Reiter, Wolfgang; Hollenstein, David Maria; Ammerer, Gustav; Pryciak, Peter M.; Colman Lerner, Alejandro Ariel
Año de publicación
2018
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
We report an unanticipated system of joint regulation by cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK), involving collaborative multi-site phosphorylation of a single substrate. In budding yeast, the protein Ste5 controls signaling through a G1 arrest pathway. Upon cell-cycle entry, CDK inhibits Ste5 via multiple phosphorylation sites, disrupting its membrane association. Using quantitative time-lapse microscopy, we examined Ste5 membrane recruitment dynamics at different cell-cycle stages. Surprisingly, in S phase, where Ste5 recruitment should be blocked, we observed an initial recruitment followed by a steep drop-off. This delayed inhibition revealed a requirement for both CDK activity and negative feedback from the pathway MAPK Fus3. Mutagenesis, mass spectrometry, and electrophoretic analyses suggest that the CDK and MAPK modify shared sites, which are most extensively phosphorylated when both kinases are active and able to bind their docking sites on Ste5. Such collaborative phosphorylation can broaden regulatory inputs and diversify output dynamics of signaling pathways. CDKs and MAPKs phosphorylate similar sites yet generally have distinct functions and substrates. Repetto et al. uncover a case where these kinases collaborate to regulate a substrate in a signal transduction pathway by phosphorylating a shared set of sites.
Fil: Repetto, María Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina
Fil: Winters, Matthew J.. University of Massachussets; Estados Unidos
Fil: Bush, Alan. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina
Fil: Reiter, Wolfgang. Max F. Perutz Laboratories; Austria
Fil: Hollenstein, David Maria. Max F. Perutz Laboratories; Austria
Fil: Ammerer, Gustav. Max F. Perutz Laboratories; Austria
Fil: Pryciak, Peter M.. University of Massachussets; Estados Unidos
Fil: Colman Lerner, Alejandro Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina
Materia
CDC28
CKS1
CLN2
CYCLIN
G PROTEIN
MATING
PHEROMONE
SIGNAL TRANSDUCTION
START
STE4
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/88500
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/88500
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling CDK and MAPK Synergistically Regulate Signaling Dynamics via a Shared Multi-site Phosphorylation Region on the Scaffold Protein Ste5Repetto, María VictoriaWinters, Matthew J.Bush, AlanReiter, WolfgangHollenstein, David MariaAmmerer, GustavPryciak, Peter M.Colman Lerner, Alejandro ArielCDC28CKS1CLN2CYCLING PROTEINMATINGPHEROMONESIGNAL TRANSDUCTIONSTARTSTE4https://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1We report an unanticipated system of joint regulation by cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK), involving collaborative multi-site phosphorylation of a single substrate. In budding yeast, the protein Ste5 controls signaling through a G1 arrest pathway. Upon cell-cycle entry, CDK inhibits Ste5 via multiple phosphorylation sites, disrupting its membrane association. Using quantitative time-lapse microscopy, we examined Ste5 membrane recruitment dynamics at different cell-cycle stages. Surprisingly, in S phase, where Ste5 recruitment should be blocked, we observed an initial recruitment followed by a steep drop-off. This delayed inhibition revealed a requirement for both CDK activity and negative feedback from the pathway MAPK Fus3. Mutagenesis, mass spectrometry, and electrophoretic analyses suggest that the CDK and MAPK modify shared sites, which are most extensively phosphorylated when both kinases are active and able to bind their docking sites on Ste5. Such collaborative phosphorylation can broaden regulatory inputs and diversify output dynamics of signaling pathways. CDKs and MAPKs phosphorylate similar sites yet generally have distinct functions and substrates. Repetto et al. uncover a case where these kinases collaborate to regulate a substrate in a signal transduction pathway by phosphorylating a shared set of sites.Fil: Repetto, María Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Winters, Matthew J.. University of Massachussets; Estados UnidosFil: Bush, Alan. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Reiter, Wolfgang. Max F. Perutz Laboratories; AustriaFil: Hollenstein, David Maria. Max F. Perutz Laboratories; AustriaFil: Ammerer, Gustav. Max F. Perutz Laboratories; AustriaFil: Pryciak, Peter M.. University of Massachussets; Estados UnidosFil: Colman Lerner, Alejandro Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaCell Press2018-03info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/88500Repetto, María Victoria; Winters, Matthew J.; Bush, Alan; Reiter, Wolfgang; Hollenstein, David Maria; et al.; CDK and MAPK Synergistically Regulate Signaling Dynamics via a Shared Multi-site Phosphorylation Region on the Scaffold Protein Ste5; Cell Press; Molecular Cell; 69; 6; 3-2018; 938-952.e61097-2765CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.molcel.2018.02.018info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S1097276518301370info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-10T13:11:44Zoai:ri.conicet.gov.ar:11336/88500instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-10 13:11:44.769CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv CDK and MAPK Synergistically Regulate Signaling Dynamics via a Shared Multi-site Phosphorylation Region on the Scaffold Protein Ste5
title CDK and MAPK Synergistically Regulate Signaling Dynamics via a Shared Multi-site Phosphorylation Region on the Scaffold Protein Ste5
spellingShingle CDK and MAPK Synergistically Regulate Signaling Dynamics via a Shared Multi-site Phosphorylation Region on the Scaffold Protein Ste5
Repetto, María Victoria
CDC28
CKS1
CLN2
CYCLIN
G PROTEIN
MATING
PHEROMONE
SIGNAL TRANSDUCTION
START
STE4
title_short CDK and MAPK Synergistically Regulate Signaling Dynamics via a Shared Multi-site Phosphorylation Region on the Scaffold Protein Ste5
title_full CDK and MAPK Synergistically Regulate Signaling Dynamics via a Shared Multi-site Phosphorylation Region on the Scaffold Protein Ste5
title_fullStr CDK and MAPK Synergistically Regulate Signaling Dynamics via a Shared Multi-site Phosphorylation Region on the Scaffold Protein Ste5
title_full_unstemmed CDK and MAPK Synergistically Regulate Signaling Dynamics via a Shared Multi-site Phosphorylation Region on the Scaffold Protein Ste5
title_sort CDK and MAPK Synergistically Regulate Signaling Dynamics via a Shared Multi-site Phosphorylation Region on the Scaffold Protein Ste5
dc.creator.none.fl_str_mv Repetto, María Victoria
Winters, Matthew J.
