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Gene Review

SLC9A3R1  -  solute carrier family 9, subfamily A (NHE3...

Homo sapiens

Synonyms: EBP50, Ezrin-radixin-moesin-binding phosphoprotein 50, NHERF, NHERF-1, NHERF1, ...
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Disease relevance of SLC9A3R1


High impact information on SLC9A3R1

  • A putative RUNX1 binding site variant between SLC9A3R1 and NAT9 is associated with susceptibility to psoriasis [1].
  • Expression of SLC9A3R1 is highest in the uppermost stratum Malpighi of psoriatic and normal skin and in inactive versus active T cells [1].
  • Here we show that the PTH1R binds to Na(+)/H(+) exchanger regulatory factors (NHERF) 1 and 2 through a PDZ-domain interaction in vitro and in PTH target cells [7].
  • We also discuss membrane proteins to which ERM and merlin bind, including those making an indirect linkage through the PDZ-containing adaptor molecules EBP50 and E3KARP [8].
  • ERM-Merlin and EBP50 protein families in plasma membrane organization and function [8].

Chemical compound and disease context of SLC9A3R1


Biological context of SLC9A3R1


Anatomical context of SLC9A3R1


Associations of SLC9A3R1 with chemical compounds

  • Agonist stimulation of the thromboxane A(2) receptor (TP receptor) resulted in an increased interaction between EBP50 and Galpha(q), suggesting that EBP50 preferentially interacts with activated Galpha(q) [17].
  • In this report, we show that EBP50 inhibits the phospholipase C (PLC)-beta-mediated inositol phosphate production of a Galpha(q)-coupled receptor as well as PLC-beta activation by the constitutively active Galpha(q)-R183C mutant [17].
  • Glutathione S-transferase-EBP50 pulled down CFTR and hNBC3 from cell lysates when expressed individually and as a complex when expressed together [18].
  • A point-mutated version of NHERF-1 (S289A), which cannot be phosphorylated on serine 289, exhibits a reduced capacity for co-immunoprecipitation from cells [12].
  • Oligomerization of full-length NHERF-1 is also enhanced by mutation of serine 289 to aspartate (S289D), which mimics the phosphorylated form of NHERF-1 [12].
  • These data suggest that in proximal tubule, NHERF1 is required for all cAMP inhibition of NHE3, which occurs through both EPAC-dependent and PKA-dependent mechanisms; in contrast, cAMP inhibits ileal NHE3 only by a PKA-dependent pathway, which is independent of NHERF1 and EPAC [19].

Physical interactions of SLC9A3R1

  • NHERF also binds to the tail of the cystic fibrosis transmembrane conductance regulator, which ends in D-T-R-L [10].
  • The delineation of the preferred binding motif for the first PDZ domain of the NHERF family of proteins allows for predictions for other proteins that may interact with NHERF or NHERF-2 [10].
  • The Na+/H+ exchanger regulatory factor (NHERF) binds to the tail of the beta2-adrenergic receptor and plays a role in adrenergic regulation of Na+/H+ exchange [10].
  • For example, as would be predicted from the beta2 receptor tail mutagenesis studies, NHERF binds to the tail of the purinergic P2Y1 receptor, a seven-transmembrane receptor with an intracellular C-terminal tail ending in D-T-S-L [10].
  • Thus, NHERF-1/EBP50 binds directly to KOR, and this association plays an important role in accelerating Na(+)/H(+) exchange [11].

Enzymatic interactions of SLC9A3R1

  • On the other hand, electrophysiological studies demonstrated that NHERF is able to stimulate the cAMP-dependent protein kinase-phosphorylated CFTR channel activity in intact cells [20].

Regulatory relationships of SLC9A3R1

  • NHERF-1/EBP50 was previously shown to regulate Na(+)/H(+)-exchanger 3 (NHE3) activities in OK cells [11].
  • We also demonstrate that EBP50 inhibits Galpha(q) signaling by preventing the interaction between Galpha(q) and the TP receptor and between activated Galpha(q) and PLC-beta1 [17].
  • Analyses of anti-EBP50 protein immunoprecipitate showed that salmeterol induced an increase in the amount of CFTR that binds to EBP50 [21].
  • PDGFR activity in cells can also be regulated in a NHERF-dependent fashion by stimulation of the beta(2)-adrenergic receptor, a known cellular binding partner for NHERF [22].
  • Based on these and additional results, we propose a model whereby dormant ezrin can be activated to bind EBP50 on its NH2-terminal end and F-actin on its COOH-terminal end [23].
  • We conclude that NHERF1 inhibits endocytosis without affecting PTH1R recycling in MC4 and PTH1R-expressing HEK-293 cells [24].

