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

Erazo, Tatiana; Espinosa-Gil, Sergio; Diéguez-Martínez, Nora; Gómez, Néstor; Lizcano, José M.

doi:10.3390/ijms21062203

Cited by 27 publications

(19 citation statements)

References 57 publications

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“…All of these findings suggest that CsTLP8 not only functions in transcriptional regulation, but also plays a role in post-transcriptional regulation. This is not unique, as the MAP kinase ERK5 possesses a kinase domain in the NH 2 -terminal region and a transcriptional activation domain and a nuclear localization signal in the COOH-terminal region, allowing this protein to regulate transcription at the nucleus by either phosphorylation or interaction with transcription factors [ 44 ]. In mouse, UBE3A is known as an E3 ubiquitin ligase, which several targets have been identified, UBE3A also functions as a transcriptional regulator of the family of nuclear receptors by interaction with IRF (Interferon Regulatory Factor) [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

A tubby-like protein CsTLP8 acts in the ABA signaling pathway and negatively regulates osmotic stresses tolerance during seed germination

Wang

et al. 2021

BMC Plant Biol

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Background TLPs (Tubby-like proteins) are widespread in eukaryotes and highly conserved in plants and animals. TLP is involved in many biological processes, such as growth, development, biotic and abiotic stress responses, while the underlying molecular mechanism remains largely unknown. In this paper we characterized the biological function of cucumber (Cucumis sativus L.) Tubby-like protein 8 (CsTLP8) in Arabidopsis. Results In cucumber, the expression of the tubby-like protein CsTLP8 was induced by NaCl treatment, but reduced by PEG (Polyethylene Glycol) and ABA (Abscisic Acid) treatment. Subcellular localization and transcriptional activation activity analysis revealed that CsTLP8 possessed two characteristics of classical transcription factors: nuclear localization and trans-activation activity. Yeast two-hybrid assay revealed interactions of CsTLP8 with CsSKP1a and CsSKP1c, suggesting that CsTLP8 might function as a subunit of E3 ubiquitin ligase. The growth activity of yeast with ectopically expressed CsTLP8 was lower than the control under NaCl and mannitol treatments. Under osmotic and salt stresses, overexpression of CsTLP8 inhibited seed germination and the growth of Arabidopsis seedlings, increased the content of MDA (Malondialdehyde), and decreased the activities of SOD (Superoxide Dismutase), POD (Peroxidase) and CAT (Catalase) in Arabidopsis seedlings. Overexpression of CsTLP8 also increased the sensitivity to ABA during seed germination and ABA-mediated stomatal closure. Conclusion Under osmotic stress, CsTLP8 might inhibit seed germination and seedling growth by affecting antioxidant enzymes activities. CsTLP8 acts as a negative regulator in osmotic stress and its effects may be related to ABA.

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Section: Discussionmentioning

confidence: 99%

A tubby-like protein CsTLP8 acts in the ABA signaling pathway and negatively regulates osmotic stresses tolerance during seed germination

Wang

et al. 2021

BMC Plant Biol

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“…The extracellular signal regulated kinase 5 (ERK5) is known to contain a classical BP NLS. Yan et al [25,37] found that the BP NLS ( 505 RKPVTAQERQREREEKR-RRR QERAKEREKRRQERER 539 ) of ERK5 is required for the nuclear targeting of ERK5 upon activation and that this NLS itself is sufficient to drive GFP to the nucleus, indicate that the ERK5 BP NLS is biologically functional.…”

Section: The Classical Nuclear Localization Signals (Cnls)mentioning

confidence: 99%

Types of nuclear localization signals and mechanisms of protein import into the nucleus

et al. 2021

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Nuclear localization signals (NLS) are generally short peptides that act as a signal fragment that mediates the transport of proteins from the cytoplasm into the nucleus. This NLS-dependent protein recognition, a process necessary for cargo proteins to pass the nuclear envelope through the nuclear pore complex, is facilitated by members of the importin superfamily. Here, we summarized the types of NLS, focused on the recently reported related proteins containing nuclear localization signals, and briefly summarized some mechanisms that do not depend on nuclear localization signals into the nucleus.

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“…Direct ERK5 activation is classically operated by the upstream MAP2K, MEK5, that has ERK5 as its only known substrate [ 2 ] and phosphorylates ERK5 at Thr218/Tyr220 in the conserved threonine–glutamic acid–tyrosine (TEY) motif of the catalytic domain [ 3 ]. MEK5-dependent phosphorylation stimulates ERK5 nuclear translocation, a key event for the regulation of cell proliferation [ 4 , 5 , 6 ]. In recent years, accumulating evidence points to a relevant role of ERK5 in the onset and progression of several types of cancer, including melanoma [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

The Hedgehog-GLI Pathway Regulates MEK5-ERK5 Expression and Activation in Melanoma Cells

Tusa

Gagliardi

Tubita

et al. 2021

IJMS

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Malignant melanoma is the deadliest skin cancer, with a poor prognosis in advanced stages. We recently showed that the extracellular signal-regulated kinase 5 (ERK5), encoded by the MAPK7 gene, plays a pivotal role in melanoma by regulating cell functions necessary for tumour development, such as proliferation. Hedgehog-GLI signalling is constitutively active in melanoma and is required for proliferation. However, no data are available in literature about a possible interplay between Hedgehog-GLI and ERK5 pathways. Here, we show that hyperactivation of the Hedgehog-GLI pathway by genetic inhibition of the negative regulator Patched 1 increases the amount of ERK5 mRNA and protein. Chromatin immunoprecipitation showed that GLI1, the major downstream effector of Hedgehog-GLI signalling, binds to a functional non-canonical GLI consensus sequence at the MAPK7 promoter. Furthermore, we found that ERK5 is required for Hedgehog-GLI-dependent melanoma cell proliferation, and that the combination of GLI and ERK5 inhibitors is more effective than single treatments in reducing cell viability and colony formation ability in melanoma cells. Together, these findings led to the identification of a novel Hedgehog-GLI-ERK5 axis that regulates melanoma cell growth, and shed light on new functions of ERK5, paving the way for new therapeutic options in melanoma and other neoplasms with active Hedgehog-GLI and ERK5 pathways.

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

Cited by 27 publications

References 57 publications

A tubby-like protein CsTLP8 acts in the ABA signaling pathway and negatively regulates osmotic stresses tolerance during seed germination

A tubby-like protein CsTLP8 acts in the ABA signaling pathway and negatively regulates osmotic stresses tolerance during seed germination

Types of nuclear localization signals and mechanisms of protein import into the nucleus

The Hedgehog-GLI Pathway Regulates MEK5-ERK5 Expression and Activation in Melanoma Cells

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