K depletion increases protein tyrosine  kinase-mediated phosphorylation of ROMK

Lin, Dao; Sterling, Hyacinth; Lerea, Kenneth M.; Welling, Paul A.; Jin, Lianhong; Giebisch, Gerhard; Wang, Wen Hui

doi:10.1152/ajprenal.00160.2002

Cited by 49 publications

(62 citation statements)

References 30 publications

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“…However, the additional mutation of WNK4 Ser 1196 to alanine restored WNK4's inhibitory effect on ROMK channels and decreased K currents to 850 ± 30 pA (n = 6). The results are consistent with the notion that c-Src acts at least in part by reducing phosphorylation at WNK4 Ser1196 (14), and that this effect is lost in the WNK4 Y1092/1094F mutant. This notion is confirmed by direct measurement of phosphorylation at this site with an antibody specific for phosphorylation at WNK4 S1196 ( Fig.…”

supporting

confidence: 90%

“…A large body of evidence has demonstrated that SFK plays an important role in inhibiting ROMK channels in the CCD (24)(25)(26)(27)(28)(29). We have previously demonstrated that SFK phosphorylates the ROMK1 channel at Tyr 337 (14) thereby facilitating internalization of ROMK channels (24). A low K intake has been shown to increase tyrosine phosphorylation of ROMK channels (11), leading to inhibition of ROMK channels and decreasing K secretion in the CCD.…”

Section: Ptp-1d Interacts With Wnk4 Via Tyr 1143 To Reduce the Inhibimentioning

confidence: 99%

“…The present study provides insights into the mechanism illustrating how SFK-induced phosphorylation of WNK4 regulates ROMK to distinguish the physiologic response to hyperkalemia and volume depletion. (14). Fig.…”

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confidence: 99%

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Src-family protein tyrosine kinase phosphorylates WNK4 and modulates its inhibitory effect on KCNJ1 (ROMK)

Lin

Yue

Yarborough

et al. 2015

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

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With-no-lysine kinase 4 (WNK4) inhibits the activity of the potassium channel KCNJ1 (ROMK) in the distal nephron, thereby contributing to the maintenance of potassium homeostasis. This effect is inhibited via phosphorylation at Ser1196 by serum/glucocorticoidinduced kinase 1 (SGK1), and this inhibition is attenuated by the Srcfamily protein tyrosine kinase (SFK). Using Western blot and mass spectrometry, we now identify three sites in WNK4 that are phosphorylated by c-Src: Tyr 1092 , Tyr 1094 , and Tyr 1143 , and show that both c-Src and protein tyrosine phosphatase type 1D (PTP-1D) coimmunoprecipitate with WNK4. Mutation of Tyr 1092 or Tyr 1143 to phenylalanine decreased the association of c-Src or PTP-1D with WNK4, respectively. Moreover, the Tyr1092Phe mutation markedly reduced ROMK inhibition by WNK4; this inhibition was completely absent in the double mutant WNK4 Y1092/1094F . Similarly, c-Src prevented SGK1-induced phosphorylation of WNK4 at Ser 1196 , an effect that was abrogated in the double mutant. WNK4 Y1143F inhibited ROMK activity as potently as wild-type (WT) WNK4, but unlike WT, the inhibitory effect of WNK4 Y1143F could not be reversed by SGK1. The failure to reverse WNK4 Y1143F -induced inhibition of ROMK by SGK1 was possibly due to enhancing endogenous SFK effect on WNK4 by decreasing the WNK4-PTP-1D association because inhibition of SFK enabled SGK1 to reverse WNK4 Y1143F -induced inhibition of ROMK. We conclude that WNK4 is a substrate of SFKs and that the association of c-Src and PTP-1D with WNK4 at Tyr 1092 and Tyr 1143 plays an important role in modulating the inhibitory effect of WNK4 on ROMK.W ith-no-lysine kinase 4 (WNK4) is expressed in the connecting tubule (CNT) and cortical collecting duct (CCD) (1, 2) and plays an important role in modulating the balance between renal K secretion and Na reabsorption (3-8). The effect of WNK4 on renal K secretion is partially mediated through inhibition of KCNJ1 (ROMK) channels in the CNT and in the CCD. ROMK inhibition is achieved by a stimulation of clathrinmediated endocytosis (1), an effect that is dependent on intersectin, a scaffold protein containing two Eps15 homology domains (9).Serum/glucocorticoid-induced kinase 1 (SGK1), a downstream mediator of aldosterone signaling, suppresses the inhibitory effect of WNK4 on ROMK channels through phosphorylation of WNK4 at Ser 1169 (2) and Ser 1196 (5). Both volume depletion and high K intake increase aldosterone and SGK1 levels (10). However, it is not clear why a high K intake or volume depletion modulates differently the effect of SGK1 on ROMK channels.Candidate regulators of differential ROMK expression in hyperkalemia and hypovolemia should be regulated in a potassiumdependent manner. One such protein is the protein tyrosine kinase c-Src, whose expression in renal cortex is reduced in states of high potassium intake (11). We have previously demonstrated a key role of c-Src in determining the effect of SGK1 on WNK4 (12). C-Src abolishes SGK1-induced phosphorylation of WNK4 and restores the inhibit...

