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Gene Review

Slc9a3r1  -  solute carrier family 9 (sodium/hydrogen...

Mus musculus

Synonyms: EBP-50, EBP50, Ezrin-radixin-moesin-binding phosphoprotein 50, NHE-RF, NHERF-1, ...
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Disease relevance of Slc9a3r1

  • There was an age-related decline in the phosphate/creatinine ratio in mutant mice such that there were no differences between wild-type and NHERF-1(-/-) by 24 to 30 wk of age despite the continued presence of hypophosphatemia [1].
  • The enteropathogenic Escherichia coli type III secretion system effector Map binds EBP50/NHERF1: implication for cell signalling and diarrhoea [2].
  • As EBP50/NHERF1 regulates ion channels in the intestine we assessed the involvement of Map in diarrhoea using the Citrobacter rodentium mouse model of EPEC [2].

High impact information on Slc9a3r1

  • Using affinity chromatography, we identified polypeptides from placental microvilli that bind the PDZ domains of EBP50 [3].
  • EPI64 colocalizes with EBP50 and ezrin in syncytiotrophoblast and cultured cell microvilli, and this localization in cultured cells is abolished by introduction of the DTYLA mutation [3].
  • The structural defects found in the EBP50(-/-) intestinal microvilli were reminiscent of those described in ezrin(-/-) mice, suggesting a role for EBP50 in organizing apical epithelial membranes [4].
  • In EBP50(-/-) mice, ERM proteins were significantly decreased specifically in BBM from kidney and small intestine epithelial cells, whereas they remained unchanged in the cytoplasm [4].
  • These studies demonstrate that association of the carboxyl terminus of the beta2AR with ezrin-binding protein 50/sodium-hydrogen exchanger regulatory factor, N-ethylmaleimide-sensitive factor, or some related proteins dictates physiologic signaling specificity and trafficking in cardiac myocytes [5].

Biological context of Slc9a3r1

  • Phosphate wasting seen in the NHERF-1(-/-) null mice provided a new experimental system for defining the role of PDZ adapters in the hormonal control of ion transport and renal disease [6].
  • PTH inhibited Na-K ATPase activity in cells expressing wild-type NHERF-1 associated with increased serine phosphorylation of the alpha subunit of the transporter [7].
  • Transfection with NHERF expressing both mutated PDZ domains resulted in diminished basal 86Rb uptake that was not inhibited further by PTH [8].
  • In contrast, deletion of the carboxy-terminal TRL amino acid motif of Npt2a significantly reduced its interaction with NHERF-1 in kidney lysates [9].
  • We have identified the Na(+)/H(+) exchanger regulatory factor (NHERF) as an important molecular component that stabilizes epidermal growth factor receptors (EGFRs) at the cell surface to restrict receptor down-regulation [10].

Anatomical context of Slc9a3r1

  • Cutting edge: negative regulation of immune synapse formation by anchoring lipid raft to cytoskeleton through Cbp-EBP50-ERM assembly [11].
  • Overexpression of Cbp reduced the mobility of the raft on the cell surface of unstimulated T cells and prevented synapse formation and subsequent T cell activation, whereas a mutant incapable of EBP50 binding restored both synapse formation and activation [11].
  • Role of NHERF-1 in regulation of the activity of Na-K ATPase and sodium-phosphate co-transport in epithelial cells [7].
  • A decrease in ezrin binding phosphoprotein-50 (EBP-50) was also detected by immunofluorescence in the foxj1(-/-) mouse pulmonary epithelium [12].
  • NHERF-1 uniquely transduces the cAMP signals that inhibit sodium-hydrogen exchange in mouse renal apical membranes [13].

Associations of Slc9a3r1 with chemical compounds

  • The present experiments using primary cultures of renal proximal tubule cells derived from wild-type and NHERF-1 knockout animals examines the regulation of NHE3 by phenylthiohydantoin (PTH) and the regulation of phosphate transport in response to alterations in the media content of phosphate [14].
  • These studies indicate defects in the renal tubule transport of phosphate, calcium, and uric acid in NHERF-1(-/-) male and female mice that could account for the increased deposition of calcium in the papilla of null mice [1].
  • Young male and female NHERF-1(-/-) mice demonstrated increased urinary excretion of phosphate and urine phosphate/creatinine ratios [1].
  • Proteomic analyses of the isolated apical RPE demonstrated the presence of CRALBP, EBP50, 11-cis-retinol dehydrogenase, cellular retinol-binding protein 1, and interphotoreceptor retinoid-binding protein [15].
  • Although NHE-RF has been recently identified as an estrogen-inducible gene, the lack of an estrogen-response element in the mouse NHE-RF 5'-non-coding-sequence and the inability to demonstrate estrogen stimulation of reporter gene expression in MCF-7 cells suggests a non-conventional or indirect mechanism for NHE-RF regulation by estrogen [16].

