Physiology AJP: Heart and Circulatory Physiology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Physiology 19: 362-369, 2004; doi:10.1152/physiol.00020.2004
1548-9213/04 $5.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (32)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Shenolikar, S.
Right arrow Articles by Weinman, E. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Shenolikar, S.
Right arrow Articles by Weinman, E. J.
Physiology, Vol. 19, No. 6, 362-369, December 2004
© 2004 Int. Union Physiol. Sci./Am. Physiol. Soc.

REVIEW

Regulation of Ion Transport by the NHERF Family of PDZ Proteins

Shirish Shenolikar, James W. Voltz, Rochelle Cunningham1 and Edward J. Weinman1,2

Department Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710
1 Department of Medicine, University of Maryland School of Medicine, and
2 Department of Veterans Affairs, Baltimore, Maryland 21201


   Abstract
 
NHERFs are the best-studied apical PDZ proteins that are highly expressed in epithelial cells. Molecular and cellular studies over the past decade show that NHERFs regulate the targeting or trafficking of ion transporters and other membrane proteins and transduce physiological and pathophysiological signals that regulate ion homeostasis in mammals.


   Introduction
Top
 Introduction
Structural insights from the...
 Diversity of NHERF targets
 Interaction of NHERFS with...
 NHERFS and Regulation of...
 Concluding Remarks
 References
 
The PDZ domain is a modular protein-interaction domain composed of ~100 amino acids and was first identified in the Drosophila Discs large (Dlg) protein that plays a key role in the differentiation of retinal epithelial cells in the fruit fly. Subsequent studies showed that the mammalian neuronal postsynaptic protein PSD-95 and the adherens junction protein ZO-1 contained a highly homologous domain, thereby defining the domain as a PSD-95, Dlg, and ZO-1 homology (PDZ) domain. Analysis of the human genome suggests the existence of 540 distinct PDZ domains in 306 different proteins, making the PDZ domain one of the most prevalent modular domains found in human proteins (39, 57). Presence of multiple PDZ domains as well as other protein-interaction domains (e.g., Src homology 2 domain, phosphotyrosine-binding domain, actin-binding, sterile alpha motif, coiled-coil, etc.) within a single polypeptide further expands the functional diversity of protein scaffolds that are able to nucleate or assemble large multiprotein complexes at specific sites or organelles in mammalian cells.

This review focuses on Na+/H+ exchanger (NHE) regulatory factors (NHERFs), the PDZ domain-containing products of two different mammalian genes. NHERF-1 is also known as ezrin-binding phosphoprotein of 50 kDa (EBP50) (45), and NHERF-2 was also identified as NHE-3 kinase A-regulatory protein (E3KARP) (68), tyrosine kinase activator-1 (TKA1), and sex-determining region of the Y chromosome (SRY-1) -interacting protein-1 (SIP-1) (41). Both NHERFs share structural homology within two tandem PDZ domains and a COOH-terminal ERM-binding domain that binds all members of the ezrin-radixin-moesin-merlin family of cytoskeletal proteins (68). In this regard, NHERFs display the structural and functional properties of many other PDZ proteins located at or near the cell surface. However, the number of NHERF targets thus far identified far exceeds that for any other PDZ protein. Thus studies of NHERF functions have provided critical insights into the diverse roles played by PDZ domain-containing protein adapters in mammalian physiology.


   Structural insights from the NHERF-1 PDZ domain
Top
 Introduction
 Structural insights from the...
Diversity of NHERF targets
 Interaction of NHERFS with...
 NHERFS and Regulation of...
 Concluding Remarks
 References
 
Random peptide libraries have been used to define primary sequences recognized by many protein-interaction domains. Such peptide displays classified PDZ domains into four groups (types I, II, III, and IV) that are distinguished by their preference for distinct tetrapeptide motifs terminating with a hydrophobic residue, often leucine or valine (53, 56). Structural studies showed that PDZ domains most commonly bound to the COOH terminals of target proteins, with the hydrophobic amino acid associating with a loop structure composed of a conserved sequence, most frequently GLGF, found in all PDZ domains. Despite considerable structural homology, the two NHERF-1 PDZ domains, termed PDZ-I and PDZ-II and characterized by the core sequence GYGF, recognized distinct synthetic peptides (59). This suggested that NHERF-1 (and possibly NHERF-2) recruited two or more protein targets at the cell surface to coordinate or communicate their functions.

Interestingly, the optimal or consensus sequences recognized by the isolated NHERF-1 PDZ domains using random peptides are not present at the COOH terminals of most known NHERF-1 targets (Table 1Go). A simple explanation may be that these short sequences adopt a different conformation as synthetic peptides than when they are fused to COOH terminals of larger polypeptides. An alternate explanation was provided by X-ray crystallography of the NHERF-1 PDZ-I domain with peptides representing the COOH terminals of three known NHERF-1 targets (20, 21). These studies suggested that the NHERF-1 PDZ-I domain adopted slightly different conformations when bound to each of these peptides. The remarkable flexibility of the NHERF-1 PDZ-I domain may explain why so many different COOH-terminal sequences are found in proteins that bind the two NHERF PDZ domains. Alternately, this may allow some cellular targets to bind both PDZ domains in a single NHERF protein. Interestingly, some proteins bind the comparable PDZ domain (PDZ-I or PDZ-II) in both NHERF proteins, whereas other targets bind only one of the two isoforms (Table 1Go).


View this table:
[in this window]
[in a new window]
  		Table 1. Cellular NHERF targets
 

   Diversity of NHERF targets
Top
 Introduction
 Structural insights from the...
 Diversity of NHERF targets
Interaction of NHERFS with...
 NHERFS and Regulation of...
 Concluding Remarks
 References
 
NHERFs are primarily localized at or near the actin cytoskeleton underlying the plasma membrane (67). Both NHERF proteins show unique concentration at the apical surface of polarized epithelial cells. Although the molecular basis by which NHERF proteins distinguish apical from basolateral membranes remains unknown, intracellular sorting of NHERFs appears to be an active and dynamic process, requiring microtubule function for the apical targeting of NHERFs in epithelial cells. Pharmacological disruption of microtubules in the rat kidney result in the redistribution of NHERF-1 from exclusively apical to increased basolateral localization. Biochemical studies of NHERF-1 also suggested that this adapter protein was loosely associated with membrane/cytoskeleton and other subcellular compartments and could be readily extracted in low-ionic-strength buffers (61).