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supporting

confidence: 90%

Section: Ptp-1d Interacts With Wnk4 Via Tyr 1143 To Reduce the Inhibimentioning

confidence: 99%

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Src-family protein tyrosine kinase phosphorylates WNK4 and modulates its inhibitory effect on KCNJ1 (ROMK)

Lin

Yue

Yarborough

et al. 2015

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

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“…Down-regulation of ROMK channel density in states of potassium deprivation is thought to involve Src-dependent channel endocytosis (42,43), whereas phosphorylation of one of the three PKA phosphorylation sites in ROMK (12), serine 44, has been implicated in physiological augmentation of active ROMK channel density (15). In the present study, we elucidate the molecular mechanism and identify a pathway for the hormonal regulation of the channel by vasopressin and aldosterone.…”

Section: Discussionmentioning

confidence: 83%

Cell Surface Expression of the ROMK (Kir 1.1) Channel Is Regulated by the Aldosterone-induced Kinase, SGK-1, and Protein Kinase A

Yoo¹,

Kim

Campo

et al. 2003

Journal of Biological Chemistry

159

146

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The Kir1.1 (ROMK) subtypes of inward rectifier K ؉ channels mediate potassium secretion and regulate sodium chloride reabsorption in the kidney. The density of ROMK channels on the cortical collecting duct apical membrane is exquisitely regulated in concert with physiological demands. Although protein kinase A-dependent phosphorylation of one of the three phospho-acceptors in Kir1.1, Ser-44, also a canonical serum-glucocorticoid-regulated kinase (SGK-1) phosphorylation site, controls the number of active channels, it is unknown whether this involves activating dormant channels already residing on the plasma membrane or recruiting new channels to the cell surface. Here we explore the mechanism and test whether SGK-1 phosphorylation of ROMK regulates cell surface expression. Removal of the phosphorylation site by point mutation (Kir1.1, S44A) dramatically attenuated the macroscopic current density in Xenopus oocytes. As measured by antibody binding of external epitope-tagged forms of Kir1.1, surface expression of Kir1.1 S44A was inhibited, paralleling the reduction in macroscopic current. In contrast, surface expression and macroscopic current density was augmented by a phosphorylation mimic mutation, Kir1.1 S44D. In vitro phosphorylation assays revealed that Ser-44 is a substrate of SGK-1 phosphorylation, and expression of SGK-1 with the wild type channel increased channel density to the same level as the phosphorylation mimic mutation. Moreover, the stimulatory effect of SGK-1 was completely abrogated by mutation of the phosphorylation site. In conclusion, SGK-1 phosphorylation of Kir1.1 drives expression on the plasmalemma. Because SGK-1 is an early aldosterone-induced gene, our results suggest a possible molecular mechanism for aldosterone-dependent regulation of the secretory potassium channel in the kidney.Extracellular potassium homeostasis, maintained by the regulation of renal potassium excretion, is dependent on the activity of weakly inward rectifying ''small conductance'' potassium channels (SK) 1 that are expressed on the apical membrane of epithelial cells in the distal nephron (1, 2). Encoded by the ROMK (Kir 1.1 or KCNJ1) gene (3, 4), these Kir channels are thought to be the major, but not exclusive (5, 6), route for potassium transport into the tubule lumen and constitute a final regulated component of the potassium secretory machinery of the kidney (7,8). Indeed, aldosterone, vasopressin, and other factors precisely regulate SK activity, controlling potassium excretion in accord with the demands of potassium balance. Because ROMK channels normally exhibit a very high open probability, near unity, physiologic augmentation of channel activity, as controlled by hormones and dietary potassium (9), is achieved largely by regulated changes in the number of active channels on the plasmalemma.Although the precise molecular mechanisms responsible for physiological augmentation of ROMK channel surface density have remained unclear, a growing body of evidence has pointed to an important role of protein kina...

