SLC9A3R1 (solute carrier family 9 (sodium/hydrogen exchanger), member 3 regulator 1)

2010-12-01   Wendy S McDonough , Michael E Berens 

The Translational Genomics Research Institute, 445 N Fifth Street, Phoenix, Arizona 85004, USA


Atlas Image
SLC9A3R1 Physical Map.


Atlas Image
DNA size 20.71 Kb; mRNA size 1978 bp; 6 exons.


The SLC9A3R1 gene is comprised of 6 exons and spans approximately 20.7 kb of genomic DNA.


The SLC9A3R1 gene encodes a 1978 bp mRNA transcript.
Reported regulatory transcription factor binding sites upstream of the SLC9A3R1 promoter region include: NF-kappaB1, HNF-4alpha2, COUP-TF1, NF-kappaB, NRSF form 2, NRSF form 1, FOXD1, PPAR-gamma2, PPAR-gamma1, GATA-1.


Atlas Image
NHERF (human)-358 aminos acids.


The SLC9A3R1 protein is composed of 353 amino acids (389 kDa).
Post-transcriptional regulation of SLC9A3R1 occurs via Serines S77-p, S162-p, S339-p, S340-p.
SLC9A3R1 is also phosphroylated on T95-p.
SLC9A3R1 has two PDZ (DHR) domains.
SLC9A3R1 can exist as a homodimer or heterodimer with SLC9A3R2.


SLC9A3R1 is expressed in liver, salivary glands, kidney, pancreas, trachea, small intestine, stomach, prostate and brain.


SLC9A3R1 is a cytoplasmic protein. SLC9A3R1 translocates from the cytoplasm to the apical cell membrane in a PODXL-dependent manner. SLC9A3R1 colocalizes with actin in microvilli-rich apical regions of the syncytiotrophoblast. SLC9A3R1 has been found in microvilli, ruffling membrane and filopodia of HeLa cells. SLC9A3R1 is also been discovered in lipid rafts of T-cells.
Subcellular localization is present in cells with apical specialized structure such as micorvili and cilia. SLC9A3R1 also has a membranous expression in cells of non-epithelial origin (astrocytes) and hematopoietic stem cells and has been found in membrane rafts in lymphocytes and at the rear edge of neutrophils.


SLC9A3R1 is a scaffold protein that connects plasma membrane proteins with members of the ezrin/moesin/radixin family and thereby helps to link them to the actin cytoskeleton to regulate their surface expression. SLC9A3R1 has been shown to be necessary for recycling of internalized ADRB2. SLC9A3R1 regulates SLC9A3 as well as its subcellular location. SLC9A3R1 is required for cAMP-mediated phosphorylation and inhibition of SLC9A3R1. SLC9A3R1 interacts with MCC. SLC9A3R1 may participate in HTR4 targeting to microvilli. SLC9A3R1 has been shown to play a role in the WNT signaling pathway.
Induction: SLC9A3R1 can be induced by estrogen.
SLC9A3R1 has been show to have binary interaction with the following proteins: CFTR, CLCN3, MSN, NF2, RDX.



SLC9A3R1 has been shown to have three natural variants.
Natural variant 110L --> V in NPHLOP2; the mutant expressed in cultured renal cells increases the generation of cyclic AMP (cAMP) by parathyroid hormone (PTH) and inhibits phosphate transport.
Natural variant 153R --> Q in NPHLOP2; the mutant expressed in cultured renal cells increases the generation of cAMP by PTH and inhibits phosphate transport.
Natural variant 225E --> K in NPHLOP2; the mutant expressed in cultured renal cells increases the generation of cAMP by PTH and inhibits phosphate transport.

