Dominant-negative regulation of WNK1 by its kidney-specific kinase-defective isoform

Subramanya, Arohan R.; Yang, Chao; Zhu, Xiaoman; Ellison, David H.

doi:10.1152/ajprenal.00280.2005

Cited by 104 publications

(117 citation statements)

References 32 publications

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“…3c), indicating that KS-WNK1 does not block L-WNK1 by translational interference. Recent findings showing the WNK1 isoforms physically interact (18) are consistent with a more direct and specific mechanism of dominant negative regulation.…”

Section: Dominant-negative Regulation Of L-wnk1 By Ks-wnk1supporting

confidence: 60%

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WNK1 kinase isoform switch regulates renal potassium excretion

Wade

Fang

Liu

et al. 2006

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

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Members of the WNK family of serine͞threonine kinases have been implicated as important modulators of salt homeostasis, regulating the balance between renal sodium reabsorption and potassium excretion. Gain-of-expression mutations in the WNK1 gene uncouple Na ؉ and K ؉ balance and cause a familial disorder of diminished renal potassium excretion, excessive sodium retention, and hypertension (pseudohypoaldosteronism type II or Gordon's syndrome). Alternative splicing of the WNK1 gene produces a kidney-specific short form of WNK1 (KS-WNK1) and a more ubiquitous long form (L-WNK1), but it is not clear how either of these isoforms influence renal potassium excretion. Here we demonstrate that KS-WNK1 and L-WNK1 converge in a pathway to regulate the renal outermedullary K ؉ channel, Kir1.1. Reconstitution studies in Xenopus oocytes reveal that L-WNK1 significantly inhibits Kir1.1 by reducing cell surface localization of the channel.

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Section: Dominant-negative Regulation Of L-wnk1 By Ks-wnk1supporting

confidence: 60%

“…Remarkably, the kinase defective splice variant, KS-WNK1, blocks the inhibitory activity of L-WNK. Recent reports indicate that L-WNK1 assembles as a tetramer (26) and that KS-WNK1 can interact with L-WNK1 to inhibit kinase activity (18). Such a dominant-negative mechanism explains how KS-WNK1 modulates the effects of L-WNK1 on Kir1.1.…”

Section: Discussionmentioning

confidence: 99%

WNK1 kinase isoform switch regulates renal potassium excretion

Wade

Fang

Liu

et al. 2006

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

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122

139

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“…For Xenopus laevis oocyte experiments, NCC (11) and WNK4-(168 -1222) (12,13) were subcloned into the expression vector pgh19. For forward trafficking studies in mammalian cells, NCC was subcloned to pcDNA3.1 (Invitrogen), and an amino-terminal hemagglutinin epitope was generated via a PCR-based strategy.…”

Section: Methodsmentioning

confidence: 99%

“…WNK4 does not affect the rate of NCC retrieval from the plasma membrane. A, decay in thiazide-sensitive 22 Na ϩ transport, measured in NCCexpressing X. laevis oocytes, assessed in the absence or presence of WNK4-(168 -1222), a WNK4 construct that stably suppresses NCC activity (12,13). Measurements were taken after NCC was maximally expressed at the cell surface (4 days post-injection), and oocytes were placed in medium containing 10M BFA.…”

Section: Wnk4 Suppresses Ncc Forward Trafficking Without Affecting Itsmentioning

confidence: 99%

WNK4 Diverts the Thiazide-sensitive NaCl Cotransporter to the Lysosome and Stimulates AP-3 Interaction

