Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

NHERF

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_393

Synonyms

Historical Background

The functional presence of NHERF-1 was implicated in the late 1980s from a series of studies of inhibition of Na+/H+ exchange in rabbit kidney brush border membrane by cyclic AMP-dependent protein kinase (PKA). It took almost another decade before the cloning and molecular identification of NHERF-1 (Weinman et al. 1995). Shortly after, NHERF-2 was cloned from a yeast two-hybrid screen as an NHE3 interacting protein and was initially named E3KARP based on its ability to mediate PKA-dependent inhibition of Na+/H+ exchanger 3 (NHE3) in PS120 fibroblasts (Yun et al. 1997). NHERF-3 was initially identified as a protein that is upregulated in low dietary phosphate and was later shown to interact with the type II Na/Pi cotransporter (Npt2a) (Gisler et al. 2001). NHERF-4 was shown to interact with the intestinal receptor guanylyl cyclase C to inhibit the catalytic activity of the receptor in response to heat-stable enterotoxin (Scott et al. 2002).

Introduction

The NHERF family consists of four related proteins that are present in the brush border membrane of the mammalian intestine, colon, and renal proximal tubules. These proteins contain 2 or 4 PSD-95/Dlg/ZO-1 (PDZ) domains (Fig. 1) (Weinman et al. 1995; Yun et al. 1997; Gisler et al. 2001; Scott et al. 2002). NHERF-1 and NHERF-2 contain two PDZ domains as well as an ezrin-radixin-moesin-merlin (ERM) binding domain at the carboxyl terminus (Lamprecht et al. 1998). NHERF-3 and NHERF-4 have four PDZ domains without ERM binding domain (Gisler et al. 2001; Scott et al. 2002). PDZ domain interaction with their interacting ligands or proteins generally occurs at the ligand COOH terminus although non-canonical interaction with an internal motif has been reported. NHERFs are able to interact with multiple proteins through their PDZ domains, including transporters, channels, transmembrane receptors, and other cytoskeleton proteins localized at or below the plasma membrane (Table 1). NHERFs play significant roles in maintenance and regulation of a broad range of cellular functions in a variety of tissues through the interactions with multiple target proteins.
NHERF, Fig. 1

Binding domains in NHERF proteins. Four members of NHERF family (NHERF1-4) are shown with PDZ domains and ERM binding regions. Numerical numbers denote lengths of amino acids

NHERF, Table 1

Interactions of NHERF proteins with ligands and other proteins

NHERF proteins

Domains

Binding partners

Authors

NHERF-1

PDZ1

β2-adrenergic receptor (β2AR)

Hall et al. (1998)

Platelet-derived growth factor receptor (PDGFR)

Maudsley et al. (2000)

κ opioid receptor

Li et al. (2002)

Parathyroid hormone receptor

Sneddon et al. (2003)

5-HT4a serotonin receptor

Joubert et al. (2004)

Epidermal growth factor receptor (EGFR)

Lazar et al. (2004)

Cystic fibrosis transmembrane conductance regulator (CFTR)

Short et al. (1998)

Trp 4 & 5 calcium channels

Tang et al. (2000)

Na+/phosphate cotransporter (Npt2a)

Gisler et al. (2001)

Phosphatase and tensin homologue (PTEN)

Takahashi et al. (2006)

G protein-coupled receptor kinase 6A

Hall et al. (1999)

Phospholipase C β-1,2 & 3

Tang et al. (2000)

PDZ2

NHE3

Weinman et al. (1995)

H+ ATPase

Breton et al. (2000)

Yes-associated protein (Yap65)

Mohler et al. (1999)

β-catenin

Shibata et al. (2003)

NHERF-2

PDZ1

PDGFR

Maudsley et al. (2000)

CFTR

Sun et al. (2000)

Trp 5 calcium channel

Embark et al. (2004)

PDZ2

β2AR

Hall et al. (1998)

PDGFR

Takahashi et al. (2006)

Lysophosphatidic acid 2 receptor (LPA2)

Oh et al. (2004)

Lysophosphatidic acid 5 receptor (LPA5)

Lin et al. (2010)

NHE3

Yun et al. (1997)

PTEN

Takahashi et al. (2006)

Cyclic GMP kinase II

Cha et al. (2005)

  

PLCβ-3

Hwang et al. (2000)

Protein kinase C (PKC)

Lee-Kwon et al. (2003)

Serum glucocorticoid regulated kinase (SGK) 1 & 3

Yun et al. (2002)

Podocalyxin

Takeda et al. (2001)

NHERF-3

PDZ1

CFTR

Wang et al. (2000)

NHE3

Gisler et al. (2003)

Renal urate anion exchanger (URAT1)

Anzai et al. (2004)

PDZ2

Proton-coupled peptide transporter (PEPT2)

Kato et al. (2004)

Intestinal anion exchanger down-regulated in adenoma (DRA)

