Identification of the human NHE-1 form of Na(+)-H+ exchanger in rabbit renal brush border membranes.

Weinman, Edward J.; Steplock, Debra; Corry, Dalila B.; Shenolikar, Shirish

doi:10.1172/jci116433

Cited by 17 publications

(7 citation statements)

References 26 publications

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“…ϩ /H ϩ exchanger regulator factor (NHERF) 2 is an adaptor protein that is responsible for organizing membrane channels and receptors (1,2). NHERF was originally identified as an essential cofactor for inhibiting a transmembrane transporter sodium-hydrogen exchanger isoform 3 (NHE3) by the cAMP-dependent protein kinase A in the kidney proximal tubule cells (1).…”

Section: Namentioning

confidence: 99%

“…NHERF was originally identified as an essential cofactor for inhibiting a transmembrane transporter sodium-hydrogen exchanger isoform 3 (NHE3) by the cAMP-dependent protein kinase A in the kidney proximal tubule cells (1). However, subsequent studies find that NHERF is densely distributed in the apical membranes of polarized epithelial cells of several mammalian tissues (2,3) and that NHERF participates in organizing the trafficking, localization, and membrane targeting of a large number of membrane receptors and channels to which NHERF binds (3)(4)(5)(6)(7)(8)(9)(10)(11)(12).…”

Section: Namentioning

confidence: 99%

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Ezrin Controls the Macromolecular Complexes Formed between an Adapter Protein Na+/H+ Exchanger Regulatory Factor and the Cystic Fibrosis Transmembrane Conductance Regulator

Dai

Jana

et al. 2005

Journal of Biological Chemistry

100

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Na؉ /H ؉ exchanger regulatory factor (NHERF) is an adapter protein that is responsible for organizing a number of cell receptors and channels. NHERF contains two amino-terminal PDZ (postsynaptic density 95/disk-large/zonula occluden-1) domains that bind to the cytoplasmic domains of a number of membrane channels or receptors. The carboxyl terminus of NHERF interacts with the FERM domain (a domain shared by protein 4.1, ezrin, radixin, and moesin) of a family of actin-binding proteins, ezrin-radixin-moesin. NHERF was shown previously to be capable of enhancing the channel activities of cystic fibrosis transmembrane conductance regulator (CFTR). Here we show that binding of the FERM domain of ezrin to NHERF regulates the cooperative binding of NHERF to bring two cytoplasmic tails of CFTR into spatial proximity to each other. We find that ezrin binding activates the second PDZ domain of NHERF to interact with the cytoplasmic tails of CFTR (C-CFTR), so as to form a specific 2:1:1 (C-CFTR) 2 ⅐NHERF⅐ezrin ternary complex. Without ezrin binding, the cytoplasmic tail of CFTR only interacts strongly with the first amino-terminal PDZ domain to form a 1:1 C-CFTR⅐NHERF complex. Immunoprecipitation and immunoblotting confirm the specific interactions of NHERF with the full-length CFTR and with ezrin in vivo. Because of the concentrated distribution of ezrin and NHERF in the apical membrane regions of epithelial cells and the diverse binding partners for the NHERF PDZ domains, the regulation of NHERF by ezrin may be employed as a general mechanism to assemble channels and receptors in the membrane cytoskeleton.Na ϩ /H ϩ exchanger regulator factor (NHERF) 2 is an adaptor protein that is responsible for organizing membrane channels and receptors (1, 2). NHERF was originally identified as an essential cofactor for inhibiting a transmembrane transporter sodium-hydrogen exchanger isoform 3 (NHE3) by the cAMP-dependent protein kinase A in the kidney proximal tubule cells (1). However, subsequent studies find that NHERF is densely distributed in the apical membranes of polarized epithelial cells of several mammalian tissues (2, 3) and that NHERF participates in organizing the trafficking, localization, and membrane targeting of a large number of membrane receptors and channels to which NHERF binds (3)(4)(5)(6)(7)(8)(9)(10)(11)(12).NHERF is a multidomain and multivalent protein that recruits different signaling partners. The amino terminus of NHERF contains two modular PDZ (name derived from the first three proteins that this domain was identified postsynaptic density 95/disk-large/zonula occluden-1) domains, PDZ1 and PDZ2 (see Fig. 1). The NHERF PDZ domains bind to the consensus PDZ-binding motif D(S/T)X(V/I/L) (X denoting any amino acid residue) at the carboxyl termini of a number of membrane channels or receptors (13)(14)(15)(16)(17)(18)(19). The carboxyl terminus of NHERF recognizes the FERM domain (a conserved domain that is shared by protein 4.1, ezrin, radixin, and moesin) of a family of cytoskeletal actin-binding proteins, ez...

