Novel phosphorylated TAK1 species with functional impact on NF-κB and β-catenin signaling in human Cutaneous T-cell lymphoma

Cutaneous T-cell lymphomas (CTCLs) represent different subtypes of lymphoproliferative disorders with no curative therapies for the advanced forms of the disease (namely mycosis fungoides and the leukemic variant, Sézary syndrome). Molecular events leading to CTCL progression are heterogeneous, howe...

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Autores: Gallardo, Fernando|||0000-0002-8996-3828, Bertran, Joan, López-Arribillaga, Erika|||0000-0002-9451-6635, González, Jéssica, Menéndez, Silvia, Sánchez, Ignacio, Colomo, Luis|||0000-0001-5236-5085, Iglesias, Mar|||0000-0002-2274-4671, Garrido, Marta, Santamaría-Babí, Luis Francisco, Torres, Ferran|||0000-0002-7355-7913, Pujol Vallverdú, Ramón M.|||0000-0002-5622-6055, Bigas Salvans, Anna|||0000-0003-4801-6899, Espinosa, Lluis|||0000-0002-2897-4099
Tipo de recurso: artículo
Fecha de publicación:2018
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:227900
Acceso en línea:https://ddd.uab.cat/record/227900
https://dx.doi.org/urn:doi:10.1038/s41375-018-0066-4
Access Level:acceso abierto
Palabra clave:Humans
Lymphoma, T-Cell, Cutaneous
Metabolism
NF-kappa B
Phosphorylation
Physiology
Receptors, Neuropeptide Y
Sezary Syndrome
Signal Transduction
Skin Neoplasms
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repository_id_str
spelling Novel phosphorylated TAK1 species with functional impact on NF-κB and β-catenin signaling in human Cutaneous T-cell lymphomaGallardo, Fernando|||0000-0002-8996-3828Bertran, JoanLópez-Arribillaga, Erika|||0000-0002-9451-6635González, JéssicaMenéndez, SilviaSánchez, IgnacioColomo, Luis|||0000-0001-5236-5085Iglesias, Mar|||0000-0002-2274-4671Garrido, MartaSantamaría-Babí, Luis FranciscoTorres, Ferran|||0000-0002-7355-7913Pujol Vallverdú, Ramón M.|||0000-0002-5622-6055Bigas Salvans, Anna|||0000-0003-4801-6899Espinosa, Lluis|||0000-0002-2897-4099HumansLymphoma, T-Cell, CutaneousMetabolismNF-kappa BPhosphorylationPhysiologyReceptors, Neuropeptide YSezary SyndromeSignal TransductionSkin NeoplasmsCutaneous T-cell lymphomas (CTCLs) represent different subtypes of lymphoproliferative disorders with no curative therapies for the advanced forms of the disease (namely mycosis fungoides and the leukemic variant, Sézary syndrome). Molecular events leading to CTCL progression are heterogeneous, however recent DNA and RNA sequencing studies highlighted the importance of NF-κB and β-catenin pathways. We here show that the kinase TAK1, known as essential in B-cell lymphoma, is constitutively activated in CTCL cells, but tempered by the MYPT1/PP1 phosphatase complex. Blocking PP1 activity, both pharmacologically and genetically, resulted in TAK1 hyperphosphorylation at residues T344, S389, T444, and T511, which have functional impact on canonical NF-κB signaling. Inhibition of TAK1 precluded NF-κB and β-catenin signaling and induced apoptosis of CTCL cell lines and primary Sézary syndrome cells both in vitro and in vivo. Detection of phosphorylated TAK1 at T444 and T344 is associated with the presence of lymphoma in a set of 60 primary human samples correlating with NF-κB and β-catenin activation. These results identified TAK1 as a potential biomarker and therapeutic target for CTCL therapy. 22018-01-0120182018-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/227900https://dx.doi.org/urn:doi:10.1038/s41375-018-0066-4reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengInstituto de Salud Carlos III https://doi.org/10.13039/501100004587 PT13-0002-002Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 PT13-0010-0005Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 PI13-00448Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 PI16-00437Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 SAF2016-75613-Ropen accesshttp://purl.org/coar/access_right/c_abf2Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.https://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:2279002026-06-06T12:50:31Z
dc.title.none.fl_str_mv Novel phosphorylated TAK1 species with functional impact on NF-κB and β-catenin signaling in human Cutaneous T-cell lymphoma
title Novel phosphorylated TAK1 species with functional impact on NF-κB and β-catenin signaling in human Cutaneous T-cell lymphoma
spellingShingle Novel phosphorylated TAK1 species with functional impact on NF-κB and β-catenin signaling in human Cutaneous T-cell lymphoma
Gallardo, Fernando|||0000-0002-8996-3828
Humans
Lymphoma, T-Cell, Cutaneous
Metabolism
NF-kappa B
Phosphorylation
Physiology
Receptors, Neuropeptide Y
Sezary Syndrome
Signal Transduction
Skin Neoplasms