Gisler et al. (2003)

PDZ3

NPT 1 & 2

Gisler et al. (2003)

PEPT2

Kato et al. (2004)

CFTR

Wang et al. (2000)

PDZ4

Organic cation transporter, novel (OCTN) 1 & 2

Kato et al. (2005)

NHERF 1 & 2

Gisler et al. (2003)

NHERF-4

PDZ1

OCTN 1 & 2

Kato et al. (2005)

PDZ2

OCTN 1 & 2

Watanabe et al. (2006)

PDZ3

Guanylyl cyclase C

Scott et al. (2002)

PDZ4

Epithelial Ca2+ channel, transient receptor potential cation channel, subfamily V, member 6 (TRPV6)

Kim et al. (2007)

NHERF-1 NHERF-2

ERM

Ezrin, Radixin, Moesin, and Merlin

Murthy et al. (1998)

NHERF Basics

Localization

NHERF-1 and NHERF-2 are expressed in a broad range of tissues and organs (Yun et al. 1997). NHERF-3 and NHERF-4 show highest expression in the kidney and gastrointestinal tract (Gisler et al. 2001; Scott et al. 2002). Immunofluorescent confocal microscopic analysis of NHERF proteins shows that NHERF proteins have different subcellular localization in polarized epithelial cells. NHERF-1 and NHERF-3 are located in the brush border membrane under basal conditions. The brush border localization of NHERF-2 was shown, but it is predominantly in the intermicrovillar clefts just below the brush border membrane. NHERF-4 is primarily distributed in the cytosol as well as in the subapical region, but not in the brush border membrane (Donowitz et al. 2005). NHERF expression in non-epithelial cells is less well documented, but the expression of NHERF-1 and NHERF-2 in neurons and astrocytes, where these proteins show a membranous expression, has been reported.

Regulation of NHERF

NHERF-1 is regulated by phosphorylation. NHERF-1 is constitutively phosphorylated on Ser 289 by G protein–coupled receptor kinase 6 (GRK 6), which enhances oligomerization of NHERF-1 (He and Yun 2010). Furthermore, NHERF-1 is phosphorylated by the cyclin-dependent kinase Cdc2 at Ser279 and Ser301, which impair oligomerization, and at S77 by protein kinase C, which interferes with parathyroid hormone (PTH)-induced signaling (Weinman et al. 2007). In contrast to NHERF-1, NHERF-2 does not appear to be regulated by phosphorylation (Lamprecht et al. 1998). Both NHERF-1 and NHERF-2 have been shown to form homotypic as well as heterotypic dimers. Dimerization of NHERF is thought to affect their interaction with other proteins. NHERF-3 mRNA expression is regulated by peroxisome proliferator-activated receptor alpha (PPARα), a ligand-activated transcription factor that plays an important role in the regulation of lipid homeostasis (Tachibana et al. 2008). Regulatory mechanism of NHERF-4 has not yet been studied.

Association with Cell Surface Proteins

Transporters and Channels

The majority of functional characterization of the NHERF family came from heterologous expression of these proteins. In addition to the importance of NHERF-1 and NHERF-2 in regulation of NHE3 by PKA, these studies have provided evidence for the importance of NHERFs for trafficking, membrane retention, and dimerization of the cystic fibrosis transmembrane regulator (CFTR) (Singh et al. 2009). Although initial studies suggested redundancy in the functions of the NHERF family, studies of rodents that are genetically targeted to delete one or more of the NHERF family members have helped to reveal distinct physiological roles of NHERF proteins. NHERF-1 is essential for cAMP- and parathyroid hormone (PTH)-induced inhibition of renal NHE3, but not intestinal NHE3 (Weinman et al. 2005). Ablation of NHERF-1 decreases forskolin-induced secretion of bicarbonate by CFTR (Singh et al. 2009). NHERF-1 is also essential for the recruitment of Npt2a to the brush border membrane of renal proximal tubule cells (Weinman et al. 2005). NHERF-2 appears to play a dual role in regulation of NHE3. Glucocorticoid- or lysophosphatidic acid (LPA)-mediated stimulation of NHE3 is dependent on the presence of NHERF-2 (He and Yun 2010). Similarly, NHERF-2 is necessary for inhibition of NHE4 by cyclic GMP kinase II (cGKII), protein kinase C (PKC), and Ca2+-mediated signaling (He and Yun 2010). NHERF-3 ablation in mouse colon abolishes cAMP- and Ca2+-induced inhibition of NHE3 (Donowitz et al. 2005). NHERF-3 is also involved in the localization of organic cation/cartinin transporter (OCTN2, Slc22a5) and H+/dipeptide transporter (PepT1, Slc15a1) in the brush border membrane (Sugiura et al. 2008). NHERF-4 activates NHE3 via a Ca2+-dependent mechanism (Zachos et al. 2008).

