Phosphorylation by PKC and PKA regulate the kinase activity and downstream signaling of WNK4

Castañeda‐Bueno, María; Arroyo, Juan Pablo; Zhang, J; Puthumana, Jeremy; Yarborough, OrLando H.; Shibata, Shigeru; Rojas‐Vega, Lorena; Gamba, Gerardo; Rinehart, Jesse; Rp, Lifton

doi:10.1073/pnas.1620315114

Cited by 51 publications

(55 citation statements)

References 51 publications

(68 reference statements)

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“…Therefore, hormones that regulate the PKA pathway could potentially be involved in the regulation of NCC SV -mediated Na + transport in DCT. There is a growing body of evidence that demonstrates that NCC abundance and phosphorylation is affected by PKC or PKA downstream of angiotensin II or vasopressin signaling, respectively (43,(50)(51)(52).…”

Section: Discussionmentioning

confidence: 99%

Dominant functional role of the novel phosphorylation site S811 in the human renal NaCl cotransporter

et al. 2018

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The NaCl cotransporter (NCC) is essential for electrolyte homeostasis and control of blood pressure. The human SLC12A3 gene, which encodes NCC, gives rise to 3 isoforms, of which only the shortest isoform [NaCl cotransporter isoform 3 (NCC)] has been studied extensively. All NCC isoforms share key phosphorylation sites at T55 and T60 that are essential mediators of NCC function. Recently, a novel phosphorylation site at S811 was identified in isoforms 1 and 2 [NaCl cotransporter splice variant (NCC)], which are only present in humans and higher primates. The aim of the current study, therefore, is to investigate the role of S811 phosphorylation in the regulation of NCC by a combination of biochemical and fluorescent microscopy analyses. We demonstrate that hypotonic low-chloride buffer increases S811 phosphorylation, whereas phosphorylation-deficient S811A mutant hinders phosphorylation at T55 and T60 in NCC and NCC. NCC S811A impairs NCC activity in a dominant-negative fashion, although it does not affect plasma membrane abundance. This effect may be explained by the heterodimerization of NCC with NCC. Taken together, our study highlights the dominant-negative effect of NCC on T55 and T60 phosphorylation and NCC activity. Here, we reveal a new function of NCC in humans that broadens the understanding on NCC regulation in blood pressure control.-Tutakhel, O. A. Z., Bianchi, F., Smits, D. A., Bindels, R. J. M., Hoenderop, J. G. J., van der Wijst, J. Dominant functional role of the novel phosphorylation site S811 in the human renal NaCl cotransporter.

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Section: Discussionmentioning

confidence: 99%

Dominant functional role of the novel phosphorylation site S811 in the human renal NaCl cotransporter

et al. 2018

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“…Besides these mechanisms, there is also evidence that AngII modulates WNK function (SanCristobal et al 2009). Of note, a recent study identified WNK4 sites that are phosphorylated downstream of AngII signaling (Castaneda-Bueno et al 2017). Interestingly, AngII phosphorylation of WNK4 modulates WNK4 kinase activity by promoting autophosphorylation of S332 of the T-loop in the kinase catalytic domain.…”

Section: Mechanisms Regulating Ncc In Dct Cellsmentioning

confidence: 99%

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor and NaCl transport mechanisms in the renal distal nephron

Shibata

2017

Journal of Endocrinology

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A key role of aldosterone and mineralocorticoid receptor is to regulate fluid volume and K + homeostasis in the body by acting on the renal distal nephron. Global responses of the kidney to elevated aldosterone levels are determined by the coordinate action of different constituent tubule cells, including principal cells, intercalated cells and distal convoluted tubule cells. Recent studies on genetic mutations causing aldosterone overproduction have identified the molecules involved in aldosterone biosynthesis in the adrenal gland, and there is also increasing evidence for mechanisms and signaling pathways regulating the balance between renal NaCl reabsorption and K + secretion, the two major effects of aldosterone. In particular, recent studies have demonstrated that mineralocorticoid receptor in intercalated cells is selectively regulated by phosphorylation, which prevents ligand binding and activation. Moreover, the ubiquitin ligase complex composed of Kelch-like 3 and Cullin 3 acts downstream of angiotensin II and plasma K + alterations, regulating Na-Cl cotransporter independently of aldosterone in distal convoluted tubule cells. These and other effects are integrated to produce appropriate kidney responses in a high-aldosterone state, and are implicated in fluid and electrolyte disorders in humans. This review summarizes the current knowledge on mechanisms modulating mineralocorticoid receptor and its downstream effectors in the distal nephron.

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“…30,31 This regulation occurs via protein kinase C (PKC), which directly phosphorylates WNK4 in two main sites, S64 and S1196, increasing WNK4 activity. 32 PKC also promotes phosphorylation of KLHL3 in a serine residue (S433) that lays in the WNK4-binding domain preventing degradation of WNK4. 33 The effects of AngII in the DCT are mediated by the AT1 receptor, a pleiotropic GPCR whose intracellular signaling mechanisms are similar to that of CaSR.…”

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confidence: 99%

The Calcium-Sensing Receptor Increases Activity of the Renal NCC through the WNK4-SPAK Pathway

Bazúa‐Valenti

Rojas‐Vega

Castañeda‐Bueno

et al. 2018

JASN

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Hypercalciuria can result from activation of the basolateral calcium-sensing receptor (CaSR), which in the thick ascending limb of Henle's loop controls Ca excretion and NaCl reabsorption in response to extracellular Ca However, the function of CaSR in the regulation of NaCl reabsorption in the distal convoluted tubule (DCT) is unknown. We hypothesized that CaSR in this location is involved in activating the thiazide-sensitive NaCl cotransporter (NCC) to prevent NaCl loss. We used a combination of and models to examine the effects of CaSR on NCC activity. Because the KLHL3-WNK4-SPAK pathway is involved in regulating NaCl reabsorption in the DCT, we assessed the involvement of this pathway as well. Thiazide-sensitive Na uptake assays in oocytes revealed that NCC activity increased in a WNK4-dependent manner upon activation of CaSR with Gd In HEK293 cells, treatment with the calcimimetic R-568 stimulated SPAK phosphorylation only in the presence of WNK4. The WNK4 inhibitor WNK463 also prevented this effect. Furthermore, CaSR activation in HEK293 cells led to phosphorylation of KLHL3 and WNK4 and increased WNK4 abundance and activity. Finally, acute oral administration of R-568 in mice led to the phosphorylation of NCC. Activation of CaSR can increase NCC activity the WNK4-SPAK pathway. It is possible that activation of CaSR by Ca in the apical membrane of the DCT increases NaCl reabsorption by NCC, with the consequent, well known decrease of Ca reabsorption, further promoting hypercalciuria.

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Phosphorylation by PKC and PKA regulate the kinase activity and downstream signaling of WNK4

Cited by 51 publications

References 51 publications

Dominant functional role of the novel phosphorylation site S811 in the human renal NaCl cotransporter

Dominant functional role of the novel phosphorylation site S811 in the human renal NaCl cotransporter

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor and NaCl transport mechanisms in the renal distal nephron

The Calcium-Sensing Receptor Increases Activity of the Renal NCC through the WNK4-SPAK Pathway

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