| Interacting proteins: O00141 and Q96PU5 |
Pubmed |
SVM Score :0.51803417 |
| This effect of SGK 1 requires physical associations of Nedd 4 2 with both SGK 1 and ENaC . 0.51803417^^^ |
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| Interacting proteins: O00141 and Q96PU5 |
Pubmed |
SVM Score :0.0 |
| Here we show that SGK and human Nedd 4 2 ( hNedd 4 2 ) converge in a common pathway to regulate epithelial Na+ absorption . ^^^ Consistent with this model , we found that SGK bound to hNedd 4 2 and hNedd 4 . ^^^ SGK phosphorylated hNedd 4 2 ( but not hNedd 4 ) , altering hNedd 4 2 function ; phosphorylation reduced the binding of hNedd 4 2 to alphaENaC , and hence , the hNedd 4 2 mediated inhibition of Na+ absorption . ^^^ These data suggest that SGK regulates epithelial Na+ absorption in part by modulating the function of hNedd 4 2 . . ^^^ |
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| Interacting proteins: O00141 and Q96PU5 |
Pubmed |
SVM Score :0.0 |
| One of the functions of SGK 1 is the phosphorylation and inactivation of the ubiquitin ligase Nedd 4 2 , which in turn could be shown to downregulate the voltage gated Na+ channel SCN5A ( hH 1 ) . ^^^ |
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| Interacting proteins: O00141 and Q96PU5 |
Pubmed |
SVM Score :0.0 |
| To characterize properties and regulation of SN 1 , substrate induced currents and / or radioactive glutamine uptake were determined in Xenopus oocytes injected with cRNA encoding SN 1 , the ubiquitin ligase Nedd 4 2 , and / or the constitutively active serum and glucocorticoid inducible kinase S422DSGK1 , its isoform SGK 3 , and the constitutively active protein kinase B T308D , S473DPKB . ^^^ Coexpression of Nedd 4 2 downregulated SN 1 mediated transport , an effect reversed by coexpression of S422DSGK1 , SGK 3 , and T308D , S473DPKB . ^^^ It is concluded that SN 1 is a target for the ubiquitin ligase Nedd 4 2 , which is inactivated by the serum and glucocorticoid inducible kinase SGK 1 , its isoform SGK 3 , and protein kinase B . . ^^^ |
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| Interacting proteins: O00141 and Q96PU5 |
Pubmed |
SVM Score :0.0 |
| These observations suggest that SGK 1 3 and Nedd 4 2 regulate ClC 2 at least in part by modulating ClC 2 abundance at the plasma membrane . . ^^^ |
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| Interacting proteins: O00141 and Q96PU5 |
Pubmed |
SVM Score :0.0 |
| The kinase activates glutamate induced current ( 1 ( GLU ) ) in Xenopus oocytes heterologously expressing EAAT 4 , an effect mimicked by its isoforms SGK 2 , 3 and PKB . 1 ( GLU ) was decreased by the ubiquitin ligase Nedd 4 2 , an effect partially but not completely reversed by additional coexpression of the SGK kinase isoforms or PKB . ^^^ According to immunohistochemistry EAAT 4 protein abundance in the cell membrane was enhanced by SGK 1 and decreased by Nedd 4 2 . ^^^ |
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| Interacting proteins: O00141 and Q96PU5 |
Pubmed |
SVM Score :0.0 |
| Nedd 4 2 phosphorylation induces serum and glucocorticoid regulated kinase ( SGK ) ubiquitination and degradation . ^^^ SGK phosphorylates Nedd 4 2 , an E 3 ubiquitin protein ligase that targets the epithelial Na+ channel ( ENaC ) for degradation . ^^^ Here we found that SGK degradation is mediated in part by Nedd 4 2 . ^^^ Consistent with this model , overexpression of Nedd 4 2 decreased steady state levels of SGK in a dose dependent manner by increasing SGK ubiquitination and degradation in the 26S proteasome . ^^^ Conversely , silencing of Nedd 4 2 by RNA interference stabilized SGK . ^^^ |
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| Interacting proteins: O00141 and Q96PU5 |
