Regulation of protein kinase C-related Protein Kinase 2 (PRK2) by an intermolecular PRK2-PRK2 interaction mediated by its N-terminal domain

Autores
Bauer, Angelika F.; Sonzogni, Silvina Veronica; Meyer, Lucas; Zeuzem, Stefan; Piiper, Albrecht; Biondi, Ricardo Miguel; Neimanis, Sonja
Año de publicación
2012
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Protein kinase C-related protein kinases (PRKs) are effectors of the Rho family of small GTPases and play a role in the development of diseases such as prostate cancer and hepatitis C. Here we examined the mechanism underlying the regulation of PRK2 by its N-terminal region. We show that the N-terminal region of PRK2 prevents the interaction with its upstream kinase, the 3-phosphoinositide-dependent kinase 1 (PDK1), which phosphorylates the activation loop of PRK2. We confirm that the N-terminal region directly inhibits the kinase activity of PRK2. However, in contrast to previous models, our data indicate that this inhibition is mediated in trans through an intermolecular PRK2-PRK2 interaction. Our results also suggest that amino acids 487-501, located in the linker region between the N-terminal domains and the catalytic domain, contribute to the PRK2-PRK2 dimer formation. This dimerization is further supported by other N-terminal domains. Additionally, we provide evidence that the region C-terminal to the catalytic domain intramolecularly activates PRK2. Finally, we discovered that the catalytic domain mediates a cross-talk between the inhibitory N-terminal region and the activating C-terminal region. The results presented here describe a novel mechanism of regulation among AGC kinases and offer new insights into potential approaches to pharmacologically regulate PRK2.
Fil: Bauer, Angelika F.. Goethe Universitat Frankfurt; Alemania
Fil: Sonzogni, Silvina Veronica. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria; Argentina. Goethe Universitat Frankfurt; Alemania
Fil: Meyer, Lucas. Goethe Universitat Frankfurt; Alemania
Fil: Zeuzem, Stefan. Goethe Universitat Frankfurt; Alemania
Fil: Piiper, Albrecht. Goethe Universitat Frankfurt; Alemania
Fil: Biondi, Ricardo Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria; Argentina. Goethe Universitat Frankfurt; Alemania
Fil: Neimanis, Sonja. Goethe Universitat Frankfurt; Alemania
Materia
PRK2
REGULATION
DIMER
PDK1
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:11336/216618

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repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Regulation of protein kinase C-related Protein Kinase 2 (PRK2) by an intermolecular PRK2-PRK2 interaction mediated by its N-terminal domainBauer, Angelika F.Sonzogni, Silvina VeronicaMeyer, LucasZeuzem, StefanPiiper, AlbrechtBiondi, Ricardo MiguelNeimanis, SonjaPRK2REGULATIONDIMERPDK1https://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Protein kinase C-related protein kinases (PRKs) are effectors of the Rho family of small GTPases and play a role in the development of diseases such as prostate cancer and hepatitis C. Here we examined the mechanism underlying the regulation of PRK2 by its N-terminal region. We show that the N-terminal region of PRK2 prevents the interaction with its upstream kinase, the 3-phosphoinositide-dependent kinase 1 (PDK1), which phosphorylates the activation loop of PRK2. We confirm that the N-terminal region directly inhibits the kinase activity of PRK2. However, in contrast to previous models, our data indicate that this inhibition is mediated in trans through an intermolecular PRK2-PRK2 interaction. Our results also suggest that amino acids 487-501, located in the linker region between the N-terminal domains and the catalytic domain, contribute to the PRK2-PRK2 dimer formation. This dimerization is further supported by other N-terminal domains. Additionally, we provide evidence that the region C-terminal to the catalytic domain intramolecularly activates PRK2. Finally, we discovered that the catalytic domain mediates a cross-talk between the inhibitory N-terminal region and the activating C-terminal region. The results presented here describe a novel mechanism of regulation among AGC kinases and offer new insights into potential approaches to pharmacologically regulate PRK2.Fil: Bauer, Angelika F.. Goethe Universitat Frankfurt; AlemaniaFil: Sonzogni, Silvina Veronica. