Protein kinase D1 (PKD1) phosphorylation on Ser203 by type i p21-activated kinase (PAK) regulates PKD1 localization
- Autores
- Chang, Jen Kuan; Ni, Yang; Han, Liang; Sinnett-Smith, James; Jacamo, Rodrigo; Rey, Osvaldo; Young, Steven H.; Rozengurt, Enrique
- Año de publicación
- 2017
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- Although PKC-mediated phosphorylation of protein kinase D1 (PKD1) has been extensively characterized, little is known about PKD1 regulation by other upstream kinases. Here we report that stimulation of epithelial or fibroblastic cells with G protein-coupled receptor agonists, including angiotensin II or bombesin, induced rapid and persistent PKD1 phosphorylation at Ser203, a highly conserved residue located within the PKD1 N-terminal domain. Exposure to PKD or PKC family inhibitors did not prevent PKD1 phosphorylation at Ser203, indicating that it is not mediated by autophosphorylation. In contrast, several lines of evidence indicated that the phosphorylation of PKD1 at Ser203 is mediated by kinases of the class I PAK subfamily, specifically 1) exposing cells to four structurally unrelated PAK inhibitors (PF-3758309, FRAX486, FRAX597, and IPA-3) that act via different mechanisms abrogated PKD1 phosphorylation at Ser203, 2) siRNA-mediated knockdown of PAK1 and PAK2 in IEC-18 and Swiss 3T3 cells blunted PKD1 phosphorylation at Ser203, 3) phosphorylation of Ser203 markedly increased in vitro when recombinant PKD1 was incubated with either PAK1 or PAK2 in the presence of ATP. PAK inhibitors did not interfere with G protein-coupled receptor activation-induced rapid translocation of PKD1 to the plasma membrane but strikingly prevented the dissociation of PKD1 from the plasma membrane and blunted the phosphorylation of nuclear targets, including class IIa histone deacetylases. We conclude that PAK-mediated phosphorylation of PKD1 at Ser203 triggers its membrane dissociation and subsequent entry into the nucleus, thereby regulating the phosphorylation of PKD1 nuclear targets, including class IIa histone deacetylases.
Fil: Chang, Jen Kuan. University of California at Los Angeles. School of Medicine; Estados Unidos
Fil: Ni, Yang. University of California at Los Angeles. School of Medicine; Estados Unidos. Shandong University; China
Fil: Han, Liang. University of California at Los Angeles. School of Medicine; Estados Unidos. Xi'an Jiaotong University; China
Fil: Sinnett-Smith, James. University of California at Los Angeles. School of Medicine; Estados Unidos
Fil: Jacamo, Rodrigo. University Of Texas Md Anderson Cancer Center;
Fil: Rey, Osvaldo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; Argentina
Fil: Young, Steven H.. University of California at Los Angeles. School of Medicine; Estados Unidos. University of Texas; Estados Unidos
Fil: Rozengurt, Enrique. University of Texas; Estados Unidos. University of California at Los Angeles. School of Medicine; Estados Unidos - Materia
-
GPCR
PKD
PAK
CANCER - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
- Repositorio
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/82596
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Protein kinase D1 (PKD1) phosphorylation on Ser203 by type i p21-activated kinase (PAK) regulates PKD1 localizationChang, Jen KuanNi, YangHan, LiangSinnett-Smith, JamesJacamo, RodrigoRey, OsvaldoYoung, Steven H.Rozengurt, EnriqueGPCRPKDPAKCANCERhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Although PKC-mediated phosphorylation of protein kinase D1 (PKD1) has been extensively characterized, little is known about PKD1 regulation by other upstream kinases. Here we report that stimulation of epithelial or fibroblastic cells with G protein-coupled receptor agonists, including angiotensin II or bombesin, induced rapid and persistent PKD1 phosphorylation at Ser203, a highly conserved residue located within the PKD1 N-terminal domain. Exposure to PKD or PKC family inhibitors did not prevent PKD1 phosphorylation at Ser203, indicating that it is not mediated by autophosphorylation. In contrast, several lines of evidence indicated that the phosphorylation of PKD1 at Ser203 is mediated by kinases of the class I PAK subfamily, specifically 1) exposing cells to four structurally unrelated PAK inhibitors (PF-3758309, FRAX486, FRAX597, and IPA-3) that act via different mechanisms abrogated PKD1 phosphorylation at Ser203, 2) siRNA-mediated knockdown of PAK1 and PAK2 in IEC-18 and Swiss 3T3 cells blunted PKD1 phosphorylation at Ser203, 3) phosphorylation of Ser203 markedly increased in vitro when recombinant PKD1 was incubated with either PAK1 or PAK2 in the presence of ATP. PAK inhibitors did not interfere with G protein-coupled receptor activation-induced rapid translocation of PKD1 to the plasma membrane but strikingly prevented the dissociation of PKD1 from the plasma membrane and blunted the phosphorylation of nuclear targets, including class IIa histone deacetylases. We conclude