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Section: Namentioning

confidence: 99%

Section: Namentioning

confidence: 99%

Ezrin Controls the Macromolecular Complexes Formed between an Adapter Protein Na+/H+ Exchanger Regulatory Factor and the Cystic Fibrosis Transmembrane Conductance Regulator

Dai

Jana

et al. 2005

Journal of Biological Chemistry

100

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“…Another ERM‐binding partner is the ERM‐binding 50 kDa phosphoprotein (EBP50) that binds the FERM domain (Reczek et al ., 1997). EBP50 is identical to the Na + /H + exchange regulator factor (NHE‐RF), a cofactor necessary for protein kinase A regulation of the renal Na + /H + exchanger, a membrane ion channel protein (Weinman et al ., 1993). NHE‐RF and its isoform, E3KARP (Yun et al ., 1997), bind the Na + /H + exchanger through their PDZ domains.…”

Section: Introductionmentioning

confidence: 99%

Structural basis of the membrane-targeting and unmasking mechanisms of the radixin FERM domain

et al. 2000

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Radixin is a member of the ezrin/radixin/moesin (ERM) family of proteins, which play a role in the formation of the membrane-associated cytoskeleton by linking actin ®laments and adhesion proteins. This cross-linking activity is regulated by phosphoinositides such as phosphatidylinositol 4,5-bisphosphate (PIP2) in the downstream of the small G protein Rho. The X-ray crystal structures of the radixin FERM domain, which is responsible for membrane binding, and its complex with inositol-(1,4,5)-trisphosphate (IP3) have been determined. The domain consists of three subdomains featuring a ubiquitin-like fold, a four-helix bundle and a phosphotyrosine-binding-like domain, respectively. These subdomains are organized by intimate interdomain interactions to form characteristic grooves and clefts. One such groove is negatively charged and so is thought to interact with basic juxtamembrane regions of adhesion proteins. IP3 binds a basic cleft that is distinct from those of pleckstrin homology domains and is located on a positively charged¯at molecular surface, suggesting an electrostatic mechanism of plasma membrane targeting. Based on the structural changes associated with IP3 binding, a possible unmasking mechanism of ERM proteins by PIP2 is proposed.

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“…These cells are a useful model for studying the specific effect of insulin on Na/H exchange, because glucose transport, Na/K pump activity and glycogen metabolism are not modulated by insulin in anuclear erythrocytes. In addition, NHE1 has been detected in human erythrocytes [16], and only this isoform was expressed in human reticulocytes [17]. Moreover, only two PKC isoforms, α and ζ, are present in mature human erythrocytes and equally distributed between cytosol and membrane [18].…”

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confidence: 99%

Insulin stimulates NHE1 activity by sequential activation of phosphatidylinositol 3‐kinase and protein kinase C ζ in human erythrocytes

Sauvage

Fathallah

Giraud

2000

European Journal of Biochemistry

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The signaling cascade linking insulin receptor stimulation to the activation of Na/H exchanger (NHE) was investigated in human erythrocytes, a simple cell model expressing the NHE1 isoform and protein kinase C (PKC) a and z isoforms only. Our results demonstrate the presence of phosphatidylinositol (PtdIns) 3-kinase in these cells and its activation by insulin. With a similar time-course, insulin also promoted both the translocation and activation of PKC z, but had no effect on PKC a. Inhibition of PtdIns 3-kinase with wortmannin prevented the activation of PKC z by insulin. Stimulation of NHE1 was observed after 10 min of insulin treatment and persisted for at least 60 min. This effect was totally abolished by wortmannin or GF 109203X, an inhibitor of all PKC isoforms, but not by Go È 6976, a specific inhibitor of conventional and novel PKCs (e.g. PKC a). These data indicate that PKC z activation is mediated by a PtdIns 3-kinase-dependent mechanism and that NHE1 stimulation involves the sequential activation of PtdIns 3-kinase and PKC z. In addition, insulin stimulation of NHE1 occurred without altering the phosphorylation state of the exchanger, suggesting that the phosphorylation of an ancillary protein by PKC z would be responsible for activation of the transporter.

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Identification of the human NHE-1 form of Na(+)-H+ exchanger in rabbit renal brush border membranes.

Cited by 17 publications

References 26 publications

Ezrin Controls the Macromolecular Complexes Formed between an Adapter Protein Na+/H+ Exchanger Regulatory Factor and the Cystic Fibrosis Transmembrane Conductance Regulator

Ezrin Controls the Macromolecular Complexes Formed between an Adapter Protein Na+/H+ Exchanger Regulatory Factor and the Cystic Fibrosis Transmembrane Conductance Regulator

Structural basis of the membrane-targeting and unmasking mechanisms of the radixin FERM domain

Insulin stimulates NHE1 activity by sequential activation of phosphatidylinositol 3‐kinase and protein kinase C ζ in human erythrocytes

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