Physical interactions of Slc9a3r1

  • Infection of NHERF-1 null cells with adenovirus-GFP-NHERF-1 increased phosphate transport and plasma membrane abundance of Npt2a [17].
  • Ezrin binding domain-deficient NHERF attenuates cAMP-mediated inhibition of Na(+)/H(+) exchange in OK cells [18].
  • In pull-down experiments, D-AKAP2 tightly bound PDZK1 as well as N+/H+ exchanger regulator factor (NHERF-1), but the latter with an apparent fourfold lower affinity [19].

Regulatory relationships of Slc9a3r1

  • The current experiments employ adenovirus-mediated gene transfer in primary cultures of mouse proximal tubule cells from NHERF-1 null mice to explore the specific role of NHERF-1 on regulated Npt2a trafficking and sodium-dependent phosphate transport [17].
  • Forskolin (34.8 +/- 6.2%) and PTH (29.7 +/- 1.8%) inhibited NHE3 activity in wild-type proximal tubule cells but neither forskolin (-3.2 +/- 3.3%) nor PTH (-16.6 +/- 8.1%) inhibited NHE3 activity in NHERF-1(-/-) cells [14].

Other interactions of Slc9a3r1

  • Additionally, following treatment of foxj1(-/-) tracheal explants with calpain inhibitor, basal bodies were observed in an apical location along with relocalization of ezrin and EBP-50 [12].
  • This was associated with a significant decrease in cAMP-stimulated phosphorylation of NHE3 immunoprecipitated from solubilized NHERF-1 (-/-) BBMs [13].
  • Targeted disruption of the mouse NHERF-1 gene eliminated NHERF-1 expression in kidney and other tissues of the mutant mice without altering NHERF-2 levels in these tissues [6].
  • These data suggested that NHERF-1 played a unique role in the apical targeting and/or trafficking of Npt2 in the mammalian kidney, a function not shared by NHERF-2 or other renal PDZ proteins [6].
  • NHERF and regulation of the renal sodium-hydrogen exchanger NHE3 [20].