G Protein–Coupled Receptors

NHERF proteins interact with several G protein–coupled receptors (GPCRs), including the β2-adrenergic receptor (β2-AR), κ-opioid receptor, PTH type 1 receptor (PTH1R), P2Y receptor, and lysophosphatidic acid receptor (Ritter and Hall 2009). The first insight into the role of NHERF in GPCR-mediated signaling came from the finding that agonist-promoted association of NHERF-1 with the carboxyl terminus of β2-AR displays NHERF-1 from NHE3 blocking the inhibition of NHE3 by PKA (Ritter and Hall 2009). Evidence shows that NHERF-1 regulates β2-AR trafficking by regulating agonist-promoted recycling of receptor proteins, which can be perturbed by interruption of NHERF-1 binding, and hence directing the receptor to lysosome (Ritter and Hall 2009). In addition, the NHERF proteins regulate GPCR-mediated signaling through selective recruitment of signaling proteins, including phospholipase C and G proteins, which could potentiate or redirect G protein–mediated signaling (Mahon et al. 2002).

Receptor Tyrosine Kinases

In addition to GPCRs, NHERFs associate with receptor tyrosine kinases, including platelet-derived growth factor receptor (PDGFR) and epidermal growth factor receptor (EGFR). The binding of NHERF-1 to the carboxyl terminus of PDGFR potentiates receptor activity only when NHERF-1 is allowed to oligomerize (Maudsley et al. 2000). Evidence shows that the interaction between PDGFR and NHERF-1 can be disrupted by phosphorylation of the carboxyl terminus of PDGFR by GRK2 (Hildreth et al. 2004). Recent study showed that NHERF-1 facilitates actin cytoskeletal reorganization mediated by PDGFR (Theisen et al. 2007). Unlike PDGFR, EGFR lacks the carboxyl terminal PDZ binding sequence, but yet it was shown that EGFR interacts with NHERF-1 involving a non-canonical internal PDZ binding motif (Lazar et al. 2004). This interaction appears to stabilize EGFR at the cell surface by restricting EGF-induced receptor degradation, which causes EGFR to remain longer at the cell surface.

NHERF as a Signaling Molecule

Cellular Signals

PDGFR is activated through dimerization and autophosphorylation upon ligand binding. NHERF-1 dimers enhance dimerization of PDGFR to potentiate mitogenic signals transduced by extracellular signal-regulated kinase (Erk) 1/2. Similarly, transient receptor potential 4 (TRP4) calcium channel associates with phospholipase C (PLC) β isoforms to activate protein kinase C signals by binding to NHERF PDZ1 domain. NHERF-1 has significant importance in PTH-mediated signaling as evidenced by the defective PTH signaling in NHERF-1-deficient mice (Weinman et al. 2005). NHERF-1 modulates PTH signaling by affecting PTH receptor recycling, membrane retention, and desensitization.

In addition to the regulation of the membrane receptors and channels, NHERF-1 interacts with Akt and inhibits PKA-mediated Erk1/2 activation by decreasing the stimulatory effect of 14–3-3 binding to B-Raf (Wang et al. 2008).

Cancer

Overexpression of NHERF-1 in breast cancer cells and the transcriptional regulation of NHERF-1 by estrogen suggested a potential role of NHERF-1 in cancer. In addition, unpublished data in our lab show the elevated expression of NHERF-2 in colon adenocarcinoma. However, the mechanism and effects of NHERFs in tumorigenesis are unclear. The interaction of NHERF-1 with PDGFR and EGFR appears to suggest an oncogenic role of NHERF-1. In addition, NHERF-1 expression is elevated in hepatocellular carcinoma where NHERF-1 complexes with β-catenin to promote Wnt signaling (Shibata et al. 2003). On the other hand, NHERF-1 or NHERF-2 recruits phosphatase and tensin homolog ( PTEN) tumor suppressor to restrict the activation of the PI3K (Georgescu et al. 2008). Therefore, NHERFs appear to play a dual role in tumorigenesis and their role in cancer requires additional studies.

Summary

From the uncertain identity as a cofactor of cAMP-induced regulation of NHE3, NHERF proteins have firmly rooted their identity as the major molecular scaffolds. The role of the NHERF proteins extends beyond the regulation of ion transporters. Growing evidence links NHERF to cancer, inflammatory diseases, hypertension, and neurological disorder. However, the functional roles and the underlying mechanisms of NHERF-mediated regulation are incompletely understood. A combination of biochemical and cellular approaches along with physiological studies using animal models lacking one or more of the NHERF proteins should advance the understanding of the physiological and pathophysiological functions of the NHERF proteins.

Notes

Acknowledgment

This work was supported by the grant from the National Institutes of Health (DK071597 and DK061418).

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Emory University School of Medicine, Division of Digestive DiseasesDepartment of MedicineAtlantaUSA