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Symbol SLC9A3R1 contributors: mct/npt/pgu - updated : 10-01-2020
HGNC name solute carrier family 9 (sodium/hydrogen exchanger), member 3 regulator 1
HGNC id 11075
Corresponding disease
NPHLOP2 nephrolithiasis/osteoporosis, hypophosphatemic 2
Location 17q25.1      Physical location : 72.744.762 - 72.765.498
Synonym name
  • solute carrier family 9 (sodium/hydrogen exchanger), isoform 3 regulatory factor 1
  • Na+/H+ exchange regulatory factor
  • ezrin-binding protein of 50 kDa
  • regulatory cofactor of Na(+)/H(+) exchanger
  • Synonym symbol(s) EBP50, NHERF, NHERF1, NPHLOP2
    TYPE functioning gene
    SPECIAL FEATURE tail to tail
    text tail to tail orientation with NAT9
    STRUCTURE 20.74 kb     6 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    text structure head-to-tail conformation masked the interaction of both PDZ domains with PDZ domain-specific ligands, such as PTEN and beta-catenin
    MAPPING cloned Y linked   status provisional
    Map cen - D17S1352 - SLC9A3R1 - D17S1839 - D17S785 - qter
    Authors Gene Map (98)
    TRANSCRIPTS type messenger
    text lack of exon 2 and disruption of the PDZ2 domain contribute to cell transformation and leads to modifications in the physiological regulation of the conformational state of SLC9A3R1 (PMID: 26788197)
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    6 - 2013 38 358 - 2009 19073137
    Type ubiquitous
       expressed in (based on citations)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveintestinesmall intestine  highly Rattus norvegicus
     liver   highly
    Endocrineadrenal gland   highly
    Nervousbrain   highly Homo sapiens
    Reproductivefemale systembreast  highly Homo sapiens
    Urinarykidneytubuleconvoluted tubule highly Homo sapiens
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    SystemCellPubmedSpeciesStageRna symbol
    Digestiveenterocyte Rattus norvegicus
    Nervousastrocyte Homo sapiens
    not specificmast cell Homo sapiens
    Reproductiveepithelial cell Homo sapiens
    Skeletonosteoblast Homo sapiens
    Urinarytubular cell Homo sapiens
    cell lineage
    cell lines
    at STAGE
    physiological period pregnancy
    Text placenta, syncytiotrophoblast
  • conserved PDZ domains at N-terminus that bound to SYK,
  • two PDZ (PSD-95-Dlg/ZO-1)-like domains, first PDZ is an interaction partner for the PDZ-binding motifs of both PRKD1 and PRKD2
  • C-terminal motif that binds to MERLIN, the product of neurofibromatosis 2 (NF2), ezrin-radixin-moesin (ERM)-binding (EB) C-terminal region that can bind to the PDZ2 domain
  • conjugated PhosphoP
    mono polymer oligo
  • solute carrier family 9, sodium/hydrogen exchanger
  • CATEGORY adaptor , transport carrier
    SUBCELLULAR LOCALIZATION     plasma membrane
    intracellular,nuclear envelope
  • colocalizing with actin, ezrin in apical microvilli
  • co-localize with AQP9 in the apical membrane of principal cells of the epididymis and the vas deferens
  • predominantly localized near the actin cytoskeleton, thus poising them near the plasma membrane where they function as scaffold
  • abundantly expressed in the apical membranes of polarized epithelial cells
  • present in the nuclear and perinuclear region in interphase cells
  • in the prophase of mitosis, redistributes to the cytoplasmic region in a phosphorylation dependent manner and during mitosis, co-localizes with protein phosphatase 2A (PP2A)
  • basic FUNCTION
  • involved in diverse aspects of epithelial membrane biology and immune synapse formation in T cells
  • estrogen-responsive gene encoding an inhibitory factor for epithelial Na+/H+ exchanger isoform 3 (NHE3)
  • contributing to attach GPCRs such as PTH1R and ADRB2 to the cytoskeleton and reducing their diffusion
  • protein that regulates trafficking of several G protein-coupled receptors
  • stabilizes the PTHR1 at the cell membrane and increases the fraction of receptor at the cell surface
  • PDZ1 phosphorylation may transduce hormonal signals to regulate the function of membrane proteins in epithelial tissues
  • required to organize complexes at the apical membranes of polarized epithelial cells and the regulation of its interactions at the apical membrane thus appears to be a dynamic process that is important for maintaining epithelial-tissue integrity
  • in the renal proximal tubules, have an important role in urate homeostasis by co-regulating urate uptake and efflux through its interactions with SLC22A12 and ABCC4, respectively