Analytical, diagnostic and therapeutic context of Slc9a3r1


  1. Longitudinal study of urinary excretion of phosphate, calcium, and uric acid in mutant NHERF-1 null mice. Weinman, E.J., Mohanlal, V., Stoycheff, N., Wang, F., Steplock, D., Shenolikar, S., Cunningham, R. Am. J. Physiol. Renal Physiol. (2006) [Pubmed]
  2. The enteropathogenic Escherichia coli type III secretion system effector Map binds EBP50/NHERF1: implication for cell signalling and diarrhoea. Simpson, N., Shaw, R., Crepin, V.F., Mundy, R., FitzGerald, A.J., Cummings, N., Straatman-Iwanowska, A., Connerton, I., Knutton, S., Frankel, G. Mol. Microbiol. (2006) [Pubmed]
  3. Identification of EPI64, a TBC/rabGAP domain-containing microvillar protein that binds to the first PDZ domain of EBP50 and E3KARP. Reczek, D., Bretscher, A. J. Cell Biol. (2001) [Pubmed]
  4. Ezrin-radixin-moesin (ERM)-binding phosphoprotein 50 organizes ERM proteins at the apical membrane of polarized epithelia. Morales, F.C., Takahashi, Y., Kreimann, E.L., Georgescu, M.M. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  5. The PDZ-binding motif of the beta2-adrenoceptor is essential for physiologic signaling and trafficking in cardiac myocytes. Xiang, Y., Kobilka, B. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  6. Targeted disruption of the mouse NHERF-1 gene promotes internalization of proximal tubule sodium-phosphate cotransporter type IIa and renal phosphate wasting. Shenolikar, S., Voltz, J.W., Minkoff, C.M., Wade, J.B., Weinman, E.J. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  7. Role of NHERF-1 in regulation of the activity of Na-K ATPase and sodium-phosphate co-transport in epithelial cells. Lederer, E.D., Khundmiri, S.J., Weinman, E.J. J. Am. Soc. Nephrol. (2003) [Pubmed]
  8. Parathyroid hormone regulation of NA+,K+-ATPase requires the PDZ 1 domain of sodium hydrogen exchanger regulatory factor-1 in opossum kidney cells. Khundmiri, S.J., Weinman, E.J., Steplock, D., Cole, J., Ahmad, A., Baumann, P.D., Barati, M., Rane, M.J., Lederer, E. J. Am. Soc. Nephrol. (2005) [Pubmed]
  9. Na+-dependent phosphate transporters in the murine osteoclast: cellular distribution and protein interactions. Khadeer, M.A., Tang, Z., Tenenhouse, H.S., Eiden, M.V., Murer, H., Hernando, N., Weinman, E.J., Chellaiah, M.A., Gupta, A. Am. J. Physiol., Cell Physiol. (2003) [Pubmed]
  10. The Na+/H+ exchanger regulatory factor stabilizes epidermal growth factor receptors at the cell surface. Lazar, C.S., Cresson, C.M., Lauffenburger, D.A., Gill, G.N. Mol. Biol. Cell (2004) [Pubmed]
  11. Cutting edge: negative regulation of immune synapse formation by anchoring lipid raft to cytoskeleton through Cbp-EBP50-ERM assembly. Itoh, K., Sakakibara, M., Yamasaki, S., Takeuchi, A., Arase, H., Miyazaki, M., Nakajima, N., Okada, M., Saito, T. J. Immunol. (2002) [Pubmed]
  12. Foxj1 regulates basal body anchoring to the cytoskeleton of ciliated pulmonary epithelial cells. Gomperts, B.N., Gong-Cooper, X., Hackett, B.P. J. Cell. Sci. (2004) [Pubmed]
  13. NHERF-1 uniquely transduces the cAMP signals that inhibit sodium-hydrogen exchange in mouse renal apical membranes. Weinman, E.J., Steplock, D., Shenolikar, S. FEBS Lett. (2003) [Pubmed]
  14. Defective parathyroid hormone regulation of NHE3 activity and phosphate adaptation in cultured NHERF-1-/- renal proximal tubule cells. Cunningham, R., Steplock, D., Wang, F., Huang, H., E, X., Shenolikar, S., Weinman, E.J. J. Biol. Chem. (2004) [Pubmed]
  15. Support for a proposed retinoid-processing protein complex in apical retinal pigment epithelium. Bonilha, V.L., Bhattacharya, S.K., West, K.A., Crabb, J.S., Sun, J., Rayborn, M.E., Nawrot, M., Saari, J.C., Crabb, J.W. Exp. Eye Res. (2004) [Pubmed]
  16. Molecular cloning of the cDNA and promoter sequences for the mouse sodium-hydrogen exchanger regulatory factor. Weinman, E.J., Steplock, D., Zhang, X., Akhter, S., Shenolikar, S. Biochim. Biophys. Acta (1999) [Pubmed]
  17. Adenoviral expression of NHERF-1 in NHERF-1 null mouse renal proximal tubule cells restores Npt2a regulation by low phosphate media and parathyroid hormone. Cunningham, R., Steplock, D., E, X., Biswas, R.S., Wang, F., Shenolikar, S., Weinman, E.J. Am. J. Physiol. Renal Physiol. (2006) [Pubmed]
  18. Ezrin binding domain-deficient NHERF attenuates cAMP-mediated inhibition of Na(+)/H(+) exchange in OK cells. Weinman, E.J., Steplock, D., Wade, J.B., Shenolikar, S. Am. J. Physiol. Renal Physiol. (2001) [Pubmed]
  19. PDZK1: II. an anchoring site for the PKA-binding protein D-AKAP2 in renal proximal tubular cells. Gisler, S.M., Madjdpour, C., Bacic, D., Pribanic, S., Taylor, S.S., Biber, J., Murer, H. Kidney Int. (2003) [Pubmed]
  20. NHERF and regulation of the renal sodium-hydrogen exchanger NHE3. Weinman, E.J., Cunningham, R., Shenolikar, S. Pflugers Arch. (2005) [Pubmed]
  21. Essential role for NHERF in cAMP-mediated inhibition of the Na+-HCO3- co-transporter in BSC-1 cells. Weinman, E.J., Evangelista, C.M., Steplock, D., Liu, M.Z., Shenolikar, S., Bernardo, A. J. Biol. Chem. (2001) [Pubmed]
  22. Identification of EBP50: A PDZ-containing phosphoprotein that associates with members of the ezrin-radixin-moesin family. Reczek, D., Berryman, M., Bretscher, A. J. Cell Biol. (1997) [Pubmed]
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