Other interactions of SLC9A3R1

  • Because the preferred binding motif of the first PDZ domain of the NHERF family of proteins is found at the C termini of a variety of intracellular proteins, NHERF and NHERF-2 may be multifunctional adaptor proteins involved in many previously unsuspected aspects of intracellular signaling [10].
  • Expanding the role of NHERF, a PDZ-domain containing protein adapter, to growth regulation [25].
  • NHERF contains two PDZ domains, the first of which is required for its interaction with the beta2 receptor [10].
  • The COOH terminus of YAP65 is necessary and sufficient to mediate association with EBP50 [13].
  • The interaction involves the C-terminal sequence (TRL) of PAG and N-terminal PDZ domain(s) of EBP50 [26].

Analytical, diagnostic and therapeutic context of SLC9A3R1


  1. A putative RUNX1 binding site variant between SLC9A3R1 and NAT9 is associated with susceptibility to psoriasis. Helms, C., Cao, L., Krueger, J.G., Wijsman, E.M., Chamian, F., Gordon, D., Heffernan, M., Daw, J.A., Robarge, J., Ott, J., Kwok, P.Y., Menter, A., Bowcock, A.M. Nat. Genet. (2003) [Pubmed]
  2. NHERF (Na+/H+ exchanger regulatory factor) gene mutations in human breast cancer. Dai, J.L., Wang, L., Sahin, A.A., Broemeling, L.D., Schutte, M., Pan, Y. Oncogene (2004) [Pubmed]
  3. Overexpression of the NF2 gene inhibits schwannoma cell proliferation through promoting PDGFR degradation. Fraenzer, J.T., Pan, H., Minimo, L., Smith, G.M., Knauer, D., Hung, G. Int. J. Oncol. (2003) [Pubmed]
  4. No association between atopic dermatitis and the SLC9A3R1-NAT9 RUNX1 binding site polymorphism in Japanese patients. Hosomi, N., Fukai, K., Oiso, N., Kato, A., Fukui, M., Ishii, M. Clin. Exp. Dermatol. (2005) [Pubmed]
  5. Stimulation by parathyroid hormone of a NHERF-1-assembled complex consisting of the parathyroid hormone I receptor, phospholipase Cbeta, and actin increases intracellular calcium in opossum kidney cells. Mahon, M.J., Segre, G.V. J. Biol. Chem. (2004) [Pubmed]
  6. The NHERF1 PDZ2 domain regulates PKA-RhoA-p38-mediated NHE1 activation and invasion in breast tumor cells. Cardone, R.A., Bellizzi, A., Busco, G., Weinman, E.J., Dell'Aquila, M.E., Casavola, V., Azzariti, A., Mangia, A., Paradiso, A., Reshkin, S.J. Mol. Biol. Cell (2007) [Pubmed]
  7. Na(+)/H(+ ) exchanger regulatory factor 2 directs parathyroid hormone 1 receptor signalling. Mahon, M.J., Donowitz, M., Yun, C.C., Segre, G.V. Nature (2002) [Pubmed]
  8. ERM-Merlin and EBP50 protein families in plasma membrane organization and function. Bretscher, A., Chambers, D., Nguyen, R., Reczek, D. Annu. Rev. Cell Dev. Biol. (2000) [Pubmed]
  9. Crystallographic characterization of the PDZ1 domain of the human Na+/H+ exchanger regulatory factor. Webster, G., Leung, T., Karthikeyan, S., Birrane, G., Ladias, J.A. Acta Crystallogr. D Biol. Crystallogr. (2001) [Pubmed]
  10. A 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, R.A., Ostedgaard, L.S., Premont, R.T., Blitzer, J.T., Rahman, N., Welsh, M.J., Lefkowitz, R.J. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  11. kappa 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., Steplock, D., Weinman, E.J., Hall, R.A., Ding, Z., Li, J., Wang, Y., Liu-Chen, L.Y. J. Biol. Chem. (2004) [Pubmed]
  12. Oligomerization of NHERF-1 and NHERF-2 PDZ domains: differential regulation by association with receptor carboxyl-termini and by phosphorylation. Lau, A.G., Hall, R.A. Biochemistry (2001) [Pubmed]
  13. Yes-associated protein 65 localizes p62(c-Yes) to the apical compartment of airway epithelia by association with EBP50. Mohler, P.J., Kreda, S.M., Boucher, R.C., Sudol, M., Stutts, M.J., Milgram, S.L. J. Cell Biol. (1999) [Pubmed]
  14. The apical Na(+)/H(+) exchanger isoform NHE3 is regulated by the actin cytoskeleton. Kurashima, K., D'Souza, S., Szászi, K., Ramjeesingh, R., Orlowski, J., Grinstein, S. J. Biol. Chem. (1999) [Pubmed]