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria; Argentina. Goethe Universitat Frankfurt; AlemaniaFil: Meyer, Lucas. Goethe Universitat Frankfurt; AlemaniaFil: Zeuzem, Stefan. Goethe Universitat Frankfurt; AlemaniaFil: Piiper, Albrecht. Goethe Universitat Frankfurt; AlemaniaFil: Biondi, Ricardo Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria; Argentina. Goethe Universitat Frankfurt; AlemaniaFil: Neimanis, Sonja. Goethe Universitat Frankfurt; AlemaniaAmerican Society for Biochemistry and Molecular Biology2012-06info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/216618Bauer, Angelika F.; Sonzogni, Silvina Veronica; Meyer, Lucas; Zeuzem, Stefan; Piiper, Albrecht; et al.; Regulation of protein kinase C-related Protein Kinase 2 (PRK2) by an intermolecular PRK2-PRK2 interaction mediated by its N-terminal domain; American Society for Biochemistry and Molecular Biology; Journal of Biological Chemistry (online); 287; 24; 6-2012; 20590-206020021-9258CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://www.jbc.org/content/287/24/20590.longinfo:eu-repo/semantics/altIdentifier/doi/10.1074/jbc.M111.327437info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T12:00:04Zoai:ri.conicet.gov.ar:11336/216618instacron: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:34982025-10-22 12:00:05.019CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Regulation of protein kinase C-related Protein Kinase 2 (PRK2) by an intermolecular PRK2-PRK2 interaction mediated by its N-terminal domain
title Regulation of protein kinase C-related Protein Kinase 2 (PRK2) by an intermolecular PRK2-PRK2 interaction mediated by its N-terminal domain
spellingShingle Regulation of protein kinase C-related Protein Kinase 2 (PRK2) by an intermolecular PRK2-PRK2 interaction mediated by its N-terminal domain
Bauer, Angelika F.
PRK2
REGULATION
DIMER
PDK1
title_short Regulation of protein kinase C-related Protein Kinase 2 (PRK2) by an intermolecular PRK2-PRK2 interaction mediated by its N-terminal domain
title_full Regulation of protein kinase C-related Protein Kinase 2 (PRK2) by an intermolecular PRK2-PRK2 interaction mediated by its N-terminal domain
title_fullStr Regulation of protein kinase C-related Protein Kinase 2 (PRK2) by an intermolecular PRK2-PRK2 interaction mediated by its N-terminal domain
title_full_unstemmed Regulation of protein kinase C-related Protein Kinase 2 (PRK2) by an intermolecular PRK2-PRK2 interaction mediated by its N-terminal domain
title_sort Regulation of protein kinase C-related Protein Kinase 2 (PRK2) by an intermolecular PRK2-PRK2 interaction mediated by its N-terminal domain
dc.creator.none.fl_str_mv Bauer, Angelika F.
Sonzogni, Silvina Veronica
Meyer, Lucas
Zeuzem, Stefan
Piiper, Albrecht
Biondi, Ricardo Miguel
Neimanis, Sonja
author Bauer, Angelika F.
author_facet Bauer, Angelika F.
Sonzogni, Silvina Veronica
Meyer, Lucas
Zeuzem, Stefan
Piiper, Albrecht
Biondi, Ricardo Miguel
Neimanis, Sonja
author_role author
author2 Sonzogni, Silvina Veronica
Meyer, Lucas
Zeuzem, Stefan
Piiper, Albrecht
Biondi, Ricardo Miguel
Neimanis, Sonja
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv PRK2
REGULATION
DIMER
PDK1
topic PRK2
REGULATION
DIMER
PDK1
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Protein kinase C-related protein kinases (PRKs) are effectors of the Rho family of small GTPases and play a role in the development of diseases such as prostate cancer and hepatitis C. Here we examined the mechanism underlying the regulation of PRK2 by its N-terminal region. We show that the N-terminal region of PRK2 prevents the interaction with its upstream kinase, the 3-phosphoinositide-dependent kinase 1 (PDK1), which phosphorylates the activation loop of PRK2. We confirm that the N-terminal region directly inhibits the kinase activity of PRK2. However, in contrast to previous models, our data indicate that this inhibition is mediated in trans through an intermolecular PRK2-PRK2 interaction. Our results also suggest that amino acids 487-501, located in the linker region between the N-terminal domains and the catalytic domain, contribute to the PRK2-PRK2 dimer formation. This dimerization is further supported by other N-terminal domains. Additionally, we provide evidence that the region C-terminal to the catalytic domain intramolecularly activates PRK2. Finally, we discovered that the catalytic domain mediates a cross-talk between the inhibitory N-terminal region and the activating C-terminal region. The results presented here describe a novel mechanism of regulation among AGC kinases and offer new insights into potential approaches to pharmacologically regulate PRK2.