that PAK-mediated phosphorylation of PKD1 at Ser203 triggers its membrane dissociation and subsequent entry into the nucleus, thereby regulating the phosphorylation of PKD1 nuclear targets, including class IIa histone deacetylases.Fil: Chang, Jen Kuan. University of California at Los Angeles. School of Medicine; Estados UnidosFil: Ni, Yang. University of California at Los Angeles. School of Medicine; Estados Unidos. Shandong University; ChinaFil: Han, Liang. University of California at Los Angeles. School of Medicine; Estados Unidos. Xi'an Jiaotong University; ChinaFil: Sinnett-Smith, James. University of California at Los Angeles. School of Medicine; Estados UnidosFil: Jacamo, Rodrigo. University Of Texas Md Anderson Cancer Center;Fil: Rey, Osvaldo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; ArgentinaFil: Young, Steven H.. University of California at Los Angeles. School of Medicine; Estados Unidos. University of Texas; Estados UnidosFil: Rozengurt, Enrique. University of Texas; Estados Unidos. University of California at Los Angeles. School of Medicine; Estados UnidosAmerican Society for Biochemistry and Molecular Biology2017-06info: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/11336/82596Chang, Jen Kuan; Ni, Yang; Han, Liang; Sinnett-Smith, James; Jacamo, Rodrigo; et al.; Protein kinase D1 (PKD1) phosphorylation on Ser203 by type i p21-activated kinase (PAK) regulates PKD1 localization; American Society for Biochemistry and Molecular Biology; Journal of Biological Chemistry (online); 292; 23; 6-2017; 9523-95390021-9258CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://www.jbc.org/cgi/pmidlookup?view=long&pmid=28408623info:eu-repo/semantics/altIdentifier/doi/10.1074/jbc.M116.771394info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5465480/info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:02:26Zoai:ri.conicet.gov.ar:11336/82596instacron: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:34982025-09-03 10:02:26.407CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
dc.title.none.fl_str_mv |
Protein kinase D1 (PKD1) phosphorylation on Ser203 by type i p21-activated kinase (PAK) regulates PKD1 localization |
title |
Protein kinase D1 (PKD1) phosphorylation on Ser203 by type i p21-activated kinase (PAK) regulates PKD1 localization |
spellingShingle |
Protein kinase D1 (PKD1) phosphorylation on Ser203 by type i p21-activated kinase (PAK) regulates PKD1 localization Chang, Jen Kuan GPCR PKD PAK CANCER |
title_short |
Protein kinase D1 (PKD1) phosphorylation on Ser203 by type i p21-activated kinase (PAK) regulates PKD1 localization |
title_full |
Protein kinase D1 (PKD1) phosphorylation on Ser203 by type i p21-activated kinase (PAK) regulates PKD1 localization |
title_fullStr |
Protein kinase D1 (PKD1) phosphorylation on Ser203 by type i p21-activated kinase (PAK) regulates PKD1 localization |
title_full_unstemmed |
Protein kinase D1 (PKD1) phosphorylation on Ser203 by type i p21-activated kinase (PAK) regulates PKD1 localization |
title_sort |
Protein kinase D1 (PKD1) phosphorylation on Ser203 by type i p21-activated kinase (PAK) regulates PKD1 localization |
dc.creator.none.fl_str_mv |
Chang, Jen Kuan Ni, Yang Han, Liang Sinnett-Smith, James Jacamo, Rodrigo Rey, Osvaldo Young, Steven H. Rozengurt, Enrique |
author |
Chang, Jen Kuan |
author_facet |
Chang, Jen Kuan Ni, Yang Han, Liang Sinnett-Smith, James Jacamo, Rodrigo Rey, Osvaldo Young, Steven H. Rozengurt, Enrique |
author_role |
author |
author2 |
Ni, Yang Han, Liang Sinnett-Smith, James Jacamo, Rodrigo Rey, Osvaldo Young, Steven H. Rozengurt, Enrique |
author2_role |
author author author author author author author |
dc.subject.none.fl_str_mv |
GPCR PKD PAK CANCER |
topic |
GPCR PKD PAK CANCER |
purl_subject.fl_str_mv |
https://purl.org/becyt/ford/1.6 https://purl.org/becyt/ford/1 |
dc.description.none.fl_txt_mv |
Although PKC-mediated phosphorylation of protein kinase D1 (PKD1) has been extensively characterized, little is known about PKD1 regulation by other upstream kinases. Here we report that stimulation of epithelial or fibroblastic cells with G protein-coupled receptor agonists, including angiotensin II or bombesin, induced rapid and persistent PKD1 phosphorylation at Ser203, a highly conserved residue located within the PKD1 N-terminal domain. Exposure to PKD or PKC family inhibitors did not prevent PKD1 phosphorylation at Ser203, indicating that it is not mediated by autophosphorylation. In contrast, several lines of evidence indicated that the phosphorylation of PKD1 at Ser203 is mediated by kinases of the class I PAK subfamily, specifically 1) exposing cells to four structurally unrelated PAK inhibitors (PF-3758309, FRAX486, FRAX597, and IPA-3) that act via different mechanisms abrogated PKD1 phosphorylation at Ser203, 2) siRNA-mediated knockdown of PAK1 and PAK2 in IEC-18 and Swiss 3T3 cells blunted PKD1 phosphorylation at Ser203, 3) phosphorylation of Ser203 markedly