Protein kinase WNK2 inhibits cell proliferation by negatively modulating the activation of MEK1/ERK1/2

Moniz, Sónia; Verı́ssimo, Fátima; Matos, Paulo; Brazão, Roberto; Silva, E; Kotelevets, Larissa; Chastre, Eric; Gespach, Christian; Jordan, Peter

doi:10.1038/sj.onc.1210706

Cited by 73 publications

(62 citation statements)

References 45 publications

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“…The degree of ERK1/2 activation and subsequent G1/S cell cycle progression that was observed following MCLR treatment is comparable to that described for other tumorigenic stimuli (Moniz et al, 2007;Moniz and Peter, 2010) and thus biologically meaningful. Considering that the ERK1/2 pathway is known to be upregulated in approximately one-third of all human cancers (Dhillon et al, 2007), our results emphasise the importance to confirm in vivo the impact of MCLR on tumour promotion at kidney level.…”

Section: Discussionsupporting

confidence: 51%

Microcystin-LR activates the ERK1/2 kinases and stimulates the proliferation of the monkey kidney-derived cell line Vero-E6

Dias

Matos

Pereira

et al. 2010

Toxicology in Vitro

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a b s t r a c tMicrocystin-LR (MCLR) is a peptide produced by freshwater cyanobacteria that induces severe hepatotoxicity in humans and animals. MCLR is also a potent tumour promoter and it has been proposed that this activity is mediated by the inhibition of protein phosphatases PP1/PP2A, possibly through the activation of proto-oncogenes c-jun, c-fos and c-myc. However, the mechanisms underlying MCLR-induced tumour promotion are still largely unknown, particularly in non-liver cells. In previous studies we have demonstrated that micromolar concentrations of MCLR induce cytotoxic effects in the kidney Vero-E6 cell line. The purpose of the present work was to evaluate whether the exposure to subcytotoxic concentrations of MCLR was sufficient to induce the proliferation of Vero-E6 cells. Through BrdU incorporation assay we show that at nanomolar concentrations MCLR stimulates cell cycle progression in Vero-E6 kidney cell line. Moreover, the analysis of mitogen-activated protein kinases p38, JNK and ERK1/2 activity revealed that the proliferative effect of MCLR is associated with the activation of the pro-proliferative ERK1/2 pathway. These results emphasise the importance to confirm in vivo the impact of MCLR on tumour promotion at kidney level.

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Section: Discussionsupporting

confidence: 51%

Microcystin-LR activates the ERK1/2 kinases and stimulates the proliferation of the monkey kidney-derived cell line Vero-E6

Dias

Matos

Pereira

et al. 2010

Toxicology in Vitro

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“…32 WNK2 reduces cell proliferation by inhibiting the MEK1/ERK1/2 signaling pathway. 36 We previously showed that WNK4 overexpression enhances ERK1/2 phosphorylation. 37 In the present study, we found that overexpression of WNK1 decreased ERK1/2 phosphorylation, whereas knockdown of WNK1 expression using an siRNA technique enhanced ERK1/2 phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

WNK1 Activates Large-Conductance Ca2+-Activated K+ Channels through Modulation of ERK1/2 Signaling

Liu

Song

Shi

et al. 2015

Journal of the American Society of Nephrology

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With no lysine (WNK) kinases are members of the serine/threonine kinase family. We previously showed that WNK4 inhibits renal large-conductance Ca 2+ -activated K + (BK) channel activity by enhancing its degradation through a lysosomal pathway. In this study, we investigated the effect of WNK1 on BK channel activity. In HEK293 cells stably expressing the a subunit of BK (HEK-BKa cells), siRNA-mediated knockdown of WNK1 expression significantly inhibited both BKa channel activity and open probability. Knockdown of WNK1 expression also significantly inhibited BKa protein expression and increased ERK1/2 phosphorylation, whereas overexpression of WNK1 significantly enhanced BKa expression and decreased ERK1/2 phosphorylation in a dose-dependent manner in HEK293 cells. Knockdown of ERK1/2 prevented WNK1 siRNA-mediated inhibition of BKa expression. Similarly, pretreatment of HEK-BKa cells with the lysosomal inhibitor bafilomycin A1 reversed the inhibitory effects of WNK1 siRNA on BKa expression in a dose-dependent manner. Knockdown of WNK1 expression also increased the ubiquitination of BKa channels. Notably, mice fed a high-K + diet for 10 days had significantly higher renal protein expression levels of BKa and WNK1 and lower levels of ERK1/2 phosphorylation compared with mice fed a normal-K + diet. These data suggest that WNK1 enhances BK channel function by reducing ERK1/2 signaling-mediated lysosomal degradation of the channel. With no lysine (WNK) kinase belongs to a family of serine/threonine kinases. Mutations of WNK1 and WNK4 are responsible for pseudohypoaldosteronism type II (PHAІІ), characterized by hypertension, hyperkalemia, and metabolic acidosis. 1,2 The disease mutation in WNK1 or WNK4 kinase resulting in hyperkalemia suggests a role of WNK in potassium handling in renal distal nephron, which contains two major potassium channels, renal outer medullary K + channels (ROMK) and Big K (BK) channels. 3,4 WNK4 inhibits ROMK channel activity and its surface expression, whereas WNK4 disease mutant enhances its inhibitory effect on ROMK. 5 WNK1 also inhibits ROMK activity; however, a kidney-specific form of WNK1 (KS-WNK1) reverses WNK1's effect on ROMK. 6 WNK4 inhibits BK channel activity and protein expression, 7-9 whereas WNK4 disease mutant also enhances its inhibitory effect on BK activity via a ubiquitin-dependent pathway. 9 BK channel (or Maxi K) is a large conductance Ca 2+ and voltage-activated K channel. 10 BK is encoded by the gene slo1 11 and is widely distributed in many different

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“…Other reports have suggested that WNK isoforms regulate proliferation and apoptosis, perhaps through caspase 3 (Moniz et al, 2007;Verissimo et al, 2006). Furthermore, in the majority of infiltrative gliomas WNK2 expression was reportedly silenced by methylation, and deletions within the WNK2 gene were found at low frequency (Hong et al, 2007).…”

Section: Other Wnk-regulated Pathwaysmentioning

confidence: 99%

The regulation of salt transport and blood pressure by the WNK-SPAK/OSR1 signalling pathway

Richardson

Alessi

2008

Journal of Cell Science

274

323

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It has recently been shown that the WNK [with-no-K(Lysand NKCC2, which are targets for the commonly used bloodpressure-lowering thiazide-diuretic and loop-diuretic drugs. The finding that mutations in WNK1, WNK4, NCC and NKCC2 cause inherited blood-pressure syndromes in humans highlights the importance of these enzymes. We argue that these new findings indicate that SPAK and OSR1 are promising drug targets for the treatment of hypertension, because inhibiting these enzymes would reduce NCC and NKCC2 activity and thereby suppress renal salt re-absorption. We also discuss unresolved and controversial questions in this field of research.

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Protein kinase WNK2 inhibits cell proliferation by negatively modulating the activation of MEK1/ERK1/2

Cited by 73 publications

References 45 publications

Microcystin-LR activates the ERK1/2 kinases and stimulates the proliferation of the monkey kidney-derived cell line Vero-E6

Microcystin-LR activates the ERK1/2 kinases and stimulates the proliferation of the monkey kidney-derived cell line Vero-E6

WNK1 Activates Large-Conductance Ca2+-Activated K+ Channels through Modulation of ERK1/2 Signaling

The regulation of salt transport and blood pressure by the WNK-SPAK/OSR1 signalling pathway

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