WNK Kinases in Development and Disease

Rodan, Aylin R.; Jenny, Andreas

doi:10.1016/bs.ctdb.2016.08.004

Cited by 48 publications

(39 citation statements)

References 210 publications

(334 reference statements)

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“…Activation by phosphorylation of WNK kinases allows them to respond to changes in intracellular chloride concentration (Cl − ) and tonicity (Richardson & Alessi, ; Zagorska et al, ). Whereas expression of WNK2 and WNK3 is usually restricted to the kidney, that of WNK1 is ubiquitous (reviewed in Rodan & Jenny, ). In agreement with these results, unwounded hTECs were found to express intermediate levels of the WNK1 mRNA transcript and only low levels of WNK2 and WNK4 whereas no expression of WNK3 was observed (Figure S2).…”

Section: Discussionmentioning

confidence: 99%

Contribution of the WNK1 kinase to corneal wound healing using the tissue‐engineered human cornea as an in vitro model

Desjardins

Couture

Germain

et al. 2019

J Tissue Eng Regen Med

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Damage to the corneal epithelium triggers important changes in the extracellular matrix (ECM) to which basal human corneal epithelial cells (hCECs) attach. These changes are perceived by integrin receptors that activate different intracellular signalling pathways, ultimately leading to re‐epithelialization of the injured epithelium. In this study, we investigated the impact of pharmacological inhibition of specific signal transduction mediators on corneal wound healing using both monolayers of hCECs and the human tissue‐engineered cornea (hTEC) as an in vitro 3D model. RNA and proteins were isolated from the wounded and unwounded hTECs to conduct gene profiling analyses and protein kinase arrays. The impact of WNK1 inhibition was evaluated on the wounded hTECs as well as on hCECs monolayers using a scratch wound assay. Gene profiling and protein kinase arrays revealed that expression and activity of several mediators from the integrin‐dependent signaling pathways were altered in response to the ECM changes occurring during corneal wound healing. Phosphorylation of the WNK1 kinase turned out to be the most striking activation event going on during this process. The inhibition of WNK1 by WNK463 reduced the rate of corneal wound closure in both the hTEC and hCECs grown in monolayer compared with their respective negative controls. WNK463 also reduced phosphorylation of the WNK1 downstream targets SPAK/OSR1 in wounded hTECs. These in vitro results allowed for a better understanding of the cellular and molecular mechanisms involved in corneal wound healing and identified WNK1 as a kinase important to ensure proper wound healing of the cornea.

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Section: Discussionmentioning

confidence: 99%

Contribution of the WNK1 kinase to corneal wound healing using the tissue‐engineered human cornea as an in vitro model

Desjardins

Couture

Germain

et al. 2019

J Tissue Eng Regen Med

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“…chloride-sensing | potassium | pseudohypoaldosteronism type II | sodium chloride cotransporter | with-no-lysine kinase 4 W ith-no-lysine kinases (WNKs), a group of serine-threonine kinases with an atypical placement of the catalytic lysine, exert broad effects including cell volume control, transepithelial ion transport, and organ development (1). WNKs regulate SLC12 family cotransporters through downstream kinases Ste20related proline/alanine-rich kinase (SPAK)/oxidative-stress response kinase-1 (OSR1) (2).…”

mentioning

confidence: 99%

WNK4 kinase is a physiological intracellular chloride sensor

Chen

Lin

et al. 2019

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

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With-no-lysine (WNK) kinases regulate renal sodium-chloride cotransporter (NCC) to maintain body sodium and potassium homeostasis. Gain-of-function mutations of WNK1 and WNK4 in humans lead to a Mendelian hypertensive and hyperkalemic disease pseudohypoaldosteronism type II (PHAII). X-ray crystal structure and in vitro studies reveal chloride ion (Cl−) binds to a hydrophobic pocket within the kinase domain of WNKs to inhibit its activity. The mechanism is thought to be important for physiological regulation of NCC by extracellular potassium. To test the hypothesis that WNK4 senses the intracellular concentration of Cl−physiologically, we generated knockin mice carrying Cl−-insensitive mutant WNK4. These mice displayed hypertension, hyperkalemia, hyperactive NCC, and other features fully recapitulating human and mouse models of PHAII caused by gain-of-function WNK4. Lowering plasma potassium levels by dietary potassium restriction increased NCC activity in wild-type, but not in knockin, mice. NCC activity in knockin mice can be further enhanced by the administration of norepinephrine, a known activator of NCC. Raising plasma potassium by oral gavage of potassium inactivated NCC within 1 hour in wild-type mice, but had no effect in knockin mice. The results provide compelling support for the notion that WNK4 is a bona fide physiological intracellular Cl−sensor and that Cl−regulation of WNK4 underlies the mechanism of regulation of NCC by extracellular potassium.

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“…WNK1 has a broad expression pattern. It encodes a kinase with a key role in kidney and neural cell functioning (Rodan & Jenny, 2017). It has a cassette exon that is regulated in a tissue-specific manner and which contributes to WNK1 protein level control by encoding a binding site for the E3 ubiquitin ligase NEDD4-2 (Vidal-Petiot et al, 2012;Roy et al, 2015).…”

Section: Validation Of Splicing Regulation Mediated By Celf1 and Elavl1mentioning

confidence: 99%

The RNA-binding proteins CELF1 and ELAVL1 cooperatively control RNA isoform production

David

Reboutier

Deschamps

et al. 2018

Preprint

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Corresponding authors: LP (Tel +33 22323 4473, luc.paillard@univ-rennes1.fr); and YA (Tel +33 22323 4475, yann.audic@univ-rennes1.fr).Running title CELF1, ELAVL1, and splice isoform production 1 5 10 15 20 ABSTRACT ELAVL1 and CELF1 are RNA-binding proteins that are involved in alternative splicing control. To explore their functional relationship, we looked for mRNAs that are differentially spliced following the depletion of CELF1, ELAVL1, or both. We found that these proteins control the usage of their target exons in the same direction. Double depletion has a greater effect than individual depletions, showing that CELF1 and ELAVL1 exert additive control. To confirm these results, we carried out RT-PCR on the alternative cassette exons of several mRNAs, including CD44, WNK1, PHACTR2, MICAL3, SPTBN1, and PPP3CB. Using FRET, we found that CELF1 and ELAVL1 directly interact in cell nuclei. We demonstrated that the combined levels of CELF1 and ELAVL1 are a valuable biomarker in several cancers, even when their individual levels may yield very limited information. CD44 alternative splicing probably accounts in part for the effects of CELF1 and ELAVL1 levels on patient survival. These data point to strong functional interactions between CELF1 and ELAVL1 in the control of mRNA isoform production, resulting in significant impacts on human pathology.

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WNK Kinases in Development and Disease

Cited by 48 publications

References 210 publications

Contribution of the WNK1 kinase to corneal wound healing using the tissue‐engineered human cornea as an in vitro model

Contribution of the WNK1 kinase to corneal wound healing using the tissue‐engineered human cornea as an in vitro model

WNK4 kinase is a physiological intracellular chloride sensor

The RNA-binding proteins CELF1 and ELAVL1 cooperatively control RNA isoform production

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