Implicated in

Entity name
Cancer progression
There is growing evidence SLC9A3R1 plays an important role in cancer progression. SLC9A3R1 functions as an adaptor protein to control cell transformation. In addition, recent evidence suggests that SLC9A3R1 has a dual role either acting as a tumor suppressor when it is localized as the cell membrane or as an oncogenic protein when it is localized in the cytoplasm (Georgescu et al., 2008).
Entity name
The invasive nature of glioblastoma multiforme presents a clinical problem rendering tumors incurable by conventional treatment modalities such as surgery, ionizing radiation, and temozolomide.
SLC9A3R1 has been implicated to play a role in sustaining glioma cell migration and invasion. SLC9A3R1 has been shown to be over-expressed in invading glioma cells as compared to the tumor core (Kislin et al., 2009).
Entity name
Breast cancer
Increased cytoplasmic expression of SLC9A3R1 in breast tumors suggests a key role of its localization and compartmentalization in defining cancerogenesis, progression, and invasion. SLC9A3R1 overexpression has been associated with increasing tumor cytohistological grade, aggressive clinical behavior, unfavorable prognosis, and increased tumor hypoxia. Moreover, SLC9A3R1 co-localizes with the oncogenic receptor HER2/neu in HER2/neu-overexpressing carcinoma and in distant metastases (Mangia et al., 2009).
The switch from apical membranous to cytoplasmic expression is compatible with a dual role for NHERF1 as a tumour suppressor or tumour promoter dependent on its subcellular localization (Georgescu et al., 2008).
Entity name
Cystic fibrosis
The inherited disease cystic fibrosis is one of the most common chronic lung diseases in children and young adults and may lead to an early death.
Cystic fibrosis transmembrane regulator (CFTR) functions as a cAMP-regulated chloride channel, and mutations in CFTR are contributory in cystic fibrosis. CFTR contains a C-terminal SLC9A3R1 consensus sequence affording the two proteins to bind with high affinity. Recent experiments have postulated two roles for SLC9A3R1 in CFTR function. Guggino, Stanton, and coworkers have proposed that NHERF functions as a membrane retention signal for CFTR (Moyer et al., 1999).
Raghuram et al. suggest that SLC9A3R1 facilitates the dimerization of CFTR leading to its full expression of chloride channel activity (Raghuram et al., 2001).
Lastly, ss2-adrenoceptors have been shown to physically interact with CFTR Na+/H+ Exchanger Regulatory Factor 1 SLC9A3R1 protein. This function of SLC9A3R1 could be a new therapeutic target in CF patients to facilitate the trafficking of mutated CFTR to plasma membrane (Bossard et al., 2011).
Entity name
Hypophosphatemia and nephrolithiasis
SLC9A3R1 plays an important role in tumor phosphorous transport. Inactivating missense mutations in SLC9AR1 have been identified in patients with hypercalciuria and neprolithiasis (Karim et al., 2008).