Consistent with the predominant localization of NHERFs at the cell surface, the growing list of potential NHERF targets (Table 1Go) shows a preponderance of membrane proteins, ion transporters, and receptors, specifically G protein-coupled receptors (GPCRs). This list may be even larger, because hormonal regulation of some membrane targets, such as NBC1 (2) and Na+-K+-ATPase (28), requires NHERF, but these proteins showed either weak or no association with the PDZ proteins. A growing number of nonmembrane targets have also been identified, arguing for a highly dynamic subcellular localization of NHERFs in mammalian cells. Interestingly, three nuclear proteins (ß-catenin, SRY-1, and transcriptional coactivator with PDZ-binding motif have been shown to bind with NHERFs, which may regulate their nuclear-cytoplasmic shuttling and/or more directly facilitate their transcriptional activity. It is tempting to speculate that PDZ adapters, such as NHERFs, may aid in the recruitment and assembly of the multiprotein transcriptional complex required to activate some genes.


   Interaction of NHERFS with Cellular Targets
Top
 Introduction
 Structural insights from the...
 Diversity of NHERF targets
 Interaction of NHERFS with...
NHERFS and Regulation of...
 Concluding Remarks
 References
 
Ligand- and second messenger-regulated NHERF binding
Although NHERFs bind some protein targets (e.g., the Na+-H+ cotransporter NHE3) (26) constitu-tively, other interactions between NHERFs and their cellular targets are highly regulated (marked with asterisks in Table 1Go), occurring only under specific physiological conditions. For example, cellular studies suggest that there is little association of NHERF-1 with the ß2-adrenergic receptor (ß2-AR) located at the plasma membrane under basal or unstimulated conditions. However, following activation by ß2-AR agonists, NHERF-1 is rapidly recruited and binds the COOH terminus of ß2-AR (14). Yet other targets, such as the {kappa}-opioid receptor and the platelet-derived growth factor receptor (PDGFR), bind NHERF-1 in the absence of ligands, but this association is greatly strengthened following receptor stimulation by appropriate hormone or growth factor (30, 35). Why NHERF binds some GPCRs constitutively and others in a ligand-regulated manner is still unclear, but a growing speculation is that specific pools of receptor devoid of other competing ligands, such as G proteins, arrestins, and G protein-coupled receptor kinases (GRKs), may be particularly well suited to binding NHERFs, which may serve a function distinct from second-messenger signaling. Consistent with this notion, the association of parathyroid hormone receptor (PTH1R) with either NHERF-2 (34) or NHERF-1 (33) impairs this receptor’s ability to elevate intracellular cAMP. Remarkably, the NHERF-bound PTH1R more effectively promotes phospho-inositide turnover (34). Thus NHERF-1 may switch PTH1R signaling from PKA to PKC and modulate the physiological functions of ion transporters and other proteins in the kidney and other tissues.

Interestingly, NHERF-2 uniquely binds {alpha}-actinin in a calcium-dependent manner (22). Because neither NHERF-2 nor {alpha}-actinin is a recognized calcium-binding protein, the effects of calcium may be indirect, perhaps acting via the rearrangement of the actin cytoskeleton that is bound by both proteins. This in turn is thought to facilitate the downregulation or internalization of targets such as NHE3 (22). This further emphasizes the experimental difficulties in identifying many NHERF targets, because prior knowledge of the physiological conditions that promote their association with NHERF is essential to decipher the function of these cellular complexes.

Covalent modification of NHERF targets
The COOH-terminal PDZ motifs in many NHERF targets, specifically those that bind the PDZ-I domain, contain one or more serines and threonines that are potentially phosphorylated by cellular protein kinases. An example of this is the ß2-AR, which is phosphorylated in vivo by GRK5 on a threonine residue within the COOH-terminal DTRL sequence. This reduces ß2-AR’s affinity for NHERF-1 and directs the phosphorylated ß2-AR to lysosomes for degradation and downregulation (4). These studies also suggest that NHERF-1 binds the internalized or vesicular pool of ß2-AR to promote its efficient recycling to the plasma membrane. At first sight, this paradigm appears at odds with earlier studies that showed that high con-centrations of agonists that clustered ß2-AR at clathrin-coated pits also recruited NHERF-1 (14). Moreover, the continued presence of the agonist promoted ß2-AR internalization and its subsequent degradation or downregulation. Whether ß2-AR present in intracellular vesicles retains the bound ligand or simply possesses the conformation of a ligand-bound ß2-AR is still unclear, but the above studies (4) suggest that NHERF-1 binds internalized and unphosphorylated ß2-AR during its journey back to the plasma membrane. Once delivered to the cell surface, ß2-AR may associate either weakly or transiently with NHERF-1 and require hormonal stimulation of the receptor to strengthen its association with the PDZ adapter.

More recent studies showed that NHERF-1 was itself subject to phosphorylation by PKC within its PDZ domain. This results in its diminished association with CFTR (43). Yet other membrane proteins are phosphorylated at serines within their PDZ motifs to yield a conformation that is more conducive to NHERF binding (17). Thus cellular signaling pathways modulate the phosphorylation of NHERFs and their targets to regulate the association and disassociation of NHERFs with their cellular targets.

