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PHLPP2 suppresses the NF-κB pathway by inactivating IKKβ kinase

The NF-κB growth pathway is constitutively activated in many cancers but its activation mechanism is unclear in most cases. We show that PHLPP2 interacts with IKKβ kinase, decreases its phosphorylation and the subsequent NF-κB activation in cancer cells. PHLPP2 is progressively lost in glioma and co...

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Autores principales: Agarwal, Nitin Kumar, Zhu, Xiaoping, Gagea, Mihai, White, Charles L., Cote, Gilbert, Georgescu, Maria-Magdalena
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3996652/
https://www.ncbi.nlm.nih.gov/pubmed/24553260
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author Agarwal, Nitin Kumar
Zhu, Xiaoping
Gagea, Mihai
White, Charles L.
Cote, Gilbert
Georgescu, Maria-Magdalena
author_facet Agarwal, Nitin Kumar
Zhu, Xiaoping
Gagea, Mihai
White, Charles L.
Cote, Gilbert
Georgescu, Maria-Magdalena
author_sort Agarwal, Nitin Kumar
collection PubMed
description The NF-κB growth pathway is constitutively activated in many cancers but its activation mechanism is unclear in most cases. We show that PHLPP2 interacts with IKKβ kinase, decreases its phosphorylation and the subsequent NF-κB activation in cancer cells. PHLPP2 is progressively lost in glioma and colorectal cancer and acts as a bona fide tumor suppressor, depending on IKKβ expression in cells. Physiologically, IKKβ activation by growth factors requires the formation of the Bcl10-MALT1 ubiquitin-ligase complex leading to NEMO/IKKγ non-degradative ubiquitination and IKKβ phosphorylation. PHLPP2 opposes the formation of this complex through interaction with Bcl10 and competitive displacement of MALT1 from Bcl10. Conversely, PHLPP2 loss enhances Bcl10-MALT1 complex formation, NEMO ubiquitination and subsequent IKKβ phosphorylation, resulting in increased NF-κB-dependent transcription of multiple target genes. Our results reveal PHLPP2 as a new biomarker of cancer progression, and implicate it as major negative regulator of NF-κB signaling.
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spelling pubmed-39966522014-04-23 PHLPP2 suppresses the NF-κB pathway by inactivating IKKβ kinase Agarwal, Nitin Kumar Zhu, Xiaoping Gagea, Mihai White, Charles L. Cote, Gilbert Georgescu, Maria-Magdalena Oncotarget Research Paper The NF-κB growth pathway is constitutively activated in many cancers but its activation mechanism is unclear in most cases. We show that PHLPP2 interacts with IKKβ kinase, decreases its phosphorylation and the subsequent NF-κB activation in cancer cells. PHLPP2 is progressively lost in glioma and colorectal cancer and acts as a bona fide tumor suppressor, depending on IKKβ expression in cells. Physiologically, IKKβ activation by growth factors requires the formation of the Bcl10-MALT1 ubiquitin-ligase complex leading to NEMO/IKKγ non-degradative ubiquitination and IKKβ phosphorylation. PHLPP2 opposes the formation of this complex through interaction with Bcl10 and competitive displacement of MALT1 from Bcl10. Conversely, PHLPP2 loss enhances Bcl10-MALT1 complex formation, NEMO ubiquitination and subsequent IKKβ phosphorylation, resulting in increased NF-κB-dependent transcription of multiple target genes. Our results reveal PHLPP2 as a new biomarker of cancer progression, and implicate it as major negative regulator of NF-κB signaling. Impact Journals LLC 2014-02-13 /pmc/articles/PMC3996652/ /pubmed/24553260 Text en Copyright: © 2014 Agarwal et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Agarwal, Nitin Kumar
Zhu, Xiaoping
Gagea, Mihai
White, Charles L.
Cote, Gilbert
Georgescu, Maria-Magdalena
PHLPP2 suppresses the NF-κB pathway by inactivating IKKβ kinase
title PHLPP2 suppresses the NF-κB pathway by inactivating IKKβ kinase
title_full PHLPP2 suppresses the NF-κB pathway by inactivating IKKβ kinase
title_fullStr PHLPP2 suppresses the NF-κB pathway by inactivating IKKβ kinase
title_full_unstemmed PHLPP2 suppresses the NF-κB pathway by inactivating IKKβ kinase
title_short PHLPP2 suppresses the NF-κB pathway by inactivating IKKβ kinase
title_sort phlpp2 suppresses the nf-κb pathway by inactivating ikkβ kinase
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3996652/
https://www.ncbi.nlm.nih.gov/pubmed/24553260
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