Pubmed IDLast YearTitleAuthors
204122912010Renal phosphate handling in human--what can we learn from hereditary hypophosphataemias?Amatschek S et al
180293482008Toward a confocal subcellular atlas of the human proteome.Barbe L et al
153029352004Large-scale characterization of HeLa cell nuclear phosphoproteins.Beausoleil SA et al
210488272010NHERF1/EBP50 in Breast Cancer: Clinical Perspectives.Bellizzi A et al
126518582003The role of the C terminus and Na+/H+ exchanger regulatory factor in the functional expression of cystic fibrosis transmembrane conductance regulator in nonpolarized cells and epithelia.Benharouga M et al
200426042010A conformational switch in the scaffolding protein NHERF1 controls autoinhibition and complex formation.Bhattacharya S et al
158051082005Receptor activity-modifying protein (RAMP) isoform-specific regulation of adrenomedullin receptor trafficking by NHERF-1.Bomberger JM et al
172371492007NHE-RF1 protein rescues DeltaF508-CFTR function.Bossard F et al
202032922011β1, β2, and β3 adrenoceptors and Na+/H+ exchanger regulatory factor 1 expression in human bronchi and their modifications in cystic fibrosis.Bossard F et al
151461972004Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation.Brandenberger R et al
116840852001Interaction between two adapter proteins, PAG and EBP50: a possible link between membrane rafts and actin cytoskeleton.Brdicková N et al
107481652000The B1 subunit of the H+ATPase is a PDZ domain-binding protein. Colocalization with NHE-RF in renal B-intercalated cells.Breton S et al
104995881999A kinase-regulated PDZ-domain interaction controls endocytic sorting of the beta2-adrenergic receptor.Cao TT et al
173325062007The NHERF1 PDZ2 domain regulates PKA-RhoA-p38-mediated NHE1 activation and invasion in breast tumor cells.Cardone RA et al
210799872010Estrogens regulate the expression of NHERF1 in normal colon during the reproductive cycle of Wistar rats.Cuello-Carrión FD et al
187546782008The relative binding affinities of PDZ partners for CFTR: a biochemical basis for efficient endocytic recycling.Cushing PR et al
200315772009Novel loci, including those related to Crohn disease, psoriasis, and inflammation, identified in a genome-wide association study of fibrinogen in 17 686 women: the Women's Genome Health Study.Danik JS et al
207364132010Alterations in the proteome of the NHERF1 knockout mouse jejunal brush border membrane vesicles.Donowitz M et al
121453372002Estrogen receptor inducibility of the human Na+/H+ exchanger regulatory factor/ezrin-radixin-moesin binding protein 50 (NHE-RF/EBP50) gene involving multiple half-estrogen response elements.Ediger TR et al
181841092008Beta-oestradiol rescues DeltaF508CFTR functional expression in human cystic fibrosis airway CFBE41o- cells through the up-regulation of NHERF1.Fanelli T et al
191392112009Investigation of association of genes NAT9, SLC9A3R1 and RAPTOR on chromosome 17q25 with psoriatic arthritis.Filer CE et al
150206812004The EBP50-moesin interaction involves a binding site regulated by direct masking on the FERM domain.Finnerty CM et al
200233832010Crosstalk between planar cell polarity signaling and miR-8 control of NHERF1-mediated actin reorganization.Flynt AS et al
192341362009Ezrin-radixin-moesin-binding phosphoprotein (EBP50), an estrogen-inducible scaffold protein, contributes to biliary epithelial cell proliferation.Fouassier L et al
209376952010The scaffolding protein EBP50 regulates microvillar assembly in a phosphorylation-dependent manner.Garbett D et al
124710242003The PDZ-binding chloride channel ClC-3B localizes to the Golgi and associates with cystic fibrosis transmembrane conductance regulator-interacting PDZ proteins.Gentzsch M et al
187819532008Roles of NHERF1/EBP50 in cancer.Georgescu MM et al
154893342004The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).Gerhard DS et al
126658012003Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides.Gevaert K et al
145318062003PDZK1: I. a major scaffolder in brush borders of proximal tubular cells.Gisler SM et al
110995002001Interaction of the type IIa Na/Pi cotransporter with PDZ proteins.Gisler SM et al
120800812002Epithelial inducible nitric-oxide synthase is an apical EBP50-binding protein that directs vectorial nitric oxide output.Glynne PA et al
96717061998A C-terminal motif found in the beta2-adrenergic receptor, P2Y1 receptor and cystic fibrosis transmembrane conductance regulator determines binding to the Na+/H+ exchanger regulatory factor family of PDZ proteins.Hall RA et al
95601621998The beta2-adrenergic receptor interacts with the Na+/H+-exchanger regulatory factor to control Na+/H+ exchange.Hall RA et al
104462101999G protein-coupled receptor kinase 6A phosphorylates the Na(+)/H(+) exchanger regulatory factor via a PDZ domain-mediated interaction.Hall RA et al
115330362001Phosphorylation and cell cycle-dependent regulation of Na+/H+ exchanger regulatory factor-1 by Cdc2 kinase.He J et al
126150542003C-terminal phosphorylation of MRP2 modulates its interaction with PDZ proteins.Hegedüs T et al
