Role of with-no-lysine [K] kinases in the pathogenesis of Gordon’s syndrome

Xie, Jingyuan; Craig, Leonard C.; Cobb, Melanie H.; Huang, Chou Long

doi:10.1007/s00467-006-0106-6

Cited by 38 publications

(36 citation statements)

References 39 publications

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“…When loaded on gel, these amplifications revealed an approximately 650-bp band from the brain tissues and an approximately 950-bp band from the DRG (Figure 2E, arrows 3 and 4). The subsequent sequencing of these 2 fragments showed that both the brain and DRG lacked exon 11 (462 bp) and that the brain additionally lacked exon 12 (285 bp) ( Figure 2F); this alternative splicing confirmed previous reports in which exons 11 and 12 were shown to be skipped in some Wnk1 mRNAs expressed in mouse tissues (13,23). Further amplifications of the region between the last exons of Wnk1 and Hsn2 were, however, more difficult because of the large distance between these primers; nonetheless, a product corresponding to the expected mRNA size (3.8 kb) could be amplified from Hsn2 to exon 24 of Wnk1 ( Figure 2E, arrow 1).…”

Section: Compound Heterozygous Mutation In Wnk1 and Hsn2 Cause Hsaniisupporting

confidence: 89%

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Mutations in the nervous system–specific HSN2 exon of WNK1 cause hereditary sensory neuropathy type II

Shekarabi¹,

Girard²,

Rivière³

et al. 2008

J. Clin. Invest.

136

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Hereditary sensory and autonomic neuropathy type II (HSANII) is an early-onset autosomal recessive disorder characterized by loss of perception to pain, touch, and heat due to a loss of peripheral sensory nerves. Mutations in hereditary sensory neuropathy type II (HSN2), a single-exon ORF originally identified in affected families in Quebec and Newfoundland, Canada, were found to cause HSANII. We report here that HSN2 is a nervous system-specific exon of the with-no-lysine(K)-1 (WNK1) gene. WNK1 mutations have previously been reported to cause pseudohypoaldosteronism type II but have not been studied in the nervous system. Given the high degree of conservation of WNK1 between mice and humans, we characterized the structure and expression patterns of this isoform in mice. Immunodetections indicated that this Wnk1/Hsn2 isoform was expressed in sensory components of the peripheral nervous system and CNS associated with relaying sensory and nociceptive signals, including satellite cells, Schwann cells, and sensory neurons. We also demonstrate that the novel protein product of Wnk1/Hsn2 was more abundant in sensory neurons than motor neurons. The characteristics of WNK1/HSN2 point to a possible role for this gene in the peripheral sensory perception deficits characterizing HSANII.

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Section: Compound Heterozygous Mutation In Wnk1 and Hsn2 Cause Hsaniisupporting

confidence: 89%

“…PHAII is a dominant disorder, the main feature of which is hypertension (12,13). Members of the WNK family contain a Ser/Thr catalytic domain similar to that of other kinases.…”

Section: Introductionmentioning

confidence: 99%

Mutations in the nervous system–specific HSN2 exon of WNK1 cause hereditary sensory neuropathy type II

Shekarabi¹,

Girard²,

Rivière³

et al. 2008

J. Clin. Invest.

136

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“…These results suggest that the role of WNK1 in mitosis does not primarily account for the lethality of its deletion. In reconstitution assays, multiple WNK family members can regulate several common effectors not limited to OSR1 and SPAK (1)(2)(3)(4). In this regard, we have been unable to detect other WNKs in HeLa cells by immunoblotting.…”

Section: Discussionmentioning

confidence: 72%

“…cytokinesis | microtubules | serine-| proline-| alanine-rich kinase T he serine/threonine protein kinase WNK1 [with no lysine (K)] is important for blood pressure regulation (1)(2)(3)(4). Positional cloning identified two of the four WNK family members as the genes mutated in a form of hypertension known as pseudohypoaldosteronism type II (5).…”