NHERF oligomerization: an expanded protein scaffold
NHERF-1 (a 58-kDa polypeptide) was isolated from renal tissues, and it demonstrated an apparent molecular size of 150 kDa (48). This suggested that purified NHERF-1 existed as a dimer. Self-association of NHERF-1 as well as its ability to form NHERF-1–NHERF-2 heterodimers was established by protein overlays (9, 48). NHERF-1 also binds another apical PDZ-domain containing adapter in the kidney, termed PDZK1 (10). The functional role of this complex in ion homeostasis is still unclear, because the PDZK1-null mice display normal serum and urinary electrolytes (24). Although the precise function of NHERF homo- and hetero-dimerization is also unknown, prior studies of the Drosophila InaD protein, which contains five PDZ domains, suggest that oligomerization generated an extended submembrane scaffold that recruited multiple targets, including receptors, ion channels, and signaling proteins, to promote visual transduction in the fruit fly (8). Recent studies indicate that a dimeric NHERF-1 may facilitate or stabilize the formation of CFTR dimers that are functionally more active ion channels (44). Yet other studies suggested that NHERF-1 dimers stabilized the ligand-induced dimerization of PDGFR to facilitate mitogenic signaling (35).

In vitro biochemical studies showed that the isolated NHERF-1 PDZ-I domain readily bound another PDZ-1 domain from either NHERF isoform, although weaker association with the PDZ-II domain was also noted (27). Other studies suggested that the region of NHERF-1 between PDZ-I and PDZ-II also played a role in NHERF-1 dimerization (9). Given such extensive protein-protein interactions within the NHERF-1 dimers, it was surprising that covalent modification at three serines at the COOH terminus of NHERF-1, which is not directly involved in dimerization, had both positive (27) and negative (16) effects of NHERF-1 dimerization. In this regard, NHERFs are phosphorylated by several protein kinases, including PKC (43), serum- and glucocorticoid-inducible kinase-1 (66), PKA (63), GRK6A (15), and cyclin-dependent protein kinases (16). Whereas mitotic phosphorylation of NHERF-1 at serines-279 and -301 inhibited NHERF-1 dimerization (16), the constitutive GRK6A-mediated phosphorylation at serine-289, when mimicked by the substitution of aspartate, enhanced NHERF-1 dimerization (27). Direct experimental evidence for an extended NHERF scaffold is still lacking, and further work will be needed to define the functional role of regulated NHERF-1 dimerization.


   NHERFS and Regulation of Ion Transport
Top
 Introduction
 Structural insights from the...
 Diversity of NHERF targets
 Interaction of NHERFS with...
 NHERFS and Regulation of...
Concluding Remarks
 References
 
Hormonal regulation of ion transport
NHERF-1 was first identified as an essential cofactor required for cAMP (and PKA) -mediated inhibition of NHE3 activity in the renal proximal tubules (61). Subsequent studies showed that NHERF-2, present in gastric epithelia, also facilitated PKA inhibition of NHE3 when coexpressed in PS120 cells. Both NHERF-1 and NHERF-2 bridged NHE3 with a PKA-bound ezrin to facilitate cAMP-mediated phosphorylation of NHE3 and inhibition of Na+/H+ exchange (60). However, studies of isolated mouse renal proximal tubule membranes from the NHERF-1-null mouse, which still contained NHERF-2, established the complete absence of cAMP-mediated inhibition of NHE3 activity (62), suggesting that only NHERF-1 was capable of mediating the cAMP signals that inhibited NHE3. These studies also suggested that NHERF-1 and NHERF-2 might fulfill distinct physiological functions in the mouse kidney.

The "signal complex" regulation described for NHE3 has also been demonstrated for the PKA regulation of CFTR activity. Although many elements of this model still remain to be defined, the NHERF-1-bound CFTR was more efficiently phosphorylated by an ezrin-bound PKA to increase chloride transport (51).

Targeting and trafficking membrane proteins
Cellular studies suggested that NHERF proteins played a critical role in the surface expression of several GPCRs, including ß2-AR (4), luteinizing hormone receptor (LHR) (23), and {kappa}-opioid receptor (30). However, the mechanism by which NHERFs target or traffic these membrane proteins from intracellular endosomal sites to the plasma membrane still remains to be defined. Analysis of renal proximal tubules from the NHERF-1-null mouse showed that NHE3 was still effectively localized in the apical surface of renal proximal tubules in the mutant mouse kidney, whereas a different NHERF target, the type-2 sodium-phosphate transporter (Npt2a), was largely redistributed to internal vesicular sites (49). The altered distribution of Npt2 may account for the significant hyperphosphaturia and reduced bone mineralization seen in the NHERF-1-null mice, which is reminiscent of human hereditary hyphosphatemic rickets also linked to the impaired Npt2a trafficking. Additional cellular studies demonstrate that NHERF-1 is required for effective cell-surface expression of Npt2a (58), whereas other studies suggest a more complex interplay between NHERF-1 and other PDZ proteins, such as PDZK1 and type II NaPi-cotransporter-associated protein 1, in the regulated trafficking of Npt2a in renal proximal tubule cells (10). Similar interchange between CFTR-associated ligand, another PDZ protein, and NHERF-1 has been proposed to regulate the recycling and internalization of CFTR to and from the plasma membrane (5).

Bridging transporters with other NHERF targets
The presence of two closely positioned PDZ domains displaying different target specificities suggests that NHERFs can bridge two different PDZ targets to coordinate their cellular functions. Indeed, previous studies showed that NHERFs can bridge both NHE3 and CFTR with the non-PDZ-containing protein ezrin (1). NHERF association also recruits phospholipase Cß3 in the vicinity of the storage-activated calcium channel, Trp4C, to harness calcium entry with phospholipid turnover and facilitate hormone signaling (55). Similarly, NHERF-2 mediates the recruitment of CFTR and ROMK (Kir 1.1) to coordinate the functions of these two ion transporters (65).

