Emerging roles for WNK kinases in cancer

Moniz, Sónia; Jordan, Peter

doi:10.1007/s00018-010-0261-6

Cited by 76 publications

(73 citation statements)

References 113 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: 78%

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: 78%

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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“…We tested the effect of WNK1 knockdown on HUVEC proliferation and growth, and noted a significantly slower proliferation rate at all times tested ( Fig. 2A), consistent with earlier findings (49,50). We tested the ability of WNK1-depleted HUVECs to migrate toward serum in a Boyden chamber assay.…”

Section: Wnk1supporting

confidence: 83%

Actions of the protein kinase WNK1 on endothelial cells are differentially mediated by its substrate kinases OSR1 and SPAK

Dbouk

Weil

Perera

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The with no lysine (K) (WNK) family of enzymes is best known for control of blood pressure through regulation of the function and membrane localization of ion cotransporters. In mice, global as well as endothelial-specific WNK1 gene disruption results in embryonic lethality due to angiogenic and cardiovascular defects. WNK1−/− embryos can be rescued by endothelial-specific expression of a constitutively active form of the WNK1 substrate protein kinase OSR1 (oxidative stress responsive 1). Using human umbilical vein endothelial cells (HUVECs), we explored mechanisms underlying the requirement of WNK1-OSR1 signaling for vascular development. WNK1 is required for cord formation in HUVECs, but the actions of the two major WNK1 effectors, OSR1 and its close relative SPAK (STE20/SPS1-related proline-, alanine-rich kinase), are distinct. SPAK is important for endothelial cell proliferation, whereas OSR1 is required for HUVEC chemotaxis and invasion. We also identified the zinc-finger transcription factor Slug in WNK1-mediated control of endothelial functions. Our study identifies a separation of functions for the WNK1-activated protein kinases OSR1 and SPAK in mediating proliferation, invasion, and gene expression in endothelial cells and an unanticipated link between WNK1 and Slug that is important for angiogenesis.endothelium | angiogenesis | migration | EMT | Slug

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“…It was reported that the activity of NCC could be down-regulated by WNK4 (Moniz et al, 2010). Our study showed that in the mammalian cells WNK3 was also a chloride sensitive kinase to NCC expression, with its effect being the opposite of WNK4.…”

supporting

confidence: 54%

WNK3 interacts with NCC

Wang

Pan

et al. 2016

Sci. China Life Sci.

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Dear Editor, NCC (Na-Cl cotransporter) is a cotransporter mainly distributed in the distal tubule of the kidney, functioning to reabsorb sodium and chloride ions from the tubular fluid into the cells of the renal distal convoluted tubule. It is a transmembrane protein belonging to the SLC12 cotransporter family of electro-neutral cation-coupled chloride cotransporters, which is closely related to hypertension (Gamba, 2005). A loss of NCC function can cause Gitelman syndrome, a disease characterized by low blood pressure, hypocalciuria, hypokalemic metabolic alkalosis, and hypomagnesemia, etc. WNK3 (With No Lysine K 3) is highly expressed in the whole length of the renal tubules (Glover et al., 2009). It was previously found to enhance the activity of NCC in Xenopus oocyte (Rinehart et al., 2005). Exploring the regulatory effect of WNK3 on NCC may be helpful to understand the occurrence of abnormal renal sodium transporters and provide new targets for the treatment of hypertension. However, whether WNK3 interacts directly with NCC in mammalian cells still remains unclear. In this article, we report the results of our co-immunoprecipitation experiments and confocal observations, confirming that WNK3 does interact with NCC and that the kinase domain of WNK3 plays an important role in the regulation of NCC.To explore whether there is reaction between WNK3 and NCC protein, Cos-7 cells were transfected by GFP-NCC with or without HA-WNK3 and co-immunoprecipitation experiments were performed 48 hours after transfection. As shown in Figure 1, anti-HA antibody with the presence of WNK3 immunoprecipitated NCC whereas serum with the absence of WNK3 did not, suggesting that the WNK3 protein interacts with NCC directly.In order to investigate the effect of WNK3 on NCC, HA-NCC was transfected into Cos-7 cells while increasing doses of HA-WNK3. Western-blot was carried out with anti-HA or anti-GAPDH antibodies 48 h later. The NCC protein expression level gradually increased with the increase of WNK3 dosage ( Figure S1 in Supporting Information). The expression of NCC and WNK3 was checked under a confocal fluorescent microscope ( Figure S2 in Supporting Information). The results showed that WNK3 increased NCC expression both on the cell membrane and in the cytoplasm. It has been confirmed that the enzyme region, the amino terminal, and/or the carboxyl terminal are the key elements of kinase activity. However, whether the enzyme region of WNK3 is necessary in regulating NCC is still unclear. We observed the changes of NCC expression after various WNK3 fragments were transferred into the cells. As shown in Figure S3 in Supporting Information, only the WNK3 fragments containing the enzyme region were able to increase the expression of NCC.WNK kinases belong to a subfamily of serine/threonine kinases. It was reported that the activity of NCC could be down-regulated by WNK4 (Moniz et al., 2010). Our study showed that in the mammalian cells WNK3 was also a chloride sensitive kinase to NCC expression, with its effect being the opposit...

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Emerging roles for WNK kinases in cancer

Cited by 76 publications

References 113 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

Actions of the protein kinase WNK1 on endothelial cells are differentially mediated by its substrate kinases OSR1 and SPAK

WNK3 interacts with NCC

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