Cargando…

SUMOylation Is Required for ERK5 Nuclear Translocation and ERK5-Mediated Cancer Cell Proliferation

The MAP kinase ERK5 contains an N-terminal kinase domain and a unique C-terminal tail including a nuclear localization signal and a transcriptional activation domain. ERK5 is activated in response to growth factors and stresses and regulates transcription at the nucleus by either phosphorylation or...

Descripción completa

Detalles Bibliográficos
Autores principales: Erazo, Tatiana, Espinosa-Gil, Sergio, Diéguez-Martínez, Nora, Gómez, Néstor, Lizcano, Jose M
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139592/
https://www.ncbi.nlm.nih.gov/pubmed/32209980
http://dx.doi.org/10.3390/ijms21062203
_version_ 1783518801332011008
author Erazo, Tatiana
Espinosa-Gil, Sergio
Diéguez-Martínez, Nora
Gómez, Néstor
Lizcano, Jose M
author_facet Erazo, Tatiana
Espinosa-Gil, Sergio
Diéguez-Martínez, Nora
Gómez, Néstor
Lizcano, Jose M
author_sort Erazo, Tatiana
collection PubMed
description The MAP kinase ERK5 contains an N-terminal kinase domain and a unique C-terminal tail including a nuclear localization signal and a transcriptional activation domain. ERK5 is activated in response to growth factors and stresses and regulates transcription at the nucleus by either phosphorylation or interaction with transcription factors. MEK5-ERK5 pathway plays an important role regulating cancer cell proliferation and survival. Therefore, it is important to define the precise molecular mechanisms implicated in ERK5 nucleo-cytoplasmic shuttling. We previously described that the molecular chaperone Hsp90 stabilizes and anchors ERK5 at the cytosol and that ERK5 nuclear shuttling requires Hsp90 dissociation. Here, we show that MEK5 or overexpression of Cdc37—mechanisms that increase nuclear ERK5—induced ERK5 Small Ubiquitin-related Modifier (SUMO)-2 modification at residues Lys6/Lys22 in cancer cells. Furthermore, mutation of these SUMO sites abolished the ability of ERK5 to translocate to the nucleus and to promote prostatic cancer PC-3 cell proliferation. We also show that overexpression of the SUMO protease SENP2 completely abolished endogenous ERK5 nuclear localization in response to epidermal growth factor (EGF) stimulation. These results allow us to propose a more precise mechanism: in response to MEK5 activation, ERK5 SUMOylation favors the dissociation of Hsp90 from the complex, allowing ERK5 nuclear shuttling and activation of the transcription.
format Online
Article
Text
id pubmed-7139592
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-71395922020-04-10 SUMOylation Is Required for ERK5 Nuclear Translocation and ERK5-Mediated Cancer Cell Proliferation Erazo, Tatiana Espinosa-Gil, Sergio Diéguez-Martínez, Nora Gómez, Néstor Lizcano, Jose M Int J Mol Sci Article The MAP kinase ERK5 contains an N-terminal kinase domain and a unique C-terminal tail including a nuclear localization signal and a transcriptional activation domain. ERK5 is activated in response to growth factors and stresses and regulates transcription at the nucleus by either phosphorylation or interaction with transcription factors. MEK5-ERK5 pathway plays an important role regulating cancer cell proliferation and survival. Therefore, it is important to define the precise molecular mechanisms implicated in ERK5 nucleo-cytoplasmic shuttling. We previously described that the molecular chaperone Hsp90 stabilizes and anchors ERK5 at the cytosol and that ERK5 nuclear shuttling requires Hsp90 dissociation. Here, we show that MEK5 or overexpression of Cdc37—mechanisms that increase nuclear ERK5—induced ERK5 Small Ubiquitin-related Modifier (SUMO)-2 modification at residues Lys6/Lys22 in cancer cells. Furthermore, mutation of these SUMO sites abolished the ability of ERK5 to translocate to the nucleus and to promote prostatic cancer PC-3 cell proliferation. We also show that overexpression of the SUMO protease SENP2 completely abolished endogenous ERK5 nuclear localization in response to epidermal growth factor (EGF) stimulation. These results allow us to propose a more precise mechanism: in response to MEK5 activation, ERK5 SUMOylation favors the dissociation of Hsp90 from the complex, allowing ERK5 nuclear shuttling and activation of the transcription. MDPI 2020-03-23 /pmc/articles/PMC7139592/ /pubmed/32209980 http://dx.doi.org/10.3390/ijms21062203 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Erazo, Tatiana
Espinosa-Gil, Sergio
Diéguez-Martínez, Nora
Gómez, Néstor
Lizcano, Jose M
SUMOylation Is Required for ERK5 Nuclear Translocation and ERK5-Mediated Cancer Cell Proliferation
title SUMOylation Is Required for ERK5 Nuclear Translocation and ERK5-Mediated Cancer Cell Proliferation
title_full SUMOylation Is Required for ERK5 Nuclear Translocation and ERK5-Mediated Cancer Cell Proliferation
title_fullStr SUMOylation Is Required for ERK5 Nuclear Translocation and ERK5-Mediated Cancer Cell Proliferation
title_full_unstemmed SUMOylation Is Required for ERK5 Nuclear Translocation and ERK5-Mediated Cancer Cell Proliferation
title_short SUMOylation Is Required for ERK5 Nuclear Translocation and ERK5-Mediated Cancer Cell Proliferation
title_sort sumoylation is required for erk5 nuclear translocation and erk5-mediated cancer cell proliferation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139592/
https://www.ncbi.nlm.nih.gov/pubmed/32209980
http://dx.doi.org/10.3390/ijms21062203
work_keys_str_mv AT erazotatiana sumoylationisrequiredforerk5nucleartranslocationanderk5mediatedcancercellproliferation
AT espinosagilsergio sumoylationisrequiredforerk5nucleartranslocationanderk5mediatedcancercellproliferation
AT dieguezmartineznora sumoylationisrequiredforerk5nucleartranslocationanderk5mediatedcancercellproliferation
AT gomeznestor sumoylationisrequiredforerk5nucleartranslocationanderk5mediatedcancercellproliferation
AT lizcanojosem sumoylationisrequiredforerk5nucleartranslocationanderk5mediatedcancercellproliferation