146083572003A putative RUNX1 binding site variant between SLC9A3R1 and NAT9 is associated with susceptibility to psoriasis.Helms C et al
145079272003GIPC binds to the human lutropin receptor (hLHR) through an unusual PDZ domain binding motif, and it regulates the sorting of the internalized human choriogonadotropin and the density of cell surface hLHR.Hirakawa T et al
190731372009Involvement of NHERF1 in apical membrane localization of MRP4 in polarized kidney cells.Hoque MT et al
190914022009Regulation of protein expression and function of octn2 in forskolin-induced syncytialization in BeWo Cells.Huang FD et al
150709042004kappa Opioid receptor interacts with Na(+)/H(+)-exchanger regulatory factor-1/Ezrin-radixin-moesin-binding phosphoprotein-50 (NHERF-1/EBP50) to stimulate Na(+)/H(+) exchange independent of G(i)/G(o) proteins.Huang P et al
202154042010Sip1, the Drosophila orthologue of EBP50/NHERF1, functions with the sterile 20 family kinase Slik to regulate Moesin activity.Hughes SC et al
118930832002Distinct cell type-specific expression of scaffolding proteins EBP50 and E3KARP: EBP50 is generally expressed with ezrin in specific epithelia, whereas E3KARP is not.Ingraffea J et al
151619432004A NHERF binding site links the betaPDGFR to the cytoskeleton and regulates cell spreading and migration.James MF et al
187841022008NHERF1 mutations and responsiveness of renal parathyroid hormone.Karim Z et al
118826632002Structural determinants of the Na+/H+ exchanger regulatory factor interaction with the beta 2 adrenergic and platelet-derived growth factor receptors.Karthikeyan S et al
155230542005PDZK1 directly regulates the function of organic cation/carnitine transporter OCTN2.Kato Y et al
155532372004Screening of the interaction between xenobiotic transporters and PDZ proteins.Kato Y et al
193082922009NHERF-1: modulator of glioblastoma cell migration and invasion.Kislin KL et al
206566842010Formation of a ternary complex among NHERF1, beta-arrestin, and parathyroid hormone receptor.Klenk C et al
195813082009The protein scaffold NHERF-1 controls the amplitude and duration of localized protein kinase D activity.Kunkel MT et al
179822582007Knockdown of NHERF1 enhances degradation of temperature rescued DeltaF508 CFTR from the cell surface of human airway cells.Kwon SH et al
191735792009The scaffold protein PDZK1 undergoes a head-to-tail intramolecular association that negatively regulates its interaction with EBP50.LaLonde DP et al
123698222002The 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.Lamprecht G et al
129546002003Ca2+-dependent inhibition of NHE3 requires PKC alpha which binds to E3KARP to decrease surface NHE3 containing plasma membrane complexes.Lee-Kwon W et al
195918392009Ezrin induces long-range interdomain allostery in the scaffolding protein NHERF1.Li J et al
161296952005Ezrin controls the macromolecular complexes formed between an adapter protein Na+/H+ exchanger regulatory factor and the cystic fibrosis transmembrane conductance regulator.Li J et al
176135302007Protein kinase C phosphorylation disrupts Na+/H+ exchanger regulatory factor 1 autoinhibition and promotes cystic fibrosis transmembrane conductance regulator macromolecular assembly.Li J et al
120040552002Ezrin-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.Li JG et al
119562112002Protein kinase C epsilon-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.Liedtke CM et al
120753542002Na(+)/H(+ ) exchanger regulatory factor 2 directs parathyroid hormone 1 receptor signalling.Mahon MJ et al
199123662009Biological role of NHERF1 protein expression in breast cancer.Mangia A et al
190343802009Alterations in oligodendrocyte proteins, calcium homeostasis and new potential markers in schizophrenia anterior temporal lobe are revealed by shotgun proteome analysis.Martins-de-Souza D et al
110461322000Platelet-derived growth factor receptor association with Na(+)/H(+) exchanger regulatory factor potentiates receptor activity.Maudsley S et al
162368062005Modulation of renal apical organic anion transporter 4 function by two PDZ domain-containing proteins.Miyazaki H et al
105622881999Yes-associated protein 65 localizes p62(c-Yes) to the apical compartment of airway epithelia by association with EBP50.Mohler PJ et al
207363782010Loss of PTEN binding adapter protein NHERF1 from plasma membrane in glioblastoma contributes to PTEN inactivation.Molina JR et al
172421912007NHERF1/EBP50 head-to-tail intramolecular interaction masks association with PDZ domain ligands.Morales FC et al
105622971999A PDZ-interacting domain in CFTR is an apical membrane polarization signal.Moyer BD et al
108529252000The PDZ-interacting domain of cystic fibrosis transmembrane conductance regulator is required for functional expression in the apical plasma membrane.Moyer BD et al
94306551998NHE-RF, a regulatory cofactor for Na(+)-H+ exchange, is a common interactor for merlin and ERM (MERM) proteins.Murthy A et al
147448772004Cellular retinaldehyde-binding protein interacts with ERM-binding phosphoprotein 50 in retinal pigment epithelium.Nawrot M et al