title_short Novel phosphorylated TAK1 species with functional impact on NF-κB and β-catenin signaling in human Cutaneous T-cell lymphoma
title_full Novel phosphorylated TAK1 species with functional impact on NF-κB and β-catenin signaling in human Cutaneous T-cell lymphoma
title_fullStr Novel phosphorylated TAK1 species with functional impact on NF-κB and β-catenin signaling in human Cutaneous T-cell lymphoma
title_full_unstemmed Novel phosphorylated TAK1 species with functional impact on NF-κB and β-catenin signaling in human Cutaneous T-cell lymphoma
title_sort Novel phosphorylated TAK1 species with functional impact on NF-κB and β-catenin signaling in human Cutaneous T-cell lymphoma
dc.creator.none.fl_str_mv Gallardo, Fernando|||0000-0002-8996-3828
Bertran, Joan
López-Arribillaga, Erika|||0000-0002-9451-6635
González, Jéssica
Menéndez, Silvia
Sánchez, Ignacio
Colomo, Luis|||0000-0001-5236-5085
Iglesias, Mar|||0000-0002-2274-4671
Garrido, Marta
Santamaría-Babí, Luis Francisco
Torres, Ferran|||0000-0002-7355-7913
Pujol Vallverdú, Ramón M.|||0000-0002-5622-6055
Bigas Salvans, Anna|||0000-0003-4801-6899
Espinosa, Lluis|||0000-0002-2897-4099
author Gallardo, Fernando|||0000-0002-8996-3828
author_facet Gallardo, Fernando|||0000-0002-8996-3828
Bertran, Joan
López-Arribillaga, Erika|||0000-0002-9451-6635
González, Jéssica
Menéndez, Silvia
Sánchez, Ignacio
Colomo, Luis|||0000-0001-5236-5085
Iglesias, Mar|||0000-0002-2274-4671
Garrido, Marta
Santamaría-Babí, Luis Francisco
Torres, Ferran|||0000-0002-7355-7913
Pujol Vallverdú, Ramón M.|||0000-0002-5622-6055
Bigas Salvans, Anna|||0000-0003-4801-6899
Espinosa, Lluis|||0000-0002-2897-4099
author_role author
author2 Bertran, Joan
López-Arribillaga, Erika|||0000-0002-9451-6635
González, Jéssica
Menéndez, Silvia
Sánchez, Ignacio
Colomo, Luis|||0000-0001-5236-5085
Iglesias, Mar|||0000-0002-2274-4671
Garrido, Marta
Santamaría-Babí, Luis Francisco
Torres, Ferran|||0000-0002-7355-7913
Pujol Vallverdú, Ramón M.|||0000-0002-5622-6055
Bigas Salvans, Anna|||0000-0003-4801-6899
Espinosa, Lluis|||0000-0002-2897-4099
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Humans
Lymphoma, T-Cell, Cutaneous
Metabolism
NF-kappa B
Phosphorylation
Physiology
Receptors, Neuropeptide Y
Sezary Syndrome
Signal Transduction
Skin Neoplasms
topic Humans
Lymphoma, T-Cell, Cutaneous
Metabolism
NF-kappa B
Phosphorylation
Physiology
Receptors, Neuropeptide Y
Sezary Syndrome
Signal Transduction
Skin Neoplasms
description Cutaneous T-cell lymphomas (CTCLs) represent different subtypes of lymphoproliferative disorders with no curative therapies for the advanced forms of the disease (namely mycosis fungoides and the leukemic variant, Sézary syndrome). Molecular events leading to CTCL progression are heterogeneous, however recent DNA and RNA sequencing studies highlighted the importance of NF-κB and β-catenin pathways. We here show that the kinase TAK1, known as essential in B-cell lymphoma, is constitutively activated in CTCL cells, but tempered by the MYPT1/PP1 phosphatase complex. Blocking PP1 activity, both pharmacologically and genetically, resulted in TAK1 hyperphosphorylation at residues T344, S389, T444, and T511, which have functional impact on canonical NF-κB signaling. Inhibition of TAK1 precluded NF-κB and β-catenin signaling and induced apoptosis of CTCL cell lines and primary Sézary syndrome cells both in vitro and in vivo. Detection of phosphorylated TAK1 at T444 and T344 is associated with the presence of lymphoma in a set of 60 primary human samples correlating with NF-κB and β-catenin activation. These results identified TAK1 as a potential biomarker and therapeutic target for CTCL therapy.
publishDate 2018
dc.date.none.fl_str_mv 2
2018-01-01
2018
2018-01-01
dc.type.none.fl_str_mv Article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://ddd.uab.cat/record/227900
https://dx.doi.org/urn:doi:10.1038/s41375-018-0066-4
url https://ddd.uab.cat/record/227900
https://dx.doi.org/urn:doi:10.1038/s41375-018-0066-4
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 PT13-0002-002
Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 PT13-0010-0005
Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 PI13-00448
Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 PI16-00437
Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 SAF2016-75613-R
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Dipòsit Digital de Documents de la UAB
instname:Universitat Autònoma de Barcelona
instname_str Universitat Autònoma de Barcelona
reponame_str Dipòsit Digital de Documents de la UAB
collection Dipòsit Digital de Documents de la UAB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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