Sumoylation and phosphorylation: hidden and overt links

Tomanov, Konstantin; Nukarinen, Ella; Vicente, Jorge; Mendiondo, Guillermina M.; Winter, Nikola; Nehlin, Lilian; Weckwerth, Wolfram; Holdsworth, Michael J.; Teige, Markus; Bachmair, Andreas

doi:10.1093/jxb/ery167

Cited by 25 publications

(19 citation statements)

References 68 publications

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“…This phosphorylation allows the recruitment of a specific PIAS SUMO E3 ligase (yet to be described), resulting in SUMOylation of ERK5 (branched SUMO chains) at residues Lys6 and Lys22. Of note, our findings show an interplay between phosphorylation and SUMOylation, as described for other proteins (reviewed in [45]). In this model, covalent SUMO modification of ERK5 would facilitate the dissociation of Hsp90 from the kinase domain (Hsp90 is not dissociated from the ERK5 SUMO-deficient mutant in response to MEK5 activation, Figure 6).…”

Section: Discussionsupporting

confidence: 80%

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

Erazo

Espinosa-Gil

Diéguez-Martínez

et al. 2020

IJMS

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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.

show abstract

Section: Discussionsupporting

confidence: 80%

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

Erazo

Espinosa-Gil

Diéguez-Martínez

et al. 2020

IJMS

View full text Add to dashboard Cite

show abstract

“…This phosphorylation allows the recruitment of a specific PIAS SUMO E3 ligase (yet to be described), resulting in SUMOylation of ERK5 (branched SUMO chains) at residues Lys6 and Lys22. Of note, our findings show an interplay between phosphorylation and SUMOylation, as described for other proteins (reviewed in [45]). In this model, covalent SUMO modification of ERK5 would facilitate the dissociation of Hsp90 from the kinase domain (Hsp90 is not dissociated from ERK5 SUMO-deficient mutant in response to MEK5 activation, Figure 6).…”

Section: Discussionsupporting

confidence: 80%

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

Erazo¹,

Espinosa-Gil²,

Diéguez-Martínez³

et al. 2020

Preprint

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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 Cdc37 overexpression -mechanisms that induce nuclear ERK5- induced ERK5 SUMO-2 modification at residues Lys6/Lys22 in cancer cells. We also show that overexpression of the SUMO protease SENP2 completely abolished endogenous ERK5 nuclear localization in response to EGF stimulation. 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. 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 transcription.

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“…Similar to SUMOylation, there are some proteins which phosphorylation associates with mitochondrial oxidative stress. Accumulating evidence shows that there is an inter-connection between SUMOylation and phosphorylation [118][119][120][121]. Recent studies have shown that obesity and aging decrease SIRT1-mediated SIRT3 deacetylation and reduce SIRT3 stability and activity [122].…”

Section: Conclusion and Further Perspectivementioning

confidence: 99%

SUMOylation-Mediated Response to Mitochondrial Stress

Cheng

Wang

2020

IJMS

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Mitochondrial stress is considered as a factor that reprograms the mitochondrial biogenesis and metabolism. As known, SUMOylation occurs through a series of stress-induced biochemical reactions. During the process of SUMOylation, the small ubiquitin-like modifier (SUMO) and its specific proteases (SENPs) are key signal molecules. Furthermore, they are considered as novel mitochondrial stress sensors that respond to the signals produced by various stresses. The responses are critical for mitochondrial homeostasis. The scope of this review is to provide an overview of the function of SUMOylation in the mitochondrial stress response, to delineate a SUMOylation-involved signal network diagram, and to highlight a number of key questions that remain answered.

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Sumoylation and phosphorylation: hidden and overt links

Cited by 25 publications

References 68 publications

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

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

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

SUMOylation-Mediated Response to Mitochondrial Stress

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