Pubmed |
SVM Score :0.0 |
| The current amplitude increase mediated by SGK 1 was not dependent on NEDD4 . 2 or RAB 5 , nor did it reflect increased cell surface expression . ^^^ In conclusion , SGK 1 stimulates Kv 4 . 3 potassium channels expressed in Xenopus oocytes by a novel mechanism distinct from the known NEDD4 . 2 dependent pathway . . ^^^ |
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| Interacting proteins: O00141 and Q96PU5 |
Pubmed |
SVM Score :0.0 |
| Post translational regulation of EAAT 2 function by co expressed ubiquitin ligase Nedd 4 2 is impacted by SGK kinases . ^^^ The serum and glucocorticoid inducible kinase ( SGK ) 1 is expressed in the brain and is known to interact with the ubiquitin ligase Nedd 4 2 to modulate membrane transporters and ion channels . ^^^ Similar to glutamate induced currents , [ 3H ] glutamate uptake and cell surface abundance of the transporter were increased by the SGK isoforms and down regulated by the ubiquitin ligase Nedd 4 2 . ^^^ |
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| Interacting proteins: O00141 and Q96PU5 |
Pubmed |
SVM Score :0.0 |
| Phosphorylation of Nedd 4 2 by Sgk 1 regulates epithelial Na ( + ) channel cell surface expression . ^^^ Here we show by expression studies in Xenopus laevis oocytes that the aldosterone induced Sgk 1 kinase interacts with the ubiquitin protein ligase Nedd 4 2 in a PY motif dependent manner and phosphorylates Nedd 4 2 on Ser 444 and , to a lesser extent , Ser 338 . ^^^ |
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| Interacting proteins: O00141 and Q96PU5 |
Pubmed |
SVM Score :0.0 |
| Aldosterone induced SGK 1 is thought to enhance ENaC surface expression by phosphorylating Nedd 4 2 and thereby preventing ENaC retrieval and degradation . ^^^ Our findings indicate that SGK 1 can stimulate ENaC activity independently of an inhibition of Nedd 4 2 mediated channel retrieval . ^^^ |
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| Interacting proteins: O00141 and Q96PU5 |
Pubmed |
SVM Score :0.0 |
| AMP and serum and glucocorticoid inducible kinase ( SGK ) regulate the epithelial Na ( + ) channel through convergent phosphorylation of Nedd 4 2 . ^^^ |
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| Interacting proteins: O00141 and Q96PU5 |
Pubmed |
SVM Score :0.0 |
| These findings are consistent with the recently described role of SGK 1 in phosphorylating the membrane associated protein Nedd 4 2 and the integral membrane Na+ / H+ exchanger isoform 3 ( NHE 3 ) and suggest a novel mechanism of regulation of SGK 1 . . ^^^ |
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| Interacting proteins: O00141 and Q96PU5 |
Pubmed |
SVM Score :0.0 |
| This effect at the level of ENaC has been recently shown to be mediated by the ubiquitin ligase Nedd 4 2 which is a direct target of SGK 1 . ^^^ Once phosphorylated by SGK 1 , Nedd 4 2 is prevented from interacting with ENaC and thus from decreasing ENaC cell surface expression . ^^^ |
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| Interacting proteins: O00141 and Q96PU5 |
Pubmed |
SVM Score :0.0 |
| Independently , we show that a peptide encompassing the PY motif of sgk 1 , previously proposed to bind to Nedd 4 2 and alter its ability to regulate ENaC , does not bind ( or binds poorly ) the WW domains of Nedd 4 2 . ^^^ |
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| Interacting proteins: O00141 and Q96PU5 |
Pubmed |
SVM Score :0.0 |
| This regulatory mechanism is impaired in Liddle ' s disease , an inherited form of human hypertension , and is controlled by Sgk 1 , an aldosterone inducible kinase which phosphorylates Nedd 4 2 . ^^^ |
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| Interacting proteins: O00141 and Q96PU5 |