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confidence: 99%

WNK1 is required for mitosis and abscission

Tu¹,

Bugde

Luby-Phelps

et al. 2011

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

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WNK [with no lysine (K)] protein kinases are found in all sequenced multicellular and many unicellular organisms. WNKs influence ion balance. Two WNK family members are associated with a single gene form of hypertension. RNA interference screens have implicated WNKs in survival and growth, and WNK1 is essential for viability of mice. We found that the majority of WNK1 is localized on cytoplasmic puncta in resting cells. During cell division, WNK1 localizes to mitotic spindles. Therefore, we analyzed mitotic phenotypes in WNK1 knockdown cells. A large percentage of WNK1 knockdown cells fail to complete cell division, displaying defects in mitotic spindles and also in abscission and cell survival. One of the bestcharacterized WNK1 targets is the protein kinase OSR1 (oxidative stress responsive 1). OSR1 regulates ion cotransporters, is activated in response to osmotic stress by WNK family members, and is largely associated with WNK1. In resting cells, the majority of OSR1, like WNK1, is on cytoplasmic puncta. OSR1 is also in nuclei. In contrast to WNK1, however, OSR1 does not concentrate around spindles during mitosis and does not show a WNK1-like localization pattern in mitotic cells. Knockdown of OSR1 has only a modest effect on cell survival and does not lead to spindle defects. We conclude that decreased cell survival associated with loss of WNK1 is attributable to defects in chromosome segregation and abscission and is independent of the effector kinase OSR1.cytokinesis | microtubules | serine-| proline-| alanine-rich kinase

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“…WNKs are activated by changes in tonicity. Cellular reconstitution studies and mouse genetics demonstrated the importance of WNK function in cell volume regulation and maintenance of blood pressure (13)(14)(15)(16)(17)(18)(19). Control of cation-chloride cotransporters through OSR1 and SPAK is among the best-documented actions of WNKs in diverse tissues (5,(20)(21)(22).…”

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confidence: 99%

Regulation of OSR1 and the sodium, potassium, two chloride cotransporter by convergent signals

Sengupta¹,

Lorente-Rodríguez²,

Earnest³

et al. 2013

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

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The Ste20 family protein kinases oxidative stress-responsive 1 (OSR1) and the STE20/SPS1-related proline-, alanine-rich kinase directly regulate the solute carrier 12 family of cation-chloride cotransporters and thereby modulate a range of processes including cell volume homeostasis, blood pressure, hearing, and kidney function. OSR1 and STE20/SPS1-related proline-, alanine-rich kinase are activated by with no lysine [K] protein kinases that phosphorylate the essential activation loop regulatory site on these kinases. We found that inhibition of phosphoinositide 3-kinase (PI3K) reduced OSR1 activation by osmotic stress. Inhibition of the PI3K target pathway, the mammalian target of rapamycin complex 2 (mTORC2), by depletion of Sin1, one of its components, decreased activation of OSR1 by sorbitol and reduced activity of the OSR1 substrate, the sodium, potassium, two chloride cotransporter, in HeLa cells. OSR1 activity was also reduced with a pharmacological inhibitor of mTOR. mTORC2 phosphorylated OSR1 on S339 in vitro, and mutation of this residue eliminated OSR1 phosphorylation by mTORC2. Thus, we identify a previously unrecognized connection of the PI3K pathway through mTORC2 to a Ste20 protein kinase and ion homeostasis.T he protein kinases oxidative stress-responsive 1 (OSR1) and its homolog the STE20/SPS1-related proline-, alanine-rich kinase (SPAK or PASK) are the mammalian members of the germ-cell kinase VI subgroup of the large Ste20 branch of the mammalian kinome. OSR1 and SPAK directly regulate the solute carrier 12 family of cation-chloride cotransporters which modulate ion homeostasis throughout the body (1, 2). OSR1/ SPAK kinase domains lie close to their N-termini and they contain two additional conserved regions named "PF1" and "PF2" [PASK and Fray (Drosophila homolog)] (3). PF1 is a C-terminal extension to the kinase domain and is required for enzyme activity (4). PF2 binds the consensus motif [(R/K)FX(V/I)] (5) in substrates including ion cotransporters and in regulators. OSR1 and SPAK are activated by with no lysine [K] (WNK) protein kinases, which phosphorylate the essential activation loop regulatory site as well as a second site in the PF1 region with an undefined function (6-9).The four WNK protein kinases are large enzymes notable for the alternative placement of the essential ATP-binding lysine residue in their catalytic domains, distinguishing them from other members of the protein kinase superfamily (10, 11). Initial attention was focused on these enzymes because certain mutations in two family members cause pseudohypoaldosteronism type II, a heritable form of hypertension (12). WNKs are activated by changes in tonicity. Cellular reconstitution studies and mouse genetics demonstrated the importance of WNK function in cell volume regulation and maintenance of blood pressure (13-19). Control of cation-chloride cotransporters through OSR1 and SPAK is among the best-documented actions of WNKs in diverse tissues (5,(20)(21)(22).WNKs also regulate serum-and glucocorticoid-inducible protein k...

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Role of with-no-lysine [K] kinases in the pathogenesis of Gordon’s syndrome

Cited by 38 publications

References 39 publications

Mutations in the nervous system–specific HSN2 exon of WNK1 cause hereditary sensory neuropathy type II

Mutations in the nervous system–specific HSN2 exon of WNK1 cause hereditary sensory neuropathy type II

WNK1 is required for mitosis and abscission

Regulation of OSR1 and the sodium, potassium, two chloride cotransporter by convergent signals

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