  • SLC9A3R1, SLC9A3R2, and PDZK1, modulate CFTR membrane retention, conductivity, and interactions with other transporters
  • PDZ domain-containing protein that interacts with the PDZ-binding motif of both PRKD1 and PRKD2
  • essential roles of SLC9A3R1 and ezrin in intracellular trafficking in epithelial cells (long-range allosteric regulation of SLC9A3R1 by ezrin enables the membrane-cytoskeleton to assemble protein complexes that control cross-talk and regulate the strength and duration of signaling)
  • involved in the membrane retention, endocytic sorting, and regulation of activity of membrane proteins and, therefore, plays important roles in their expression, membrane localization and functional regulation
  • important regulator of the pathogenesis of breast tumors
  • critical factor that regulates microvilli assembly and whose activity is regulated by signaling pathways and occupation of its PDZ2 domain
  • critical for neointima formation and induces vascular smooth muscle cells proliferation by decreasing S-phase kinase protein stability, thereby accelerating the degradation of the cell cycle inhibitor CDKN1A
  • implicated in cell division via reversible phosphorylation of the protein with cyclin dependent kinase and PP2A in normal cells
  • exerts a major role in potentiating G protein-coupled receptor (GPCR) internalization
  • modular PDZ domain scaffolding protein, coordinating the assembly of an obligate ternary complex with SLC34A1 and the PKA-anchoring protein EZR to facilitate PTH-responsive cAMP signaling events
  • microvillar scaffolding protein, retaining specific proteins in microvilli and necessary for microvillar biogenesis
  • associates with SLC34A2 in enterocytes and regulates SLC34A2 adaptation
  • is required for normal osteoblast differentiation and matrix synthesis, and in its absence, compensatory mechanisms maintain bone mass, but bone strength is reduced
  • roles for SLC9A3R1 and SLC9A3R2 on the regulation of C3AR1 signaling in human mast cells
  • adaptor protein required for epithelial morphogenesis, implicated in the progression of various human malignancies
  • role for SLC9A3R1 in ependymal morphogenesis with direct application to the diagnosis of ependymal tumors
  • important role for SLC9A3R1 in the regulation of Planar Cell Polarity (PCP) signaling and the development of functional motile cilia
  • is a PDZ-scaffold protein that was initially identified as an organizer and regulator of transporters and channels at the apical side of epithelia through actin-binding ezrin-moesin-radixin protein
  • important role of SLC3A3R1 in the epithelial-mesenchymal transition (EMT) of non-small-cell lung cancer cells, as well as migration
  • could have a previously unknown function in pregnancy and in the development of human embryos
  • PDZ-scaffold protein initially identified as an organizer and modulator of transporters and channels at the apical side of epithelia via actin-binding ezrin-moesin-radixin proteins
  • played an essential role in regulating liver cancer progression
  • role of SLC9A3R1 gene in the pathogenesis of age-related hearing loss (ARHL) opening new perspectives in terms of diagnosis, prevention and treatment
  • during lactation, SLC9A3R1 is required for the proper expression and apical localization of ATP2B2, which, in turn, contributes to preventing the premature activation of STAT3 and the lysosome-mediated cell death pathway that usually occur only early in mammary involution
    a component
  • significant role for the multiprotein complex CFTR-SLC9A3R1-EZR-actin in maintaining tight junctions organisation and barrier function, suggesting that the RHOA/ROCK pathway is involved
    small molecule
  • ezrin-radixin-myosin (ERM)
  • PAG1
  • interacting with RAMP3 (inhibits CRLR/RAMP3 complex internalization by tethering the complex to the actin cytoskeleton)
  • interacting with the C terminus of GPCRs
  • recruits various GPCRs, ion transporters, and other proteins to the plasma membrane of epithelia and other cells
  • interacting with GNB2L1 via a NHERF1-PDZ1 domain
  • interacting with TBC1D10A
  • interaction with ABCC4 (major determinant of ABCC4 trafficking to apical membranes of kidney cells)
  • interacting with MCC
  • interacts with the PDZ-binding motif of both PRKD1 and PRKD2
  • interaction with ABCC2 (binds to ABCC2, and plays a critical role in the canalicular expression of ABCC2 and its function as a determinant of glutathione-dependent, bile acid-independent bile flow)