Pubmed |
SVM Score :0.0 |
| Characterization of the interactions between Nedd 4 2 , ENaC , and sgk 1 using surface plasmon resonance . ^^^ Unlike Nedd 4 1 , Nedd 4 2 also interacts with the aldosterone induced channel activating kinase sgk 1 . ^^^ The current study uses surface plasmon resonance to quantify the binding of the four WW domains of Nedd 4 2 to synthetic peptides corresponding to the PY motifs of ENaC and sgk 1 . ^^^ The measurements demonstrate that WW 3 and WW 4 are the only Nedd 4 2 domains interacting with both ENaC and sgk 1 and that their binding constants are in the 1 6 microM range . . ^^^ |
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| Interacting proteins: O00141 and Q96PU5 |
Pubmed |
SVM Score :0.0 |
| SGK 1 regulates Nedd 4 2 , a ubiquitin ligase that prepares cell membrane proteins for degradation . ^^^ To test whether Nedd 4 2 , SGK 1 , SGK 3 and protein kinase B regulate EAAT 1 , cRNA encoding EAAT 1 was injected into Xenopus oocytes with or without additional injection of wild type Nedd 4 2 , constitutively active S422DSGK1 , inactive K127NSGK1 , wild type SGK 3 and / or constitutively active T308D , S473DPKB . ^^^ Site directed mutagenesis of the SGK 1 phosphorylation sites in the Nedd 4 2 protein ( S382A , S468ANedd4 2 ) and in the EAAT 1 protein ( T482AEAAT1 , T482DEAAT1 ) significantly blunts the effect of S422DSGK1 . ^^^ |
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| Interacting proteins: O00141 and Q96PU5 |
Pubmed |
SVM Score :0.0 |
| Concerted action of ENaC , Nedd 4 2 , and Sgk 1 in transepithelial Na ( + ) transport . ^^^ Two regulatory proteins have gained interest in recent years : the ubiquitin protein ligase neural precursor cell expressed , developmentally downregulated gene 4 isoform Nedd 4 2 , which negatively controls ENaC cell surface expression , and serum glucocorticoid inducible kinase 1 ( Sgk 1 ) , which is an aldosterone and insulin dependent , positive regulator of ENaC density at the plasma membrane . ^^^ Here , we summarize present ideas about Sgk 1 and Nedd 4 2 and the lines of experimental evidence , suggesting that they act sequentially in the regulatory pathways governed by aldosterone and insulin and regulate ENaC number at the plasma membrane . . ^^^ |
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| Interacting proteins: O00141 and Q96PU5 |
Pubmed |
SVM Score :0.0 |
| When the phosphorylation level of human Nedd 4 2 Ser ( 448 ) ( known to be phosphorylated by the Sgk 1 kinase ) was determined with a specific anti pSer ( 448 ) antibody , we observed stronger basal phosphorylation of Nedd 4 2 P355L . ^^^ |
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| Interacting proteins: O00141 and Q96PU5 |
Pubmed |
SVM Score :0.0 |
| Nedd 4 2 is , in turn , a target of the serum and glucocorticoid inducible kinase SGK 1 , which phosphorylates and , thus , inactivates the ubiquitin ligase . ^^^ We hypothesized that ClC Ka / barttin is stimulated by SGK 1 , and down regulated by Nedd 4 2 , an effect that may be reversed by SGK 1 and its isoforms , SGK 2 or SGK 3 . ^^^ METHODS : To test this hypothesis , ClC Ka / barttin was heterologously expressed in Xenopus oocytes with or without the additional expression of Nedd 4 2 , SGK 1 , SGK 2 , SGK 3 , constitutively active S422DSGK1 , or inactive K127NSGK1 . ^^^ Moreover , S422DSGK1 , SGK 1 , and SGK 3 also phosphorylated Nedd 4 2 and thereby inhibited Nedd 4 2 binding to its target . ^^^ |
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| Interacting proteins: O00141 and Q96PU5 |
Pubmed |
SVM Score :0.0 |
