Protein tyrosine kinase is expressed and regulates ROMK1 location in the cortical collecting duct

Lin, Dao‐Hong; Sterling, Hyacinth; Yang, Baofeng; Hebert, Steven C.; Giebisch, Gerhard; Wang, Wenhui

doi:10.1152/ajprenal.00301.2003

Cited by 63 publications

(59 citation statements)

References 30 publications

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“…After demonstrating that deletion of NOXII diminished the effect of low K intake on c-Src expression, we examined the effect of low K intake on tyrosine phosphorylation of ROMK. Similar to rat kidney, 8,13 low K intake stimulates tyrosine phosphorylation of ROMK in mouse kidney. Figure 4 is a Western blot showing that K depletion increased the tyrosine phosphorylation of ROMK by 180 Ϯ 10% (n ϭ 6; P Ͻ 0.01) in WT mice.…”

Section: Resultsmentioning

confidence: 89%

Role of gp91phox-Containing NADPH Oxidase in Mediating the Effect of K Restriction on ROMK Channels and Renal K Excretion

Babilonia

Lin²,

Zhang³

et al. 2007

Journal of the American Society of Nephrology

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Previous study has demonstrated that superoxide and the related products are involved in mediating the effect of low K intake on renal K secretion and ROMK channel activity in the cortical collecting duct (CCD). This study investigated the role of gp91 phox -containing NADPH oxidase (NOXII) in mediating the effect of low K intake on renal K excretion and ROMK channel activity in gp91(Ϫ/Ϫ) mice. K depletion increased superoxide levels, phosphorylation of c-Jun, expression of c-Src, and tyrosine phosphorylation of ROMK in renal cortex and outer medulla in wild-type (WT) mice. In contrast, tempol treatment in WT mice abolished whereas deletion of gp91 significantly attenuated the effect of low K intake on superoxide production, c-Jun phosphorylation, c-Src expression, and tyrosine phosphorylation of ROMK. Patch-clamp experiments demonstrated that low K intake decreased mean product of channel number (N) and open probability (P) (NP o ) of ROMK channels from 1.1 to 0.4 in the CCD. However, the effect of low K intake on ROMK channel activity was significantly attenuated in the CCD from gp91(Ϫ/Ϫ) mice and completely abolished by tempol treatment. Immunocytochemical staining also was used to examine the ROMK distribution in WT, gp91(Ϫ/Ϫ), and WT mice with tempol treatment in response to K restriction. K restriction decreased apical staining of ROMK in WT mice. In contrast, a sharp apical ROMK staining was observed in the tempol-treated WT or gp91(Ϫ/Ϫ) mice. Metabolic cage study further showed that urinary K loss is significantly higher in gp91(Ϫ/Ϫ) mice than in WT mice. It is concluded that superoxide anions play a key role in suppressing K secretion during K restriction and that NOXII is involved in mediating the effect of low K intake on renal K secretion and ROMK channel activity.

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Section: Resultsmentioning

confidence: 89%

Role of gp91phox-Containing NADPH Oxidase in Mediating the Effect of K Restriction on ROMK Channels and Renal K Excretion

Babilonia

Lin²,

Zhang³

et al. 2007

Journal of the American Society of Nephrology

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“…Previous studies have demonstrated that low K intake inhibits ROMK channel activity (4, 5) by stimulating internalization of ROMK channels (25,26). Low K intake increases superoxide anions and its related products, and they are involved in mediating the effect of low K intake on ROMK channels because suppression of superoxide production increased the ROMK channel activity in the CCD from rats fed with KD diet (4).…”

Section: Discussionmentioning

confidence: 99%

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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“…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: 98%

“…In addition to direct phosphorylation, SFK regulates ROMK channel activity by suppressing SGK1-induced phosphorylation of WNK4, thereby restoring WNK4-induced inhibition of ROMK channels (12,13). Such a mechanism could play an important role in suppressing ROMK channel activity during volume depletion, which maintains a high SFK activity (11,14,24).…”

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

confidence: 99%

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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Protein tyrosine kinase is expressed and regulates ROMK1 location in the cortical collecting duct

Cited by 63 publications

References 30 publications

Role of gp91phox-Containing NADPH Oxidase in Mediating the Effect of K Restriction on ROMK Channels and Renal K Excretion

Role of gp91phox-Containing NADPH Oxidase in Mediating the Effect of K Restriction on ROMK Channels and Renal K Excretion

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

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

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