119672292002ClC-3B, a novel ClC-3 splicing variant that interacts with EBP50 and facilitates expression of CFTR-regulated ORCC.Ogura T et al
170819832006Global, in vivo, and site-specific phosphorylation dynamics in signaling networks.Olsen JV et al
147020392004Complete sequencing and characterization of 21,243 full-length human cDNAs.Ota T et al
170788682006Suppression of breast cancer cell growth by Na+/H+ exchanger regulatory factor 1 (NHERF1).Pan Y et al
124037792002The cystic fibrosis transmembrane conductance regulator interacts with and regulates the activity of the HCO3- salvage transporter human Na+-HCO3- cotransport isoform 3.Park M et al
124440182003The COOH termini of NBC3 and the 56-kDa H+-ATPase subunit are PDZ motifs involved in their interaction.Pushkin A et al
111586342001Regulation of cystic fibrosis transmembrane conductance regulator single-channel gating by bivalent PDZ-domain-mediated interaction.Raghuram V et al
93145371997Identification of EBP50: A PDZ-containing phosphoprotein that associates with members of the ezrin-radixin-moesin family.Reczek D et al
112852852001Identification of EPI64, a TBC/rabGAP domain-containing microvillar protein that binds to the first PDZ domain of EBP50 and E3KARP.Reczek D et al
185887532008Epithelial genes in chronic rhinosinusitis with and without nasal polyps.Richer SL et al
126264932003Galphaq-coupled receptor internalization specifically induced by Galphaq signaling. Regulation by EBP50.Rochdi MD et al
121936062002Regulation of GTP-binding protein alpha q (Galpha q) signaling by the ezrin-radixin-moesin-binding phosphoprotein-50 (EBP50).Rochdi MD et al
179116012007Inhibition of T cell activation by cyclic adenosine 5'-monophosphate requires lipid raft targeting of protein kinase A type I by the A-kinase anchoring protein ezrin.Ruppelt A et al
128300002003EBP50, a beta-catenin-associating protein, enhances Wnt signaling and is over-expressed in hepatocellular carcinoma.Shibata T et al
96774121998An apical PDZ protein anchors the cystic fibrosis transmembrane conductance regulator to the cytoskeleton.Short DB et al
165198192006Analysis of polymorphisms in 16 genes in type 1 diabetes that have been associated with other immune-mediated diseases.Smyth DJ et al
129201192003Activation-independent parathyroid hormone receptor internalization is regulated by NHERF1 (EBP50).Sneddon WB et al
175930792007Expression and clinicopathological significance of oestrogen-responsive ezrin-radixin-moesin-binding phosphoprotein 50 in breast cancer.Song J et al
196157322009Defining the human deubiquitinating enzyme interaction landscape.Sowa ME et al
124779322002Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.Strausberg RL et al
153425562004Sequence comparison of human and mouse genes reveals a homologous block structure in the promoter regions.Suzuki Y et al
164565422006PTEN tumor suppressor associates with NHERF proteins to attenuate PDGF receptor signaling.Takahashi Y et al
109802022000Association of mammalian trp4 and phospholipase C isozymes with a PDZ domain-containing protein, NHERF.Tang Y et al
126210352003Stimulation of beta 2-adrenergic receptor increases cystic fibrosis transmembrane conductance regulator expression in human airway epithelial cells through a cAMP/protein kinase A-independent pathway.Taouil K et al
166159182006Structural basis for NHERF recognition by ERM proteins.Terawaki S et al
178952472007Phosphorylation of PDZ1 domain attenuates NHERF-1 binding to cellular targets.Voltz JW et al
205621042010Na/H exchanger regulatory factors control parathyroid hormone receptor signaling by facilitating differential activation of G(alpha) protein subunits.Wang B et al
178848162007NHERF1 regulates parathyroid hormone receptor membrane retention without affecting recycling.Wang B et al
191883352009NHERF1 regulates parathyroid hormone receptor desensitization: interference with beta-arrestin binding.Wang B et al
96136081998Peptide binding consensus of the NHE-RF-PDZ1 domain matches the C-terminal sequence of cystic fibrosis transmembrane conductance regulator (CFTR).Wang S et al
145802132003A C-terminal PDZ motif in NHE3 binds NHERF-1 and enhances cAMP inhibition of sodium-hydrogen exchange.Weinman EJ et al
208025362011Direct interaction between NHERF1 and Frizzled regulates β-catenin signaling.Wheeler DS et al
199959082010Ephrin B1 regulates bone marrow stromal cell differentiation and bone formation by influencing TAZ transactivation via complex formation with NHERF1.Xing W et al
146049812004Assembly and trafficking of a multiprotein ROMK (Kir 1.1) channel complex by PDZ interactions.Yoo D et al
90963371997cAMP-mediated inhibition of the epithelial brush border Na+/H+ exchanger, NHE3, requires an associated regulatory protein.Yun CH et al
201406362010Regulation of human organic anion transporter 4 by protein kinase C and NHERF-1: altering the endocytosis of the transporter.Zhang Q et al
176022832008Comparison of the interaction of human organic anion transporter hOAT4 with PDZ proteins between kidney cells and placental cells.Zhou F et al

