Serum- and Glucocorticoid-Regulated Kinase 1 Regulates Ubiquitin Ligase Neural Precursor Cell-Expressed, Developmentally Down-Regulated Protein 4-2 by Inducing Interaction with 14-3-3

Bhalla, Vivek; Daidié, Dorothée; Li, Hongyan; Pao, Alan C.; LaGrange, Lila P.; Wang, Jian; Vandewalle, Alain; Stockand, James D.; Staub, Olivier; Pearce, David

doi:10.1210/me.2005-0193

Cited by 164 publications

(181 citation statements)

References 73 publications

(81 reference statements)

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“…The effects of AII signaling in renal epithelia are further supported by the results of renal transplantation between wildtype mice and mice deficient for Agtr1a, which showed that the absence of renal AT1R reduces blood pressure (46). These findings are also consistent with studies demonstrating that phosphorylation can either negatively (47) or positively (48) regulate the activity of E3 ubiquitin ligases. KLHL2, which can also bind WNK4 (49), may be regulated by the same mechanism, because the segment spanning S433 in KLHL3 is virtually identical in KLHL2 (Fig.…”

Section: Discussionsupporting

confidence: 77%

Angiotensin II signaling via protein kinase C phosphorylates Kelch-like 3, preventing WNK4 degradation

Shibata

Arroyo

Castañeda‐Bueno

et al. 2014

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

102

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Hypertension contributes to the global burden of cardiovascular disease. Increased dietary K + reduces blood pressure; however, the mechanism has been obscure. Human genetic studies have suggested that the mechanism is an obligatory inverse relationship between renal salt reabsorption and K + secretion. Mutations in the kinases with-no-lysine 4 (WNK4) or WNK1, or in either Cullin 3 (CUL3) or Kelch-like 3 (KLHL3)-components of an E3 ubiquitin ligase complex that targets WNKs for degradation-cause constitutively increased renal salt reabsorption and impaired K + secretion, resulting in hypertension and hyperkalemia. The normal mechanisms that regulate the activity of this ubiquitin ligase and levels of WNKs have been unknown. We posited that missense mutations in KLHL3 that impair binding of WNK4 might represent a phenocopy of the normal physiologic response to volume depletion in which salt reabsorption is maximized. We show that KLHL3 is phosphorylated at serine 433 in the Kelch domain (a site frequently mutated in hypertension with hyperkalemia) by protein kinase C in cultured cells and that this phosphorylation prevents WNK4 binding and degradation. This phosphorylation can be induced by angiotensin II (AII) signaling. Consistent with these in vitro observations, AII administration to mice, even in the absence of volume depletion, induces renal KLHL3 S433 phosphorylation and increased levels of both WNK4 and the NaCl cotransporter. Thus, AII, which is selectively induced in volume depletion, provides the signal that prevents CUL3/KLHL3-mediated degradation of WNK4, directing the kidney to maximize renal salt reabsorption while inhibiting K + secretion in the setting of volume depletion.renin-angiotensin-aldosterone system | distal tubule | hypertension | posttranslational modification | PHAII H ypertension affects 1 billion people worldwide and is a major risk factor for death from stroke, myocardial infarction, and congestive heart failure. The study of Mendelian forms of hypertension has demonstrated the key role of increased renal salt reabsorption in disease pathogenesis (1-4). Observational and intervention trials (5, 6) also indicate that increased dietary K + lowers blood pressure; however, the mechanism of this effect has been unclear.Pseudohypoaldosteronism type II (PHAII; Online Mendelian Inheritance in Man no. 145260), featuring hypertension and hyperkalemia, has revealed a previously unrecognized mechanism that regulates the balance between renal salt reabsorption and K + secretion in response to aldosterone (7). Aldosterone is produced by the adrenal glomerulosa in volume depletion, in response to angiotensin II (AII), and in hyperkalemia via membrane depolarization (8). In volume depletion, aldosterone maximizes renal salt reabsorption, whereas in hyperkalemia, aldosterone promotes maximal renal K + secretion. Volume depletion increases both the NaCl cotransporter (NCC) (9) and electrogenic Na + reabsorption via the epithelial Na + channel (ENaC) (10). The lumen-negative potential produced by ENa...