A much simpler concept is that NHERF targets may compete for binding to endogenous NHERFs and thereby modulate each other’s functions that require their association with NHERFs. Thus ligand activation of ß2-AR can increase intracellular cAMP and inhibit NHE3 activity or recruit and sequester NHERF-1 to enhance NHE3 activity (14). Such bimodal regulation of NHE3 by ß2-AR may depend on the spatial and temporal organization of these components in different cell types and rely on different physiological conditions. NHE3 and CFTR also compete for the same (NHERF-bound) ezrin-PKA complex to reciprocally regulate each other’s function in response to hormones (1).

NHERFs and human disease
Alterations in human genes that encode some NHERF targets have been linked to reduced NHERF-1 binding. Thus the decreased interaction of NHERF-1 with several mutant merlins may play a role in the development of benign tumors found in human neurofibromatosis (54). Similarly, mutations in the CFTR have been linked to decreased affinity for the NHERF-1 PDZ-I domain and may contribute to reduced targeting of the mutant CFTR proteins to the apical surface of lung and other epithelial cells as well as altered hormonal regulation of chloride transport noted in human cystic fibrosis (37, 44). Although some mutations in CFTR result in complete loss of the COOH-terminal sequence that constitutes a PDZ-binding motif, other mutant CFTRs retain an intact PDZ motif. This suggests that the context or conformation of the COOH-terminal sequence may also play a role in effective association of CFTR with NHERF-1 and/or NHERF-2. This also raises the possibility that altered expression or mutations in some of the more than 50 proposed NHERF targets and/or the NHERF proteins may contribute to human disease.


   Concluding Remarks
Top
 Introduction
 Structural insights from the...
 Diversity of NHERF targets
 Interaction of NHERFS with...
 NHERFS and Regulation of...
 Concluding Remarks
References
 
This review focused on the NHERF family of PDZ proteins to highlight some of the key regulatory paradigms used by PDZ proteins to control ion transporters and other cellular targets (Table 1Go). Emerging studies point to yet other mechanisms by which PDZ domain-containing proteins, specifically NHERFs, may either directly or indirectly regulate ion transporters. We also discussed the ability of some transporters to exchange NHERFs with other PDZ proteins to control their surface expression. Npt2a, whose surface expression and activity may be acutely regulated by NHERF-1, may demonstrate a variation on this theme. Chronic exposure to low serum phosphate that increases the expression of another PDZ protein in the kidney, PDZK1 (6), may lead to the displacement of NHERF-1, modulating Npt2a function.

Finally, the unique ability of NHERFs to target ion transporters and other proteins specifically to apical membranes remains poorly understood, as are the physiological signals that allow NHERFs to enter the nucleus and regulate genes that potentially encode transporters and other regulatory proteins. A key challenge for future studies will be to identify appropriate cellular systems and assays that will allow us to decipher the trafficking and function of NHERFs in different subcellular compartments.

In conclusion, tremendous progress has been made, particularly over the past 5 years, in identifying the cellular targets of NHERFs (Table 1Go) and deciphering the cellular mechanisms by which these PDZ proteins regulate ion transport (FIGURE 1Go). Further advances, such as the development of new genetic models and utilization of combined molecular, cellular, and physiological approaches, promises rapid progress in the understanding of NHERF functions in the years to come.



View larger version (47K):
[in this window]
[in a new window]
  		FIGURE 1. Regulation of ion transport proteins by NHERFs
Regulatory paradigms displayed by Na+/H+ exchanger regulatory factors (NHERFs) include the tethering of plasma membrane-localized ion transporters to the underlying actin cytoskeleton to stabilize or target these transporters to the cell surface and enhance their transport functions. These PDZ proteins also recruit other accessory proteins. Thus NHERFs, via their association with actin-associated ERM proteins, bridge transporters with signal transducers, such as PKA (and other kinases), to facilitate hormonal regulation of ion transport. Yet other transporters are primarily regulated by dynamic trafficking to and from the plasma membrane. The trafficking of ion transporters is also mediated by their association with NHERFs, which may cooperate to direct the endosomal pool of transporters to the plasma membrane or, in response to specific physiological stimuli, internalize the cell surface proteins and direct them to lysosomes for degradation and inactivation. Finally, growing evidence suggests that NHERFs shuttle in and out of the nucleus, where they may associate with DNA-binding proteins or transcriptional factors to promote the activation of genes that may include transporters and other regulatory proteins. Thus NHERFs orchestrate a variety of events in several subcellular compartments to both positively and negatively regulate ion transport in mammalian cells.

 


   References
Top
 Introduction
 Structural insights from the...
 Diversity of NHERF targets
 Interaction of NHERFS with...
 NHERFS and Regulation of...
 Concluding Remarks
 References
 