  • interaction of PDZK1 with SLC9A3R1 is enhanced by the occupancy of its adjacent PDZ domain
  • cAMP-dependent inhibition of SLC9A3 activity requires either SLC9A3R1 or SLC9A3R2
  • bound to an internal PDZ binding motif in megalin (LRP2)
  • direct interaction with both tubulin and myosin IIa suggested that SLC9A3R1 could regulate cell migration and cytokinesis by linking MYO2A fibers and microtubule network
  • interacts via its PDZ domains with PHLPP1/PHLPP2 and scaffolds heterotrimeric complexes with PTEN
  • FGF23 synergizes potentially with PTH to inhibit phosphate transport by facilitating the activation of the PTH signal transduction pathway
  • couples CXCR2 to its downstream effector phospholipase C (PLCB2), forming a macromolecular complex, through a PDZ-based interaction
  • SLC9A3R1 and SLC9A3R2 are SCARB1 protein binding partners that play a negative role in the regulation of SCARB1 expression, selective CE (cholesteryl ester) transport, and steroidogenesis
  • interaction between SLC9A3R1 and CXCR2 or PLCB2 is PDZ motif-dependent
  • binds to the main renal phosphate transporter SLC34A1 and to the parathyroid hormone (PTH) receptor
  • interacts with the C-tail of the P2RY12 and unlike many other GPCRs, SLC9A3R1 interaction is required for effective P2RY12 internalization
  • arrestin can serve as an adaptor to promote SLC9A3R1 interaction with a GPCR to facilitate effective SLC9A3R1-dependent receptor internalization
  • associates with SLC34A2 but not PDZK1
  • involved in PKA-dependent activation of CFTR by interacting with CFTR via its PDZ domains and with ezrin via its C-terminal domain
  • SLC9A3R1 interacts with SLC1A3 during ER export, while SLC9A3R2 interacts with SLC1A3 in the secretory pathway from the ERGIC to the plasma membrane, thereby modulating the cell surface expression of SLC1A3
  • PDZK1 and SLC9A3R1 regulate the transport function of SLCO1A2 by modulating protein internalization via a clathrin-dependent pathway and by enhancing protein stability
  • interaction of ABCB4 with SLC9A3R1 through its PDZ-like motif plays a critical role in the regulation of ABCB4 expression and stability at the canalicular plasma membrane
  • interaction OF CFTR, SLC9A3R1, and RAPGEF3 is promoted by RAPGEF3 activation, triggering its translocation to the plasma membrane and binding to SLC9A3R1
  • SLC9A3R1 is a new binding partner for GPER1 and its overexpression promotes protein stability and activation of GPER1 in ER-positive invasive breast cancer (IBC)
  • SLC9A3R1 acts with ATP2B2 to regulate ERBB2 signaling and membrane retention in breast cancers
  • SLC9A3R1, SLC9A3R2 down-regulated SCARB1 at least in part via the ubiquitin/proteasome pathway
  • inhibits CTNNB1-mediated proliferation of cervical cancer cells through suppression of ACTN4 expression
  • cell & other
    induced by estrogen
    inhibited by phosphorylation of the PDZ1 domain, that attenuated its binding to physiological targets
    corresponding disease(s) NPHLOP2
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral   LOH    
    in breast carcinoma with higher aggressiveness
    constitutional     --over  
    in the uppermost stratum Malpighi of psoriatic skin
    constitutional       loss of function
    leads to impairment in the function of ABCC2, a major determinant of glutathione-dependent, bile acid-independent bile flow
    constitutional germinal mutation      
    increased the generation of cyclic AMP (cAMP) by parathyroid hormone (PTH) and inhibited phosphate transport, leading to nephrolithiasis or bone demineralization
    tumoral     --over  
    in circulatory peripheral lymphocytes from patients with breast cancer
    tumoral     --other  
    significant disruption of all three members of the PTEN-SLC9A3R1-PHLPP1 tumor suppressor network in high-grade glioma
    Variant & Polymorphism
    Candidate gene
  • SLC9A3R1 measurements in circulatory lymphocytes of breast cancer patients may be a valid method for the prediction of breast cancer occurrence and prognosis, and may have value in the management of cancer patients
  • Therapy target
    repressing SLC9A3R1 expression exhibited significant anticancer effects via the induction of G0/G1 phase arrest, apoptosis and ROS generation
  • phosphate transport in brush border membrane vesicles and proximal tubule cells from Nherf-1-null mice were resistant to the inhibitory effect of Fgf23
  • Nherf1-null mice display reduced bone formation and wide mineralizing fronts despite elimination of phosphate wasting by dietary supplementation