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PKCε phosphorylates MIIP and promotes colorectal cancer metastasis through inhibition of RelA deacetylation

EGFR signaling is implicated in NF-κB activation. However, the concrete mechanisms by which the core transducer of NF-κB signaling pathway, RelA/p65 is regulated under EGFR activation remains to be further clarified. Here, we show that EGF stimulation induces PKCε-dependent phosphorylation of migrat...

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Autores principales: Chen, Tao, Li, Jingjie, Xu, Meidong, Zhao, Qin, Hou, Yingyong, Yao, Liqing, Zhong, Yunshi, Chou, Ping-Chieh, Zhang, Wei, Zhou, Pinghong, Jiang, Yuhui
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5643311/
https://www.ncbi.nlm.nih.gov/pubmed/29038521
http://dx.doi.org/10.1038/s41467-017-01024-2
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author Chen, Tao
Li, Jingjie
Xu, Meidong
Zhao, Qin
Hou, Yingyong
Yao, Liqing
Zhong, Yunshi
Chou, Ping-Chieh
Zhang, Wei
Zhou, Pinghong
Jiang, Yuhui
author_facet Chen, Tao
Li, Jingjie
Xu, Meidong
Zhao, Qin
Hou, Yingyong
Yao, Liqing
Zhong, Yunshi
Chou, Ping-Chieh
Zhang, Wei
Zhou, Pinghong
Jiang, Yuhui
author_sort Chen, Tao
collection PubMed
description EGFR signaling is implicated in NF-κB activation. However, the concrete mechanisms by which the core transducer of NF-κB signaling pathway, RelA/p65 is regulated under EGFR activation remains to be further clarified. Here, we show that EGF stimulation induces PKCε-dependent phosphorylation of migration and invasion inhibitory protein (MIIP) at Ser303; this phosphorylation promotes the interaction between MIIP and RelA in the nucleus, by which MIIP prevents histone deacetylase 6 (HDAC6)-mediated RelA deacetylation, and thus enhances transcriptional activity of RelA and facilitates tumor metastasis. Meanwhile PP1, which functions as a phosphatase, is found to mediate MIIP-S303 dephosphorylation and its expression level inversely correlates with metastatic capability of tumor cells. Moreover, clinical analyses indicate the level of MIIP-S303 phosphorylation correlates with colorectal cancer (CRC) metastasis and prognosis. These findings uncover an unidentified mechanism underlying the precise regulation of NF-κB by EGF, and highlight the critical role of nuclear MIIP in tumor metastasis.
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spelling pubmed-56433112017-10-18 PKCε phosphorylates MIIP and promotes colorectal cancer metastasis through inhibition of RelA deacetylation Chen, Tao Li, Jingjie Xu, Meidong Zhao, Qin Hou, Yingyong Yao, Liqing Zhong, Yunshi Chou, Ping-Chieh Zhang, Wei Zhou, Pinghong Jiang, Yuhui Nat Commun Article EGFR signaling is implicated in NF-κB activation. However, the concrete mechanisms by which the core transducer of NF-κB signaling pathway, RelA/p65 is regulated under EGFR activation remains to be further clarified. Here, we show that EGF stimulation induces PKCε-dependent phosphorylation of migration and invasion inhibitory protein (MIIP) at Ser303; this phosphorylation promotes the interaction between MIIP and RelA in the nucleus, by which MIIP prevents histone deacetylase 6 (HDAC6)-mediated RelA deacetylation, and thus enhances transcriptional activity of RelA and facilitates tumor metastasis. Meanwhile PP1, which functions as a phosphatase, is found to mediate MIIP-S303 dephosphorylation and its expression level inversely correlates with metastatic capability of tumor cells. Moreover, clinical analyses indicate the level of MIIP-S303 phosphorylation correlates with colorectal cancer (CRC) metastasis and prognosis. These findings uncover an unidentified mechanism underlying the precise regulation of NF-κB by EGF, and highlight the critical role of nuclear MIIP in tumor metastasis. Nature Publishing Group UK 2017-10-16 /pmc/articles/PMC5643311/ /pubmed/29038521 http://dx.doi.org/10.1038/s41467-017-01024-2 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Chen, Tao
Li, Jingjie
Xu, Meidong
Zhao, Qin
Hou, Yingyong
Yao, Liqing
Zhong, Yunshi
Chou, Ping-Chieh
Zhang, Wei
Zhou, Pinghong
Jiang, Yuhui
PKCε phosphorylates MIIP and promotes colorectal cancer metastasis through inhibition of RelA deacetylation
title PKCε phosphorylates MIIP and promotes colorectal cancer metastasis through inhibition of RelA deacetylation
title_full PKCε phosphorylates MIIP and promotes colorectal cancer metastasis through inhibition of RelA deacetylation
title_fullStr PKCε phosphorylates MIIP and promotes colorectal cancer metastasis through inhibition of RelA deacetylation
title_full_unstemmed PKCε phosphorylates MIIP and promotes colorectal cancer metastasis through inhibition of RelA deacetylation
title_short PKCε phosphorylates MIIP and promotes colorectal cancer metastasis through inhibition of RelA deacetylation
title_sort pkcε phosphorylates miip and promotes colorectal cancer metastasis through inhibition of rela deacetylation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5643311/
https://www.ncbi.nlm.nih.gov/pubmed/29038521
http://dx.doi.org/10.1038/s41467-017-01024-2
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