  1. Bagorda A, Guerra L, Di Sole F, Hemle-Kolb C, Cardone RA, Fanelli T, Reshkin SJ, Gisler SM, Murer H, and Casavola V. Reciprocal protein kinase A regulatory interactions between cystic fibrosis transmembrane conductance regulator and Na+/H+ exchanger isoform 3 in a renal polarized epithelial cell model. J Biol Chem 277: 21480–21488, 2002.[Abstract/Free Full Text]
  2. Bernardo AA, Kear FT, Santos AV, Ma J, Steplock D, Robey RB, and Weinman EJ. Basolateral Na(+)/HCO(3)(-) cotransport activity is regulated by the dissociable Na(+)/H(+) exchanger regulatory factor. J Clin Invest 104: 195–201, 1999.[Web of Science][Medline]
  3. Breton S, Wiederhold T, Marshansky V, Nsumu NN, Ramesh V, and Brown D. The B1 subunit of the H+ATPase is a PDZ domain-binding protein. Colocalization with NHE-RF in renal B-intercalated cells. J Biol Chem 275: 18219–18224, 2000.[Abstract/Free Full Text]
  4. Cao TT, Deacon HW, Reczek D, Bretscher A, and von Zastrow M. A kinase-regulated PDZ-domain interaction controls endocytic sorting of the ß2-adrenergic receptor. Nature 401: 286–290, 1999.[CrossRef][Medline]
  5. Cheng J, Moyer BD, Milewski M, Loffing J, Ikeda M, Mickle JE, Cutting GR, Li M, Stanton BA, and Guggino WB. A Golgi-associated PDZ domain protein modulates cystic fibrosis transmembrane regulator plasma membrane expression. J Biol Chem 277: 3520–3529, 2002.[Abstract/Free Full Text]
  6. Custer M, Spindler B, Verrey F, Murer H, and Biber J. Identification of a new gene product (diphor-1) regulated by dietary phosphate. Am J Physiol Renal Physiol 273: F801–F806, 1997.[Abstract/Free Full Text]
  7. DeMarco SJ, Chicka MC, and Strehler EE. Plasma membrane Ca2+ ATPase isoform 2b interacts preferentially with Na+/H+ exchanger regulatory factor 2 in apical plasma membranes. J Biol Chem 277: 10506–10511, 2002.[Abstract/Free Full Text]
  8. Fanning AS and Anderson JM. Protein modules as organizers of membrane structure. Curr Opin Cell Biol 11: 432–439, 1999.[CrossRef][Web of Science][Medline]
  9. Fouassier L, Yun CC, Fitz JG, and Doctor RB. Evidence for ezrin-radixin-moesin-binding phosphoprotein 50 (EBP50) self-association through PDZ-PDZ interactions. J Biol Chem 275: 25039–25045, 2000.[Abstract/Free Full Text]
  10. Gisler SM, Pribanic S, Bacic D, Forrer P, Gantenbein A, Sabourin LA, Tsuji A, Zhao ZS, Manser E, Biber J, and Murer H. PDZK1: I. a major scaffolder in brush borders of proximal tubular cells. Kidney Int 64: 1733–1745, 2003.[CrossRef][Web of Science][Medline]
  11. Gisler SM, Stagljar I, Traebert M, Bacic D, Biber J, and Murer H. Interaction of the type IIa Na/Pi cotransporter with PDZ proteins. J Biol Chem 276: 9206–9213, 2001.[Abstract/Free Full Text]
  12. Glynne PA, Darling KE, Picot J, and Evans TJ. Epithelial inducible nitric-oxide synthase is an apical EBP50-binding protein that directs vectorial nitric oxide output. J Biol Chem 277: 33132–33138, 2002.[Abstract/Free Full Text]
  13. Hall RA, Ostedgaard LS, Premont RT, Blitzer JT, Rahman N, Welsh MJ, and Lefkowitz RJ. A C-terminal motif found in the ß2-adrenergic receptor, P2Y1 receptor and cystic fibrosis transmembrane conductance regulator determines binding to the Na+/H+ exchanger regulatory factor family of PDZ proteins. Proc Natl Acad Sci USA 95: 8496–8501, 1998.[Abstract/Free Full Text]
  14. Hall RA, Premont RT, Chow CW, Blitzer JT, Pitcher JA, Claing A, Stoffel RH, Barak LS, Shenolikar S, Weinman EJ, Grinstein S, and Lefkowitz RJ. The ß2-adrenergic receptor interacts with the Na+/H+-exchanger regulatory factor to control Na+/H+ exchange. Nature 392: 626–630, 1998.[CrossRef][Medline]
  15. Hall RA, Spurney RF, Premont RT, Rahman N, Blitzer JT, Pitcher JA, and Lefkowitz RJ. G protein-coupled receptor kinase 6A phosphorylates the Na(+)/H(+) exchanger regulatory factor via a PDZ domain-mediated interaction. J Biol Chem 274: 24328–24334, 1999.[Abstract/Free Full Text]
  16. He J, Lau AG, Yaffe MB, and Hall RA. Phosphorylation and cell cycle-dependent regulation of Na+/H+ exchanger regulatory factor-1 by Cdc2 kinase. J Biol Chem 276: 41559–41565, 2001.[Abstract/Free Full Text]
  17. Hegedus T, Sessler T, Scott R, Thelin W, Bakos E, Varadi A, Szabo K, Homolya L, Milgram SL, and Sarkadi B. C-terminal phosphorylation of MRP2 modulates its interaction with PDZ proteins. Biochem Biophys Res Commun 302: 454–461, 2003.[CrossRef][Web of Science][Medline]
  18. Hwang JI, Heo K, Shin KJ, Kim E, Yun C, Ryu SH, Shin HS, and Suh PG. Regulation of phospholipase C-ß3 activity by Na+/H+ exchanger regulatory factor 2. J Biol Chem 275: 16632–16637, 2000.[Abstract/Free Full Text]
  19. Kanai F, Marignani PA, Sarbassova D, Yagi R, Hall RA, Donowitz M, Hisaminato A, Fujiwara T, Ito Y, Cantley LC, and Yaffe MB. TAZ: a novel transcriptional co-activator regulated by interactions with 14-3-3 and PDZ domain proteins. EMBO J 19: 6778–6791, 2000.[CrossRef][Web of Science][Medline]
  20. Karthikeyan S, Leung T, and Ladias JA. Structural basis of the Na+/H+ exchanger regulatory factor PDZ1 interaction with the carboxyl-terminal region of the cystic fibrosis transmembrane conductance regulator. J Biol Chem 276: 19683–19686, 2001.[Abstract/Free Full Text]
  21. Karthikeyan S, Leung T, and Ladias JA. Structural determinants of the Na+/H+ exchanger regulatory factor interaction with the ß2 adrenergic and platelet-derived growth factor receptors. J Biol Chem 277: 18973–18978, 2002.[Abstract/Free Full Text]
  22. Kim JH, Lee-Kwon W, Park JB, Ryu SH, Yun CH, and Donowitz M. Ca(2+)-dependent inhibition of Na+/H+ exchanger 3 (NHE3) requires an NHE3–E3KARP–{alpha}-actinin-4 complex for oligomerization and endocytosis. J Biol Chem 277: 23714—23724, 2002.[Abstract/Free Full Text]
  23. Kishi M, Liu X, Hirakawa T, Reczek D, Bretscher A, and Ascoli M. Identification of two distinct structural motifs that, when added to the C-terminal tail of the rat lh receptor, redirect the internalized hormone-receptor complex from a degradation to a recycling pathway. Mol Endocrinol 15: 1624–1635, 2001.[Abstract/Free Full Text]