increased in vitro when recombinant PKD1 was incubated with either PAK1 or PAK2 in the presence of ATP. PAK inhibitors did not interfere with G protein-coupled receptor activation-induced rapid translocation of PKD1 to the plasma membrane but strikingly prevented the dissociation of PKD1 from the plasma membrane and blunted the phosphorylation of nuclear targets, including class IIa histone deacetylases. We conclude that PAK-mediated phosphorylation of PKD1 at Ser203 triggers its membrane dissociation and subsequent entry into the nucleus, thereby regulating the phosphorylation of PKD1 nuclear targets, including class IIa histone deacetylases. Fil: Chang, Jen Kuan. University of California at Los Angeles. School of Medicine; Estados Unidos Fil: Ni, Yang. University of California at Los Angeles. School of Medicine; Estados Unidos. Shandong University; China Fil: Han, Liang. University of California at Los Angeles. School of Medicine; Estados Unidos. Xi'an Jiaotong University; China Fil: Sinnett-Smith, James. University of California at Los Angeles. School of Medicine; Estados Unidos Fil: Jacamo, Rodrigo. University Of Texas Md Anderson Cancer Center; Fil: Rey, Osvaldo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; Argentina Fil: Young, Steven H.. University of California at Los Angeles. School of Medicine; Estados Unidos. University of Texas; Estados Unidos Fil: Rozengurt, Enrique. University of Texas; Estados Unidos. University of California at Los Angeles. School of Medicine; Estados Unidos |
description |
Although PKC-mediated phosphorylation of protein kinase D1 (PKD1) has been extensively characterized, little is known about PKD1 regulation by other upstream kinases. Here we report that stimulation of epithelial or fibroblastic cells with G protein-coupled receptor agonists, including angiotensin II or bombesin, induced rapid and persistent PKD1 phosphorylation at Ser203, a highly conserved residue located within the PKD1 N-terminal domain. Exposure to PKD or PKC family inhibitors did not prevent PKD1 phosphorylation at Ser203, indicating that it is not mediated by autophosphorylation. In contrast, several lines of evidence indicated that the phosphorylation of PKD1 at Ser203 is mediated by kinases of the class I PAK subfamily, specifically 1) exposing cells to four structurally unrelated PAK inhibitors (PF-3758309, FRAX486, FRAX597, and IPA-3) that act via different mechanisms abrogated PKD1 phosphorylation at Ser203, 2) siRNA-mediated knockdown of PAK1 and PAK2 in IEC-18 and Swiss 3T3 cells blunted PKD1 phosphorylation at Ser203, 3) phosphorylation of Ser203 markedly increased in vitro when recombinant PKD1 was incubated with either PAK1 or PAK2 in the presence of ATP. PAK inhibitors did not interfere with G protein-coupled receptor activation-induced rapid translocation of PKD1 to the plasma membrane but strikingly prevented the dissociation of PKD1 from the plasma membrane and blunted the phosphorylation of nuclear targets, including class IIa histone deacetylases. We conclude that PAK-mediated phosphorylation of PKD1 at Ser203 triggers its membrane dissociation and subsequent entry into the nucleus, thereby regulating the phosphorylation of PKD1 nuclear targets, including class IIa histone deacetylases. |
publishDate |
2017 |
dc.date.none.fl_str_mv |
2017-06 |
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/11336/82596 Chang, Jen Kuan; Ni, Yang; Han, Liang; Sinnett-Smith, James; Jacamo, Rodrigo; et al.; Protein kinase D1 (PKD1) phosphorylation on Ser203 by type i p21-activated kinase (PAK) regulates PKD1 localization; American Society for Biochemistry and Molecular Biology; Journal of Biological Chemistry (online); 292; 23; 6-2017; 9523-9539 0021-9258 CONICET Digital CONICET |
url |
http://hdl.handle.net/11336/82596 |
identifier_str_mv |
Chang, Jen Kuan; Ni, Yang; Han, Liang; Sinnett-Smith, James; Jacamo, Rodrigo; et al.; Protein kinase D1 (PKD1) phosphorylation on Ser203 by type i p21-activated kinase (PAK) regulates PKD1 localization; American Society for Biochemistry and Molecular Biology; Journal of Biological Chemistry (online); 292; 23; 6-2017; 9523-9539 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/cgi/pmidlookup?view=long&pmid=28408623 info:eu-repo/semantics/altIdentifier/doi/10.1074/jbc.M116.771394 info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5465480/ |
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 |
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reponame:CONICET Digital (CONICET) instname:Consejo Nacional de Investigaciones Científicas y Técnicas |
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CONICET Digital (CONICET) |
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Consejo Nacional de Investigaciones Científicas y Técnicas |
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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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13.13397 |