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“…We have demonstrated previously that low K intake stimulates the production of superoxide anions and its related products, which in turn increase PTK expression and activity (4,5). Increased PTK activity stimulates tyrosine phosphorylation of ROMK channels and subsequently enhances the internalization of the ROMK channels (6,7). Furthermore, we have shown that low K intake stimulates ERK and p38 MAPK, which inhibits ROMK channels by a PTKindependent pathway.…”

mentioning

confidence: 72%

Inhibitor of growth 4 (ING4) is up-regulated by a low K intake and suppresses renal outer medullary K channels (ROMK) by MAPK stimulation

Zhang

Lin

Jin

et al. 2007

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

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Dietary K intake plays an important role in the regulation of renal K secretion: a high K intake stimulates whereas low K intake suppresses renal K secretion. Our previous studies demonstrated that the Src family protein-tyrosine kinase and mitogen-activated protein kinase (MAPK) are involved in mediating the effect of low K intake on renal K channels and K secretion. However, the molecular mechanism by which low K intake stimulates MAPK is not completely understood. Here we show that inhibitor of growth 4 (ING4), a protein with a highly conserved plant homeodomain finger motif, is involved in mediating the effect of low K intake on MAPK. K restriction stimulates the expression of ING4 in the kidney and superoxide anions, and its related products are involved in mediating the effect of low K intake on ING4 expression. We used HEK293 cells to express ING4 and observed that expression of ING4 increased the phosphorylation of p38 and ERK MAPK, whereas down-regulation of ING4 with small interfering RNA decreased the phosphorylation of p38 and ERK. Immunocytochemistry showed that ING4 was expressed in the renal outer medullary potassium (ROMK)-positive tubules. Moreover, ING4 decreased K currents in Xenopus oocytes injected with ROMK channel cRNA. This inhibitory effect was reversed by blocking p38 and ERK MAPK. These data provide evidence for the role of ING4 in mediating the effect of low K intake on ROMK channel activity by stimulation of p38 and ERK MAPK.ERK ͉ hypokalemia ͉ p38 ͉ renal potassium metabolism ͉ superoxide I t is well known that low K intake suppresses renal K secretion by increasing K absorption and inhibiting K secretion (1, 2). The inhibitory effect of low K intake on renal K secretion is partially achieved by removing renal outer medullary potassium (ROMK)-like small conductance K channels from the apical membrane of principal cells in the cortical collecting duct (CCD) through a protein-tyrosine kinase (PTK)-dependent mechanism (3). We have demonstrated previously that low K intake stimulates the production of superoxide anions and its related products, which in turn increase PTK expression and activity (4, 5). Increased PTK activity stimulates tyrosine phosphorylation of ROMK channels and subsequently enhances the internalization of the ROMK channels (6, 7). Furthermore, we have shown that low K intake stimulates ERK and p38 MAPK, which inhibits ROMK channels by a PTKindependent pathway. However, the mechanism by which low K intake stimulates MAPK activity is not completely understood.Inhibitor of growth 4 (ING4) is a member of the ING family proteins. They have been shown to regulate cell cycle, transcription and oncogenesis (8), and to promote UV-induced apoptosis of skin cells (9). ING4 also plays an important role in inhibiting tumor growth and angiogenesis in brain tumor cells (10). Because K restriction causes renal hypertrophy (11) through stimulation of growth factor levels (12), it is possible that that ING family proteins may also be involved in mediating the effect of low K intake on...

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K depletion increases protein tyrosine kinase-mediated phosphorylation of ROMK

Cited by 49 publications

References 30 publications

Src-family protein tyrosine kinase phosphorylates WNK4 and modulates its inhibitory effect on KCNJ1 (ROMK)

Src-family protein tyrosine kinase phosphorylates WNK4 and modulates its inhibitory effect on KCNJ1 (ROMK)

Cell Surface Expression of the ROMK (Kir 1.1) Channel Is Regulated by the Aldosterone-induced Kinase, SGK-1, and Protein Kinase A

Inhibitor of growth 4 (ING4) is up-regulated by a low K intake and suppresses renal outer medullary K channels (ROMK) by MAPK stimulation

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