  24. Kocher O, Pal R, Roberts M, Cirovic C, and Gilchrist A. Targeted disruption of the PDZK1 gene by homologous recombination. Mol Cell Biol 23: 1175–1180, 2003.[Abstract/Free Full Text]
  25. Lamprecht G, Heil A, Baisch S, Lin-Wu E, Yun CC, Kalbacher H, Gregor M, and Seidler U. The down regulated in adenoma (dra) gene product binds to the second PDZ domain of the NHE3 kinase A regulatory protein (E3KARP), potentially linking intestinal Cl–/HCO3– exchange to Na+/H+ exchange. Biochemistry 41: 12336–12342, 2002.[CrossRef][Medline]
  26. Lamprecht G, Weinman EJ, and Yun CH. The role of NHERF and E3KARP in the cAMP-mediated inhibition of NHE3. J Biol Chem 273: 29972–29978, 1998.[Abstract/Free Full Text]
  27. Lau AG and Hall RA. Oligomerization of NHERF-1 and NHERF-2 PDZ domains: differential regulation by association with receptor carboxyl-termini and by phosphorylation. Biochemistry 40: 8572–8580, 2001.[CrossRef][Medline]
  28. Lederer ED, Khundmiri SJ, and Weinman EJ. Role of NHERF-1 in regulation of the activity of Na-K ATPase and sodium-phosphate co-transport in epithelial cells. J Am Soc Nephrol 14: 1711–1719, 2003.[Abstract/Free Full Text]
  29. Lee-Kwon W, Kawano K, Choi JW, Kim JH, and Donowitz M. Lysophosphatidic acid stimulates brush border Na+/H+ exchanger 3 (NHE3) activity by increasing its exocytosis by an NHE3 kinase A regulatory protein-dependent mechanism. J Biol Chem 278: 16494–16501, 2003.[Abstract/Free Full Text]
  30. Li JG, Chen C, and Liu-Chen LY. Ezrin-radixin-moesin-binding phosphoprotein-50/Na+/H+ exchanger regulatory factor (EBP50/NHERF) blocks U50,488H-induced down-regulation of the human kappa opioid receptor by enhancing its recycling rate. J Biol Chem 277: 27545–27552, 2002.[Abstract/Free Full Text]
  31. Li Y, Li J, Straight SW, and Kershaw DB. PDZ domain-mediated interaction of rabbit podocalyxin and Na+/H+ exchange regulatory factor-2. Am J Physiol Renal Physiol 282: F1129–F1139, 2002.[Abstract/Free Full Text]
  32. Liedtke CM, Yun CH, Kyle N, and Wang D. Protein kinase C {varepsilon}-dependent regulation of cystic fibrosis transmembrane regulator involves binding to a receptor for activated C kinase (RACK1) and RACK1 binding to Na+/H+ exchange regulatory factor. J Biol Chem 277: 22925–22933, 2002.[Abstract/Free Full Text]
  33. Mahon MJ, Cole JA, Lederer ED, and Segre GV. Na+/H+ exchanger-regulatory factor 1 mediates inhibition of phosphate transport by parathyroid hormone and second messengers by acting at multiple sites in opossum kidney cells. Mol Endocrinol 17: 2355–2364, 2003.[Abstract/Free Full Text]
  34. Mahon MJ, Donowitz M, Yun CC, and Segre GV. Na+/H+ exchanger regulatory factor 2 directs parathyroid hormone 1 receptor signalling. Nature 417: 858–861, 2002.[CrossRef][Medline]
  35. Maudsley S, Zamah AM, Rahman N, Blitzer JT, Luttrell LM, Lefkowitz RJ, and Hall RA. Platelet-derived growth factor receptor association with Na+/H+ exchanger regulatory factor potentiates receptor activity. Mol Cell Biol 20: 8352–8363, 2000.[Abstract/Free Full Text]
  36. Mohler PJ, Kreda SM, Boucher RC, Sudol M, Stutts MJ, and Milgram SL. Yes-associated protein 65 localizes p62(c-Yes) to the apical compartment of airway epithelia by association with EBP50. J Cell Biol 147: 879–890, 1999.[Abstract/Free Full Text]
  37. Moyer BD, Denton J, Karlson KH, Reynolds D, Wang S, Mickle JE, Milewski M, Cutting GR, Guggino WB, Li M, and Stanton BA. A PDZ-interacting domain in CFTR is an apical membrane polarization signal. J Clin Invest 104: 1353–1361, 1999.[Web of Science][Medline]
  38. Nawrot M, West K, Huang J, Possin DE, Bretscher A, Crabb JW, and Saari JC. Cellular retinaldehyde-binding protein interacts with ERM-binding phosphoprotein 50 in retinal pigment epithelium. Invest Ophthalmol Vis Sci 45: 393–401, 2004.[Abstract/Free Full Text]
  39. Nourry C, Grant SG, and Borg JP. PDZ domain proteins: plug and play! Sci STKE 2003: RE7, 2003.[Medline]
  40. Ogura T, Furukawa T, Toyozaki T, Yamada K, Zheng YJ, Katayama Y, Nakaya H, and Inagaki N. ClC-3B, a novel ClC-3 splicing variant that interacts with EBP50 and facilitates expression of CFTR-regulated ORCC. FASEB J 16: 863–865, 2002.[Abstract/Free Full Text]
  41. Poulat F, Barbara PS, Desclozeaux M, Soullier S, Moniot B, Bonneaud N, Boizet B, and Berta P. The human testis determining factor SRY binds a nuclear factor containing PDZ protein interaction domains. J Biol Chem 272: 7167–7172, 1997.[Abstract/Free Full Text]
  42. Pushkin A, Abuladze N, Newman D, Muronets V, Sassani P, Tatishchev S, and Kurtz I. The COOH termini of NBC3 and the 56-kDa H+-ATPase subunit are PDZ motifs involved in their interaction. Am J Physiol Cell Physiol 284: C667–C673, 2003.[Abstract/Free Full Text]
  43. Raghuram V, Hormuth H, and Foskett JK. A kinase-regulated mechanism controls CFTR channel gating by disrupting bivalent PDZ domain interactions. Proc Natl Acad Sci USA 100: 9620–9625, 2003.[Abstract/Free Full Text]
  44. Raghuram V, Mak DD, and Foskett JK. Regulation of cystic fibrosis transmembrane conductance regulator single-channel gating by bivalent PDZ-domain-mediated interaction. Proc Natl Acad Sci USA 98: 1300–1305, 2001.[Abstract/Free Full Text]
  45. Reczek D, Berryman M, and Bretscher A. Identification of EBP50: A PDZ-containing phosphoprotein that associates with members of the ezrin-radixin-moesin family. J Cell Biol 139: 169–179, 1997.[Abstract/Free Full Text]
  46. Reczek D and Bretscher A. Identification of EPI64, a TBC/rabGAP domain-containing microvillar protein that binds to the first PDZ domain of EBP50 and E3KARP. J Cell Biol 153: 191–206, 2001.[Abstract/Free Full Text]
  47. Rochdi MD, Watier V, La Madeleine C, Nakata H, Kozasa T, and Parent JL. Regulation of GTP-binding protein {alpha}q (G{alpha}q) signaling by the ezrin-radixin-moesin-binding phosphoprotein-50 (EBP50). J Biol Chem 277: 40751–40759, 2002.[Abstract/Free Full Text]
  48. Shenolikar S, Minkoff CM, Steplock DA, Evangelista C, Liu M, and Weinman EJ. N-terminal PDZ domain is required for NHERF dimerization. FEBS Lett 489: 233–236, 2001.[CrossRef][Web of Science][Medline]