Other Information

Locus ID:

NCBI: 9368
MIM: 604990
HGNC: 11075
Ensembl: ENSG00000109062


dbSNP: 9368
ClinVar: 9368
TCGA: ENSG00000109062


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Tight junctionKEGGko04530
Tight junctionKEGGhsa04530

Protein levels (Protein atlas)

Not detected


Entity IDNameTypeEvidenceAssociationPKPDPMIDs


Pubmed IDYearTitleCitations
146083572003A putative RUNX1 binding site variant between SLC9A3R1 and NAT9 is associated with susceptibility to psoriasis.71
218045992012PTEN, NHERF1 and PHLPP form a tumor suppressor network that is disabled in glioblastoma.64
128300002003EBP50, a beta-catenin-associating protein, enhances Wnt signaling and is over-expressed in hepatocellular carcinoma.62
173325062007The NHERF1 PDZ2 domain regulates PKA-RhoA-p38-mediated NHE1 activation and invasion in breast tumor cells.61
187841022008NHERF1 mutations and responsiveness of renal parathyroid hormone.60
191655272009Prefrontal cortex shotgun proteome analysis reveals altered calcium homeostasis and immune system imbalance in schizophrenia.56
187546782008The relative binding affinities of PDZ partners for CFTR: a biochemical basis for efficient endocytic recycling.55
129201192003Activation-independent parathyroid hormone receptor internalization is regulated by NHERF1 (EBP50).54
178848162007NHERF1 regulates parathyroid hormone receptor membrane retention without affecting recycling.53
172421912007NHERF1/EBP50 head-to-tail intramolecular interaction masks association with PDZ domain ligands.51


Wendy S McDonough ; Michael E Berens

SLC9A3R1 (solute carrier family 9 (sodium/hydrogen exchanger), member 3 regulator 1)

Atlas Genet Cytogenet Oncol Haematol. 2010-12-01

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