Fil: Bauer, Angelika F.. Goethe Universitat Frankfurt; Alemania
Fil: Sonzogni, Silvina Veronica. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria; Argentina. Goethe Universitat Frankfurt; Alemania
Fil: Meyer, Lucas. Goethe Universitat Frankfurt; Alemania
Fil: Zeuzem, Stefan. Goethe Universitat Frankfurt; Alemania
Fil: Piiper, Albrecht. Goethe Universitat Frankfurt; Alemania
Fil: Biondi, Ricardo Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria; Argentina. Goethe Universitat Frankfurt; Alemania
Fil: Neimanis, Sonja. Goethe Universitat Frankfurt; Alemania
description Protein kinase C-related protein kinases (PRKs) are effectors of the Rho family of small GTPases and play a role in the development of diseases such as prostate cancer and hepatitis C. Here we examined the mechanism underlying the regulation of PRK2 by its N-terminal region. We show that the N-terminal region of PRK2 prevents the interaction with its upstream kinase, the 3-phosphoinositide-dependent kinase 1 (PDK1), which phosphorylates the activation loop of PRK2. We confirm that the N-terminal region directly inhibits the kinase activity of PRK2. However, in contrast to previous models, our data indicate that this inhibition is mediated in trans through an intermolecular PRK2-PRK2 interaction. Our results also suggest that amino acids 487-501, located in the linker region between the N-terminal domains and the catalytic domain, contribute to the PRK2-PRK2 dimer formation. This dimerization is further supported by other N-terminal domains. Additionally, we provide evidence that the region C-terminal to the catalytic domain intramolecularly activates PRK2. Finally, we discovered that the catalytic domain mediates a cross-talk between the inhibitory N-terminal region and the activating C-terminal region. The results presented here describe a novel mechanism of regulation among AGC kinases and offer new insights into potential approaches to pharmacologically regulate PRK2.
publishDate 2012
dc.date.none.fl_str_mv 2012-06
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/11336/216618
Bauer, Angelika F.; Sonzogni, Silvina Veronica; Meyer, Lucas; Zeuzem, Stefan; Piiper, Albrecht; et al.; Regulation of protein kinase C-related Protein Kinase 2 (PRK2) by an intermolecular PRK2-PRK2 interaction mediated by its N-terminal domain; American Society for Biochemistry and Molecular Biology; Journal of Biological Chemistry (online); 287; 24; 6-2012; 20590-20602
0021-9258
CONICET Digital
CONICET
url http://hdl.handle.net/11336/216618
identifier_str_mv Bauer, Angelika F.; Sonzogni, Silvina Veronica; Meyer, Lucas; Zeuzem, Stefan; Piiper, Albrecht; et al.; Regulation of protein kinase C-related Protein Kinase 2 (PRK2) by an intermolecular PRK2-PRK2 interaction mediated by its N-terminal domain; American Society for Biochemistry and Molecular Biology; Journal of Biological Chemistry (online); 287; 24; 6-2012; 20590-20602
0021-9258
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://www.jbc.org/content/287/24/20590.long
info:eu-repo/semantics/altIdentifier/doi/10.1074/jbc.M111.327437
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
dc.publisher.none.fl_str_mv American Society for Biochemistry and Molecular Biology
publisher.none.fl_str_mv American Society for Biochemistry and Molecular Biology
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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