Subramanya

Liu²,

Ellison

et al. 2009

Journal of Biological Chemistry

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With-no-lysine kinase 4 (WNK4) inhibits electroneutral sodium chloride reabsorption by attenuating the cell surface expression of the thiazide-sensitive NaCl cotransporter (NCC). The underlying mechanism for this effect remains poorly understood. Here, we explore how WNK4 affects the trafficking of NCC through its interactions with intracellular sorting machinery. An analysis of NCC cell surface lifetime showed that WNK4 did not alter the net rate of cotransporter internalization. In contrast, direct measurements of forward trafficking revealed that WNK4 attenuated the rate of NCC surface delivery, inhibiting the anterograde movement of cotransporters traveling to the plasma membrane from the trans-Golgi network. The response was paralleled by a dramatic reduction in NCC protein abundance, an effect that was sensitive to the lysosomal protease inhibitor leupeptin, insensitive to proteasome inhibition, and attenuated by endogenous WNK4 knockdown. Subcellular localization studies performed in the presence of leupeptin revealed that WNK4 enhanced the accumulation of NCC in lysosomes. Moreover, NCC immunoprecipitated with endogenous AP-3 complexes, and WNK4 increased the fraction of cotransporters that associate with this adaptor, which facilitates cargo transport to lysosomes. WNK4 expression also increased LAMP-2-positive lysosomal content, indicating that the kinase may act by a general AP-3-dependent mechanism to promote cargo delivery into the lysosomal pathway. Taken together, these findings indicate that WNK4 inhibits NCC activity by diverting the cotransporter to the lysosome for degradation by way of an AP-3 transport carrier.The with-no-Lysine (WNK) 2 kinases are a unique family of serine-threonine protein kinases that regulate ion transport in diverse epithelia (1). In the kidney the gene products of several members of the WNK family, including WNK1, WNK3, and WNK4, converge in a signaling network that coordinates distal nephron sodium chloride and potassium handling. WNK4 participates in this network by suppressing NaCl reabsorption via the thiazide-sensitive NaCl cotransporter (NCC, SLC12A3), and potassium secretion via the potassium channel Kir 1.1 (ROMK) (2, 3). The importance of this signaling pathway is underscored by a link to human disease; WNK4 mutations cause familial hyperkalemic hypertension (pseudohypoaldosteronism type II, Gordon's syndrome), an autosomal dominant disorder featuring chloride-dependent thiazide-sensitive hypertension and hyperkalemia (4). These mutations release NCC from inhibition, leading to an increase in renal sodium chloride reabsorption and blood pressure (2, 5).Ample evidence demonstrates that WNK4 suppresses NCC activity, at least in part by modulating its cell surface expression. This effect has been observed at steady state in multiple heterologous overexpression systems, including Xenopus oocytes (2, 5, 6), COS-7 cells (7), and polarized Madin-Darby canine kidney cells epithelia (8). More recently, the inhibitory effect of wild type WNK4 on NCC has been verified in...

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“…The function of KS-WNK1 has been examined. KS-WNK1 by itself has no effects on NCC and ROMK1, but antagonizes the full length WNK1-mediated regulation of NCC and ROMK (Lazrak et al, 2006;Subramanya et al, 2006;Wade et al, 2006). As a key pathway for renal K + secretion, ROMK1 is regulated by dietary K + intake (Chu et al, 2003).…”

Section: Full Length Vs Kidney-specific Wnk1mentioning

confidence: 99%

WNKs: protein kinases with a unique kinase domain

Huang

Kuy²,

Wang³

et al. 2007

Exp Mol Med

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WNKs (with-no-lysine [K]) are a family of serine-threonine protein kinases with an atypical placement of the catalytic lysine relative to all other protein kinases. The roles of WNK kinases in regulating ion transport were first revealed by the findings that mutations of two members cause a genetic hypertension and hyperkalemia syndrome. More recent studies suggest that WNKs are pleiotropic protein kinases with important roles in many cell processes in addition to ion transport. Here, we review roles of WNK kinases in the regulation of ion balance, cell signaling, survival, and proliferation, and embryonic organ development.

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Dominant-negative regulation of WNK1 by its kidney-specific kinase-defective isoform

Cited by 104 publications

References 32 publications

WNK1 kinase isoform switch regulates renal potassium excretion

WNK1 kinase isoform switch regulates renal potassium excretion

WNK4 Diverts the Thiazide-sensitive NaCl Cotransporter to the Lysosome and Stimulates AP-3 Interaction

WNKs: protein kinases with a unique kinase domain

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