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Article

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

Institut de Neurociències and Departament de Bioquímica i Biología Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain
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Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(6), 2203; https://doi.org/10.3390/ijms21062203
Received: 28 January 2020 / Revised: 16 March 2020 / Accepted: 21 March 2020 / Published: 23 March 2020
(This article belongs to the Special Issue Targeting MAPK in Cancer)
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. View Full-Text
Keywords: MAP kinase; ERK5; Bmk1; SUMO; nuclear translocation; transcription; cell proliferation; cancer; Hsp90; Cdc37 MAP kinase; ERK5; Bmk1; SUMO; nuclear translocation; transcription; cell proliferation; cancer; Hsp90; Cdc37
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MDPI and ACS Style

Erazo, T.; Espinosa-Gil, S.; Diéguez-Martínez, N.; Gómez, N.; Lizcano, J.M. SUMOylation Is Required for ERK5 Nuclear Translocation and ERK5-Mediated Cancer Cell Proliferation. Int. J. Mol. Sci. 2020, 21, 2203. https://doi.org/10.3390/ijms21062203

AMA Style

Erazo T, Espinosa-Gil S, Diéguez-Martínez N, Gómez N, Lizcano JM. SUMOylation Is Required for ERK5 Nuclear Translocation and ERK5-Mediated Cancer Cell Proliferation. International Journal of Molecular Sciences. 2020; 21(6):2203. https://doi.org/10.3390/ijms21062203

Chicago/Turabian Style

Erazo, Tatiana, Sergio Espinosa-Gil, Nora Diéguez-Martínez, Néstor Gómez, and Jose M. Lizcano 2020. "SUMOylation Is Required for ERK5 Nuclear Translocation and ERK5-Mediated Cancer Cell Proliferation" International Journal of Molecular Sciences 21, no. 6: 2203. https://doi.org/10.3390/ijms21062203

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