  49. Shenolikar S, Voltz JW, Minkoff CM, Wade JB, and Weinman EJ. Targeted disruption of the mouse NHERF-1 gene promotes internalization of proximal tubule sodium-phosphate cotransporter type IIa and renal phosphate wasting. Proc Natl Acad Sci USA 99: 11470–11475, 2002.[Abstract/Free Full Text]
  50. Shibata T, Chuma M, Kokubu A, Sakamoto M, and Hirohashi S. EBP50, a ß-catenin-associating protein, enhances Wnt signaling and is over-expressed in hepatocellular carcinoma. Hepatology 38: 178–186, 2003.[Medline]
  51. Short DB, Trotter KW, Reczek D, Kreda SM, Bretscher A, Boucher RC, Stutts MJ, and Milgram SL. An apical PDZ protein anchors the cystic fibrosis transmembrane conductance regulator to the cytoskeleton. J Biol Chem 273: 19797–19801, 1998.[Abstract/Free Full Text]
  52. Sitaraman SV, Wang L, Wong M, Bruewer M, Hobert M, Yun CH, Merlin D, and Madara JL. The adenosine 2b receptor is recruited to the plasma membrane and associates with E3KARP and Ezrin upon agonist stimulation. J Biol Chem 277: 33188–33195, 2002.[Abstract/Free Full Text]
  53. Songyang Z, Fanning AS, Fu C, Xu J, Marfatia SM, Chishti AH, Crompton A, Chan AC, Anderson JM, and Cantley LC. Recognition of unique carboxyl-terminal motifs by distinct PDZ domains. Science 275: 73–77, 1997.[Abstract/Free Full Text]
  54. Stokowski RP and Cox DR. Functional analysis of the neurofibromatosis type 2 protein by means of disease-causing point mutations. Am J Hum Genet 66: 873–891, 2000.[CrossRef][Web of Science][Medline]
  55. Tang Y, Tang J, Chen Z, Trost C, Flockerzi V, Li M, Ramesh V, and Zhu MX. Association of mammalian trp4 and phospholipase C isozymes with a PDZ domain-containing protein, NHERF. J Biol Chem 275: 37559–37564, 2000.[Abstract/Free Full Text]
  56. Vaccaro P, Brannetti B, Montecchi-Palazzi L, Philipp S, Citterich MH, Cesareni G, and Dente L. Distinct binding specificity of the multiple PDZ domains of INADL, a human protein with homology to INAD from Drosophila melanogaster. J Biol Chem 276: 42122–42130, 2001.[Abstract/Free Full Text]
  57. Van Ham M and Hendriks W. PDZ domains-glue and guide. Mol Biol Rep 30: 69–82, 2003.[CrossRef][Web of Science][Medline]
  58. Wade JB, Liu J, Coleman RA, Cunningham R, Steplock DA, Lee-Kwon W, Pallone TL, Shenolikar S, and Weinman EJ. Localization and interaction of NHERF isoforms in the renal proximal tubule of the mouse. Am J Physiol Cell Physiol 285: C1494–C1503, 2003.[Abstract/Free Full Text]
  59. Wang S, Raab RW, Schatz PJ, Guggino WB, and Li M. Peptide binding consensus of the NHE-RF-PDZ1 domain matches the C-terminal sequence of cystic fibrosis transmembrane conductance regulator (CFTR). FEBS Lett 427: 103–108, 1998.[CrossRef][Web of Science][Medline]
  60. Weinman EJ, Minkoff C, and Shenolikar S. Signal complex regulation of renal transport proteins: NHERF and regulation of NHE3 by PKA. Am J Physiol Renal Physiol 279: F393–F399, 2000.[Abstract/Free Full Text]
  61. Weinman EJ, Steplock D, and Shenolikar S. CAMP-mediated inhibition of the renal brush border membrane Na+-H+ exchanger requires a dissociable phosphoprotein cofactor. J Clin Invest 92: 1781–1786, 1993.[Web of Science][Medline]
  62. Weinman EJ, Steplock D, and Shenolikar S. NHERF-1 uniquely transduces the cAMP signals that inhibit sodium-hydrogen exchange in mouse renal apical membranes. FEBS Lett 536: 141–144, 2003.[CrossRef][Web of Science][Medline]
  63. Weinman EJ, Steplock D, Tate K, Hall RA, Spurney RF, and Shenolikar S. Structure-function of recombinant Na/H exchanger regulatory factor (NHE-RF). J Clin Invest 101: 2199–2206, 1998.[Web of Science][Medline]
  64. Weinman EJ, Wang Y, Wang F, Greer C, Steplock D, and Shenolikar S. A C-terminal PDZ motif in NHE3 binds NHERF-1 and enhances cAMP inhibition of sodium-hydrogen exchange. Biochemistry 42: 12662–12668, 2003.[CrossRef][Medline]
  65. Yoo D, Flagg TP, Olsen O, Raghuram V, Foskett JK, and Welling PA. Assembly and trafficking of a multiprotein ROMK (Kir1.1) channel complex by PDZ interactions. J Biol Chem 279: 6863–6873, 2003.[Medline]
  66. Yun CC, Palmada M, Embark HM, Fedorenko O, Feng Y, Henke G, Setiawan I, Boehmer C, Weinman EJ, Sandrasagra S, Korbmacher C, Cohen P, Pearce D, and Lang F. The Serum and glucocorticoid-inducible kinase SGK1 and the Na+/H+ exchange regulating factor NHERF2 synergize to stimulate the renal outer medullary K+ channel ROMK1. J Am Soc Nephrol 13: 2823–2830, 2002.[Abstract/Free Full Text]
  67. Yun CH, Lamprecht G, Forster DV, and Sidor A. NHE3 kinase A regulatory protein E3KARP binds the epithelial brush border Na+/H+ exchanger NHE3 and the cytoskeletal protein ezrin. J Biol Chem 273: 25856–25863, 1998.[Abstract/Free Full Text]
  68. Yun CH, Oh S, Zizak M, Steplock D, Tsao S, Tse CM, Weinman EJ, and Donowitz M. cAMP-mediated inhibition of the epithelial brush border Na+/H+ exchanger, NHE3, requires an associated regulatory protein. Proc Natl Acad Sci USA 94: 3010–3015, 1997.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 J. Biol. Chem.Home page
M. T. Kunkel, E. L. Garcia, T. Kajimoto, R. A. Hall, and A. C. Newton
The Protein Scaffold NHERF-1 Controls the Amplitude and Duration of Localized Protein Kinase D Activity
J. Biol. Chem., September 4, 2009; 284(36): 24653 - 24661.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Renal Physiol.Home page
A. Sindic, C. Huang, A.-P. Chen, Y. Ding, W. A. Miller-Little, D. Che, M. F. Romero, and R. T. Miller
MUPP1 complexes renal K+ channels to alter cell surface expression and whole cell currents
Am J Physiol Renal Physiol, July 1, 2009; 297(1): F36 - F45.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Biol. CellHome page
B. Wang, Y. Yang, and P. A. Friedman
Na/H Exchange Regulatory Factor 1, a Novel AKT-associating Protein, Regulates Extracellular Signal-regulated Kinase Signaling through a B-Raf-Mediated Pathway
Mol. Biol. Cell, April 1, 2008; 19(4): 1637 - 1645.
[Abstract] [Full Text] [PDF]