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Section: Discussionsupporting

confidence: 77%

Angiotensin II signaling via protein kinase C phosphorylates Kelch-like 3, preventing WNK4 degradation

Shibata

Arroyo

Castañeda‐Bueno

et al. 2014

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

102

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“…Similar cooperative effects were seen on Nedd4-2-dependent ubiquitin ligase activity when using ENaC as substrate ( Fig. 3B): ENaC (␣-subunit) was heavily ubiquitinated in a Nedd4-2-dependent fashion, and SGK1 had a substantial inhibitory effect, as has been shown (24,25). We also observed modest but consistent inhibition of Nedd4-2 by GILZ1 alone (Fig.…”

supporting

confidence: 86%

“…Ubiquitination assays were performed as described (24) in HEK 293T cells. Cotransfections were performed as specified in the figures.…”

Section: Experimental Methodsmentioning

confidence: 99%

Epithelial sodium channel regulated by differential composition of a signaling complex

Soundararajan¹,

Melters²,

Shih³

et al. 2009

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

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Hormonal control of transepithelial sodium (Na ؉ ) transport utilizes phosphatidylinositide 3 -kinase (PI3K) and Raf-MAPK/ERK kinase (MEK)-ERK-dependent signaling pathways, which impact numerous cell functions. How signals transmitted by these pathways are sorted and appropriately transmitted to alter Na ؉ transport without altering other physiologic processes is not well understood. Here, we report the identification of a signaling complex that selectively modulates the cell surface expression of the epithelial sodium channel (ENaC), an ion channel that is essential for fluid and electrolyte balance in mammals. Raf-1 and the ubiquitin ligase, Nedd4-2, are constitutively-expressed inhibitory components of this ENaC regulatory complex, which interact with, and decrease the expression of, cell surface ENaC. The activities of Nedd4-2 and Raf-1 are inhibited cooperatively by the PI3K-dependent kinase serum-and glucocorticoid-induced kinase 1 (SGK1), and the Raf-1-interacting protein glucocorticoid-induced leucine zipper (GILZ1), which are aldosterone-stimulated components of the complex. Together, SGK1 and GILZ1 synergistically stimulate ENaC cell surface expression. Interestingly, GILZ1 and SGK1 do not have synergistic, and in fact have opposite, effects on an unrelated activity, FKHRL1-driven gene transcription. Together, these data suggest that GILZ1 and SGK1 provide a physical and functional link between the PI3K-and Raf-1-dependent signaling modules and represent a unique mechanism for specifically controlling Na ؉ transport without inappropriately activating other cell functions.glucocorticoid-induced leucine zipper protein ͉ Nedd4-2 ͉ Raf-1 ͉ serum-and glucocorticoid-induced kinase 1

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“…Alanine mutations at these three sites diminish SGK1 and PKA-stimulated ENaC cell surface expression and activity (1,14). SGK1 and/or PKA-mediated Nedd4-2 phosphorylation-dependent interaction with 14-3-3 scaffolding proteins prevents subsequent interaction with and ubiquitination of ENaC (15)(16)(17). Aldosterone stimulates SGK1 expression, whereas vasopressin activates PKA.…”

Section: Nedd4-2mentioning

confidence: 99%

Neural Precursor Cell-expressed Developmentally Down-regulated Protein 4-2 (Nedd4-2) Regulation by 14-3-3 Protein Binding at Canonical Serum and Glucocorticoid Kinase 1 (SGK1) Phosphorylation Sites

Chandran

Dong

et al. 2011

Journal of Biological Chemistry

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Background: Coordinate regulation by kinases and 14-3-3 proteins regulates sodium transport through phosphorylation and inhibition of E3 ligases. Results: Phosphorylation at similar but distinct target motifs can either inhibit or stabilize E3 ligases. Conclusion: E3 ligases integrate multiple kinase inputs to regulate sodium transport and protein stability. Significance: These findings broaden our knowledge of how E3 ligases and sodium transport are regulated by phosphorylation.

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Serum- and Glucocorticoid-Regulated Kinase 1 Regulates Ubiquitin Ligase Neural Precursor Cell-Expressed, Developmentally Down-Regulated Protein 4-2 by Inducing Interaction with 14-3-3

Cited by 164 publications

References 73 publications

Angiotensin II signaling via protein kinase C phosphorylates Kelch-like 3, preventing WNK4 degradation

Angiotensin II signaling via protein kinase C phosphorylates Kelch-like 3, preventing WNK4 degradation

Epithelial sodium channel regulated by differential composition of a signaling complex

Neural Precursor Cell-expressed Developmentally Down-regulated Protein 4-2 (Nedd4-2) Regulation by 14-3-3 Protein Binding at Canonical Serum and Glucocorticoid Kinase 1 (SGK1) Phosphorylation Sites

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