| PURPOSE OF REVIEW : The serum and glucocorticoid inducible kinase 1 ( SGK 1 ) is induced in the aldosterone sensitive distal nephron ( ASDN ) where it may stimulate Na reabsorption , partly by inhibiting ubiquitin ligase Nedd 4 2 mediated retrieval of epithelial Na+ channel ENaC from the luminal membrane . ^^^ RECENT FINDINGS : Thiazolidinediones , i . e . activators of peroxisome proliferator activated receptor gamma ( PPAR gamma ) , upregulate SGK 1 and ENaC mRNA expression and increase cell surface expression of ENaC alpha in a human cortical collecting duct cell line . cAMP / protein kinase A can induce phosphorylation and inhibition of Nedd 4 2 independent of SGK 1 . ^^^ Part of ENaC stimulation by SGK 1 appears dependent on a SGK 1 consensus motif in ENaC alpha and independent of Nedd 4 2 . ^^^ Nedd 4 2 integrates influences of cAMP / protein kinase A and SGK 1 . ^^^ SGK 1 can activate ENaC in part directly and independent of Nedd 4 2 . ^^^ |
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| Interacting proteins: O00141 and Q96PU5 |
Pubmed |
SVM Score :0.0 |
| The interaction is dependent on Sgk 1 catalyzed phosphorylation of hNedd 4 2 at Ser 468 . ^^^ Our findings suggest that 14 3 3 proteins modulate the cell surface density of ENaC cooperatively with Sgk 1 kinase by maintaining hNedd 4 2 in an inactive phosphorylated state . . ^^^ Nedd 4 2 function is negatively regulated by phosphorylation via a serum and glucocorticoid inducible protein kinase ( Sgk 1 ) , which serves as a mechanism to inhibit the ubiquitination dependent degradation of ENaC . ^^^ We found that this interaction preserved the activity of the Sgk 1 stimulated ENaC dependent Na+ current while disrupting the interaction decreased ENaC density on the Xenopus laevis oocytes surface possibly by enhancing Nedd 4 2 mediated ubiquitination that leads to ENaC degradation . ^^^ |
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| Interacting proteins: O00141 and Q96PU5 |
Pubmed |
SVM Score :0.0 |
| Expression of the serum and glucocorticoid kinase ( Sgk 1 ) was decreased and that of the ubiquitin protein ligase Nedd 4 2 was increased . ^^^ Reduced ENaC function is likely due to decreased Sgk 1 and increased Nedd 4 2 mRNA expression leading to reduced ENaC expression in the membrane . ^^^ |
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| Interacting proteins: O00141 and Q96PU5 |
Pubmed |
SVM Score :0.0 |
| Sgk 1 mRNA did not change , whereas Nedd 4 2 protein was reduced by > 50 % 2 4 weeks after BDL . ^^^ |
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| Interacting proteins: O00141 and Q96PU5 |
Pubmed |
SVM Score :0.0 |
| Previous work in Xenopus laevis oocytes suggested that Sgk 1 phosphorylates specific residues ( Ser 212 and Ser 328 ) on the ubiquitin protein ligase Nedd 4 2 , an enzyme that directly interacts with ENaC and negatively controls channel density at the plasma membrane . ^^^ Hence , these data provide evidence in cortical collecting duct cells in vitro and in vivo that Sgk 1 dependent phosphorylation of Nedd 4 2 is part of the aldosterone response . . ^^^ |
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| Interacting proteins: O00141 and Q96PU5 |
Pubmed |
SVM Score :0.0 |
| Increased channel activity induced by WNK 1 depends on SGK 1 and the E 3 ubiquitin ligase Nedd 4 2 . ^^^ |
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| Interacting proteins: O00141 and Q96PU5 |
Pubmed |
SVM Score :0.0 |
| Urinary protein excretion , renal abundance of mRNA and protein of ENaC subunits , as well as the ENaC regulatory serum glucocorticoid inducible kinase ( Sgk 1 ) and Nedd 4 2 , were assessed . ^^^ Sgk 1 mRNA expression did not change and Nedd 4 2 protein expression was only decreased at days 1 and 2 in Wistar rats . ^^^ Sgk 1 , Nedd 4 2 and analbuminemia are not important regulatory factors of ENaC protein expression in experimental NS . . ^^^ |