Home page
 Physiol. Rev.Home page
M. Donowitz and X. Li
Regulatory Binding Partners and Complexes of NHE3
Physiol Rev, July 1, 2007; 87(3): 825 - 872.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Biol. CellHome page
R. A. Cardone, A. Bellizzi, G. Busco, E. J. Weinman, M. E. Dell'Aquila, V. Casavola, A. Azzariti, A. Mangia, A. Paradiso, and S. J. Reshkin
The NHERF1 PDZ2 Domain Regulates PKA-RhoA-p38-mediated NHE1 Activation and Invasion in Breast Tumor Cells
Mol. Biol. Cell, May 1, 2007; 18(5): 1768 - 1780.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Gastrointest. Liver Physiol.Home page
A. J. Moeser, P. K. Nighot, K. A. Ryan, J. G. Wooten, and A. T. Blikslager
Prostaglandin-mediated inhibition of Na+/H+ exchanger isoform 2 stimulates recovery of barrier function in ischemia-injured intestine
Am J Physiol Gastrointest Liver Physiol, November 1, 2006; 291(5): G885 - G894.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
G. J. Pepe, M. G. Burch, and E. D. Albrecht
Developmental Regulation of the Sodium/Hydrogen Ion Exchangers and Their Regulatory Factors in Baboon Placental Syncytiotrophoblast
Endocrinology, June 1, 2006; 147(6): 2986 - 2996.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Biol. CellHome page
B. Cha, M. Tse, C. Yun, O. Kovbasnjuk, S. Mohan, A. Hubbard, M. Arpin, and M. Donowitz
The NHE3 Juxtamembrane Cytoplasmic Domain Directly Binds Ezrin: Dual Role in NHE3 Trafficking and Mobility in the Brush Border
Mol. Biol. Cell, June 1, 2006; 17(6): 2661 - 2673.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
M. Donowitz, B. Cha, N. C Zachos, C. L Brett, A. Sharma, C. M. Tse, and X. Li
NHERF family and NHE3 regulation
J. Physiol., August 15, 2005; 567(1): 3 - 11.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
W. R Thelin, C. A Hodson, and S. L Milgram
Beyond the brush border: NHERF4 blazes new NHERF turf
J. Physiol., August 15, 2005; 567(1): 13 - 19.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (32)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Shenolikar, S.
Right arrow Articles by Weinman, E. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Shenolikar, S.
Right arrow Articles by Weinman, E. J.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2004 by the Int. Union Physiol. Sci./Am. Physiol. Soc.