Bush, Alan
Reiter, Wolfgang
Hollenstein, David Maria
Ammerer, Gustav
Pryciak, Peter M.
Colman Lerner, Alejandro Ariel
author Repetto, María Victoria
author_facet Repetto, María Victoria
Winters, Matthew J.
Bush, Alan
Reiter, Wolfgang
Hollenstein, David Maria
Ammerer, Gustav
Pryciak, Peter M.
Colman Lerner, Alejandro Ariel
author_role author
author2 Winters, Matthew J.
Bush, Alan
Reiter, Wolfgang
Hollenstein, David Maria
Ammerer, Gustav
Pryciak, Peter M.
Colman Lerner, Alejandro Ariel
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv CDC28
CKS1
CLN2
CYCLIN
G PROTEIN
MATING
PHEROMONE
SIGNAL TRANSDUCTION
START
STE4
topic CDC28
CKS1
CLN2
CYCLIN
G PROTEIN
MATING
PHEROMONE
SIGNAL TRANSDUCTION
START
STE4
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv We report an unanticipated system of joint regulation by cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK), involving collaborative multi-site phosphorylation of a single substrate. In budding yeast, the protein Ste5 controls signaling through a G1 arrest pathway. Upon cell-cycle entry, CDK inhibits Ste5 via multiple phosphorylation sites, disrupting its membrane association. Using quantitative time-lapse microscopy, we examined Ste5 membrane recruitment dynamics at different cell-cycle stages. Surprisingly, in S phase, where Ste5 recruitment should be blocked, we observed an initial recruitment followed by a steep drop-off. This delayed inhibition revealed a requirement for both CDK activity and negative feedback from the pathway MAPK Fus3. Mutagenesis, mass spectrometry, and electrophoretic analyses suggest that the CDK and MAPK modify shared sites, which are most extensively phosphorylated when both kinases are active and able to bind their docking sites on Ste5. Such collaborative phosphorylation can broaden regulatory inputs and diversify output dynamics of signaling pathways. CDKs and MAPKs phosphorylate similar sites yet generally have distinct functions and substrates. Repetto et al. uncover a case where these kinases collaborate to regulate a substrate in a signal transduction pathway by phosphorylating a shared set of sites.
Fil: Repetto, María Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina
Fil: Winters, Matthew J.. University of Massachussets; Estados Unidos
Fil: Bush, Alan. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina
Fil: Reiter, Wolfgang. Max F. Perutz Laboratories; Austria
Fil: Hollenstein, David Maria. Max F. Perutz Laboratories; Austria
Fil: Ammerer, Gustav. Max F. Perutz Laboratories; Austria
Fil: Pryciak, Peter M.. University of Massachussets; Estados Unidos
Fil: Colman Lerner, Alejandro Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina
description We report an unanticipated system of joint regulation by cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK), involving collaborative multi-site phosphorylation of a single substrate. In budding yeast, the protein Ste5 controls signaling through a G1 arrest pathway. Upon cell-cycle entry, CDK inhibits Ste5 via multiple phosphorylation sites, disrupting its membrane association. Using quantitative time-lapse microscopy, we examined Ste5 membrane recruitment dynamics at different cell-cycle stages. Surprisingly, in S phase, where Ste5 recruitment should be blocked, we observed an initial recruitment followed by a steep drop-off. This delayed inhibition revealed a requirement for both CDK activity and negative feedback from the pathway MAPK Fus3. Mutagenesis, mass spectrometry, and electrophoretic analyses suggest that the CDK and MAPK modify shared sites, which are most extensively phosphorylated when both kinases are active and able to bind their docking sites on Ste5. Such collaborative phosphorylation can broaden regulatory inputs and diversify output dynamics of signaling pathways. CDKs and MAPKs phosphorylate similar sites yet generally have distinct functions and substrates. Repetto et al. uncover a case where these kinases collaborate to regulate a substrate in a signal transduction pathway by phosphorylating a shared set of sites.
publishDate 2018
dc.date.none.fl_str_mv 2018-03
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/88500
Repetto, María Victoria; Winters, Matthew J.; Bush, Alan; Reiter, Wolfgang; Hollenstein, David Maria; et al.; CDK and MAPK Synergistically Regulate Signaling Dynamics via a Shared Multi-site Phosphorylation Region on the Scaffold Protein Ste5; Cell Press; Molecular Cell; 69; 6; 3-2018; 938-952.e6
1097-2765
CONICET Digital
CONICET
url http://hdl.handle.net/11336/88500
identifier_str_mv Repetto, María Victoria; Winters, Matthew J.; Bush, Alan; Reiter, Wolfgang; Hollenstein, David Maria; et al.; CDK and MAPK Synergistically Regulate Signaling Dynamics via a Shared Multi-site Phosphorylation Region on the Scaffold Protein Ste5; Cell Press; Molecular Cell; 69; 6; 3-2018; 938-952.e6
1097-2765
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1016/j.molcel.2018.02.018
info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S1097276518301370
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Cell Press
publisher.none.fl_str_mv Cell Press
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 12.993085

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