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Review
. 2003;13(1):29-40.
doi: 10.1159/000070247.

Concerted roles of SGK1 and the Na+/H+ exchanger regulatory factor 2 (NHERF2) in regulation of NHE3

C Chris Yun  1
Affiliations
Review

Concerted roles of SGK1 and the Na+/H+ exchanger regulatory factor 2 (NHERF2) in regulation of NHE3

C Chris Yun. Cell Physiol Biochem. 2003.

Abstract

Na+/H+ exchanger regulatory factors, NHERF1 and NHERF2, are structurally related proteins and highly expressed in epithelial cells. These proteins are initially identified as accessory proteins in the regulation of Na+/H+ exchanger isoform 3, NHE3. In addition to regulation of NHE3, recent studies demonstrate the importance of NHERF1 and NHERF2 in recycling and localization of membrane receptors, ion channels and transporters. Recent studies show that serum- and glucocorticoid-induced kinase 1 (SGK1) specifically interacts with NHERF2 but not with NHERF1, adding to the growing number of differences between the two proteins. The association of SGK1 with NHERF2 is necessary for stimulation of NHE3 activity by glucocorticoids. In addition, SGK1 together with NHERF2 stimulates the K+ channel ROMK1, suggesting a broader role of SGK1 in regulation of ion transport.

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Figures

Fig. 1
Fig. 1
Proposed organization of proteins involved in the PKA-dependent regulation of NHE3.
Fig.2
Fig.2
Effect of dexamethasone in OK cells. A. OK and OK/NHERF2 cells were incubated in 1μM dexamethasone for 24 hr. Northern blot analysis shows an increase in NHE3 mRNA abundance in both cell lines. B. OK, C. OK/NHERF1, D. OK/NHERF2, NHE3 activity is determined fluorometrically. •, control; ▴, dexamethasone treated. Reproduced with permission from ref (14).
Fig. 3
Fig. 3
In vitro interaction between SGK1 and NHERF2. (A) SGK1 and SGK3, but not SGK2 interacts with GST-NHERF2. There is no interaction with GST control or GST-NHERF1. (B) Deletion of the C-terminal 4 amino acids completely blocks the interaction with NHERF2. (C) SGK1 interacts with the second PDZ domains of NHERF2. Significantly weaker interaction with the first PDZ domain is also observed. (D) NHERF2 dimerizes via the first PDZ domain. Reproduced with permission from ref [14].
Fig.4
Fig.4
SGK1 is necessary for the dexamethasone-dependent activation of NHE3. Hemagglutinin (HA) tagged SGK1/K127Q is expressed in OK cells. The stimulatory dexamethasone effect is markedly blocked by the presence of HA-SGK/K127Q. Reproduced with permission from ref (14).
Fig. 5
Fig. 5
A model of glucocorticoid-dependent stimulation of NHE3.
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