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| Interacting proteins: O00141 and Q96PU5 |
Pubmed |
SVM Score :0.0 |
| Recent evidence has established that SGK 1 phosphorylates and inhibits Nedd 4 2 ( neural precursor cell expressed , developmentally down regulated protein 4 2 ) , a ubiquitin ligase that decreases cell surface expression of the channel and possibly stimulates its degradation . ^^^ The mechanistic basis for this SGK 1 induced Nedd 4 2 inhibition is currently unknown . ^^^ In this study we show that SGK 1 mediated phosphorylation of Nedd 4 2 induces its interaction with members of the 14 3 3 family of regulatory proteins . ^^^ Through functional characterization of Nedd 4 2 mutant proteins , we demonstrate that this interaction is required for SGK 1 mediated inhibition of Nedd 4 2 . ^^^ The concerted action of SGK 1 and 14 3 3 appears to disrupt Nedd 4 2 mediated ubiquitination of ENaC , thus providing a mechanism by which SGK 1 modulates the ENaC mediated Na ( + ) current . ^^^ |
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| Interacting proteins: O00141 and Q96PU5 |
Pubmed |
SVM Score :0.0 |
| Moreover , we studied by real time reverse transcriptase polymerase chain reaction the effect of vasopressin on proteins implicated in the regulation of ENaC ( Nedd 4 2 , prostasin , Sgk 1 ) . ^^^ The apical immunostaining of ENaC increased in response to sodium restriction , as expected , but dDAVP did not further enhance this apical labelling . dDAVP increased the gene expression of prostasin in the cortex but not that of Nedd 4 2 and Sgk 1 . ^^^ |
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| Interacting proteins: O00141 and Q96PU5 |
Pubmed |
SVM Score :0.0 |
| Nedd 4 2 , a ubiquitin protein isopeptide ligase , tags ENaC with ubiquitin for internalization and degradation , but when it is phosphorylated by the aldosterone induced kinase , SGK 1 , Nedd 4 2 is inhibited and apical ENaC density and sodium absorption increase . ^^^ In polarized mCCD epithelia , aldosterone elicited significant , time dependent increases in the expression of alpha ENaC , SGK 1 , phospho Nedd 4 2 , and 14 3 3beta without altering total Nedd 4 2 . ^^^ Incubation of cell extracts with a selective phospho Nedd 4 2 antibody blocked the aldosterone induced association of 14 3 3beta with Nedd 4 2 , implicating SGK 1 phosphorylation at Ser 328 as the primary site of 14 3 3beta binding . ^^^ |
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| Interacting proteins: O00141 and Q96PU5 |
Pubmed |
SVM Score :0.0 |
| We previously demonstrated that 14 3 3 specifically binds one of the E 3 enzymes , Nedd 4 2 ( a human gene product of KIAA 0439 , termed hNedd 4 2 ) , which can be phosphorylated by serum glucocorticoid inducible protein kinase 1 ( SGK 1 ) ; this binding protects the phosphorylated / inactive hNedd 4 2 from phosphatase catalyzed dephosphorylation [ Ichimura , T . , et al . ( 2005 ) J . ^^^ Importantly , a mutant of hNedd 4 2 , which can be phosphorylated by SGK 1 but can not bind 14 3 3 , reduced SGK 1 mediated stimulation of the ENaC induced current in Xenopus laevis oocytes . ^^^ |
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| Interacting proteins: O00141 and Q96PU5 |
Pubmed |
SVM Score :0.0 |
| NA |
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| Interacting proteins: O00141 and Q96PU5 |
Pubmed |
SVM Score :0.0 |
| NA |
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| Interacting proteins: O00141 and Q96PU5 |
Pubmed |
SVM Score :0.0 |
| NA |
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| Interacting proteins: O00141 and Q96PU5 |
Pubmed |
SVM Score :0.0 |
| NA |
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