  15. The PDZ-binding chloride channel ClC-3B localizes to the Golgi and associates with cystic fibrosis transmembrane conductance regulator-interacting PDZ proteins. Gentzsch, M., Cui, L., Mengos, A., Chang, X.B., Chen, J.H., Riordan, J.R. J. Biol. Chem. (2003) [Pubmed]
  16. Ligand-induced recruitment of Na+/H+-exchanger regulatory factor to the PDGF (platelet-derived growth factor) receptor regulates actin cytoskeleton reorganization by PDGF. Demoulin, J.B., Seo, J.K., Ekman, S., Grapengiesser, E., Hellman, U., Rönnstrand, L., Heldin, C.H. Biochem. J. (2003) [Pubmed]
  17. Regulation of GTP-binding protein alpha q (Galpha q) signaling by the ezrin-radixin-moesin-binding phosphoprotein-50 (EBP50). Rochdi, M.D., Watier, V., La Madeleine, C., Nakata, H., Kozasa, T., Parent, J.L. J. Biol. Chem. (2002) [Pubmed]
  18. The cystic fibrosis transmembrane conductance regulator interacts with and regulates the activity of the HCO3- salvage transporter human Na+-HCO3- cotransport isoform 3. Park, M., Ko, S.B., Choi, J.Y., Muallem, G., Thomas, P.J., Pushkin, A., Lee, M.S., Kim, J.Y., Lee, M.G., Muallem, S., Kurtz, I. J. Biol. Chem. (2002) [Pubmed]
  19. Tissue-specific regulation of sodium/proton exchanger isoform 3 activity in Na(+)/H(+) exchanger regulatory factor 1 (NHERF1) null mice. cAMP inhibition is differentially dependent on NHERF1 and exchange protein directly activated by cAMP in ileum versus proximal tubule. Murtazina, R., Kovbasnjuk, O., Zachos, N.C., Li, X., Chen, Y., Hubbard, A., Hogema, B.M., Steplock, D., Seidler, U., Hoque, K.M., Tse, C.M., De Jonge, H.R., Weinman, E.J., Donowitz, M. J. Biol. Chem. (2007) [Pubmed]
  20. The 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., Sharma, M., So, J., Haardt, M., Drzymala, L., Popov, M., Schwapach, B., Grinstein, S., Du, K., Lukacs, G.L. J. Biol. Chem. (2003) [Pubmed]
  21. Stimulation 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., Hinnrasky, J., Hologne, C., Corlieu, P., Klossek, J.M., Puchelle, E. J. Biol. Chem. (2003) [Pubmed]
  22. Platelet-derived growth factor receptor association with Na(+)/H(+) exchanger regulatory factor potentiates receptor activity. Maudsley, S., Zamah, A.M., Rahman, N., Blitzer, J.T., Luttrell, L.M., Lefkowitz, R.J., Hall, R.A. Mol. Cell. Biol. (2000) [Pubmed]
  23. The carboxyl-terminal region of EBP50 binds to a site in the amino-terminal domain of ezrin that is masked in the dormant molecule. Reczek, D., Bretscher, A. J. Biol. Chem. (1998) [Pubmed]
  24. NHERF1 regulates parathyroid hormone receptor membrane retention without affecting recycling. Wang, B., Bisello, A., Yang, Y., Romero, G.G., Friedman, P.A. J. Biol. Chem. (2007) [Pubmed]
  25. Expanding the role of NHERF, a PDZ-domain containing protein adapter, to growth regulation. Voltz, J.W., Weinman, E.J., Shenolikar, S. Oncogene (2001) [Pubmed]
  26. Interaction between two adapter proteins, PAG and EBP50: a possible link between membrane rafts and actin cytoskeleton. Brdicková, N., Brdicka, T., Andera, L., Spicka, J., Angelisová, P., Milgram, S.L., Horejsí, V. FEBS Lett. (2001) [Pubmed]
  27. cAMP-mediated inhibition of the epithelial brush border Na+/H+ exchanger, NHE3, requires an associated regulatory protein. Yun, C.H., Oh, S., Zizak, M., Steplock, D., Tsao, S., Tse, C.M., Weinman, E.J., Donowitz, M. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  28. Tracking of Quantum Dot-labeled CFTR Shows Near Immobilization by C-Terminal PDZ Interactions. Haggie, P.M., Kim, J.K., Lukacs, G.L., Verkman, A.S. Mol. Biol. Cell (2006) [Pubmed]
  29. Overexpression, purification, and characterization of PDZ domain proteins NHERF and E3KARP in Escherichia coli. Park, K.S., Jeong, M.S., Kim, J.H., Jang, S.B. Protein Expr. Purif. (2005) [Pubmed]
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