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Gene Review

SLC9A3R2  -  solute carrier family 9, subfamily A (NHE3...

Homo sapiens

Synonyms: E3KARP, NHE3 kinase A regulatory protein E3KARP, NHE3RF2, NHERF-2, NHERF2, ...
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Disease relevance of SLC9A3R2

  • The 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 [1].
  • Overexpression, purification, and characterization of PDZ domain proteins NHERF and E3KARP in Escherichia coli [2].
  • In effusions, SIP1 may be the main regulator of E-cadherin, but with a lesser level of suppression compared with primary tumors and solid metastases [3].
  • IgM immunoreactivity to Sip1 C-ter was significantly higher in patients with Behçet's disease and in patients with primary vasculitis than in the other groups of patients and healthy subjects tested (P < 10-4 by Mann-Whitney test) [4].

High impact information on SLC9A3R2

  • NHERF2 simultaneously binds phospholipase C beta 1 and an atypical, carboxyl-terminal PDZ consensus motif, ETVM, of the PTH1R through PDZ1 and PDZ2, respectively [5].
  • P2Y1 receptor signaling is controlled by interaction with the PDZ scaffold NHERF-2 [6].
  • Finally, we found that coexpression of P2Y(1)R with NHERF-2 in glial cells prolongs P2Y(1)R-mediated Ca(2+) signaling, whereas disruption of the P2Y(1)R-NHERF-2 interaction by point mutations attenuates the duration of P2Y(1)R-mediated Ca(2+) responses [6].
  • 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 [7].
  • Using its second PDZ domain, NHERF2 was found to indirectly link LPA(2) to PLC-beta3 to form a complex, and the other PLC-beta isozymes were not included in the protein complex [8].

Biological context of SLC9A3R2

  • These studies furthermore reveal that oligomerization of NHERF-1, but not NHERF-2, is highly regulated by association with other proteins and by phosphorylation [9].
  • E3KARP has a restricted tissue distribution with the highest expression being found in lung [10].
  • The Na(+)/H(+) exchanger regulatory factor 2 (NHERF2/TKA-1/E3KARP) contains two PSD-95/Dlg/ZO-1 (PDZ) domains which interact with the PDZ docking motif (X-(S/T)-X-(V/L)) of proteins to mediate the assembly of transmembrane and cytosolic proteins into functional signal transduction complexes [11].
  • We suggest a model in which both NHE3 and dra bind to the second PDZ domain of E3KARP and that linking of the transporters occurs through dimerization of E3KARP [1].
  • Experiments using fusion proteins demonstrated that this was a direct interaction between an internal binding site in the C terminus of ClC-5 and the PDZ2 module of NHERF2 [12].

Anatomical context of SLC9A3R2


Associations of SLC9A3R2 with chemical compounds

  • The adenosine 2b receptor is recruited to the plasma membrane and associates with E3KARP and Ezrin upon agonist stimulation [14].
  • The action of the kinases and NHERF-2 may link urinary citrate excretion to proximal tubular H(+) secretion [17].
  • ERM proteins are membrane cytoskeletal linkers that are negatively regulated by an intramolecular association between domains known as NH(2)- and COOH-ERM association domains (N- and C-ERMADs) that mask sites for binding membrane-associated proteins, such as EBP50 and E3KARP, and F-actin [18].
  • This distinct nephron localization suggests different physiologic roles for NHERF and NHERF2 [19].
  • PKCalpha and E3KARP coimmunoprecipitated from cell lysates; this occurred to a lesser extent at basal [Ca2+]i and was increased with ionomycin exposure [20].

Physical interactions of SLC9A3R2

  • E3KARP binds an internal region within the NHE3 C-terminal cytoplasmic tail, defining a new mode of PDZ domain interaction [21].
  • As shown earlier for the human homolog of NHERF, we also found that the cytoskeletal protein ezrin binds to the carboxyl-terminal domain of E3KARP [21].
  • The PDZ binding motif located at the COOH terminus of CFTR interacts preferentially with the second PDZ domain of E3KARP, with nanomolar affinity [22].
  • There is a 3-phosphoinositide-dependent protein kinase 1 (PDK1) interacting fragment (PIF) in the tail of NHERF2 [11].
  • Furthermore, PLC-beta3 interacted with NHERF2 rather than with other PDZ-containing proteins [16].

Regulatory relationships of SLC9A3R2

  • PTH treatment of cells that express the NHERF2 PTH1R complex markedly activates phospholipase C beta and inhibits adenylyl cyclase through stimulation of inhibitory G proteins (G(i/o) proteins) [5].
  • However, it is still unclear how E3KARP leads to the LPA-induced exocytosis of NHE3 [23].
  • Thus NHERF1 and NHERF2 differentially regulate albumin uptake by mechanisms that ultimately alter the cell-surface levels of ClC-5 [12].

Other interactions of SLC9A3R2

  • 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 [7].
  • The distributions of NHE3 and E3KARP were not affected by treatment with 8-bromo-cAMP [21].
  • We also found that ezrin associates with E3KARP in vivo [22].
  • Moreover, confocal immunofluorescence microscopy of polarized Calu-3 monolayers shows that E3KARP and CFTR are co-localized at the apical membrane domain [22].
  • Serum- and glucocorticoid-induced protein kinase 1 (SGK1) also carries a putative PDZ-binding motif (D-S-F-L) at its carboxy tail, implicated in the specific interaction with NHERF2 [11].

Analytical, diagnostic and therapeutic context of SLC9A3R2


  1. The 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., Heil, A., Baisch, S., Lin-Wu, E., Yun, C.C., Kalbacher, H., Gregor, M., Seidler, U. Biochemistry (2002) [Pubmed]
  2. 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]
  3. Expression of E-cadherin transcriptional regulators in ovarian carcinoma. Elloul, S., Silins, I., Trop??, C.G., Benshushan, A., Davidson, B., Reich, R. Virchows Arch. (2006) [Pubmed]
  4. Identification and characterization of the carboxy-terminal region of Sip-1, a novel autoantigen in Behçet's disease. Delunardo, F., Conti, F., Margutti, P., Alessandri, C., Priori, R., Siracusano, A., Riganò, R., Profumo, E., Valesini, G., Sorice, M., Ortona, E. Arthritis Res. Ther. (2006) [Pubmed]
  5. 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]
  6. P2Y1 receptor signaling is controlled by interaction with the PDZ scaffold NHERF-2. Fam, S.R., Paquet, M., Castleberry, A.M., Oller, H., Lee, C.J., Traynelis, S.F., Smith, Y., Yun, C.C., Hall, R.A. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  7. 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]
  8. NHERF2 specifically interacts with LPA2 receptor and defines the specificity and efficiency of receptor-mediated phospholipase C-beta3 activation. Oh, Y.S., Jo, N.W., Choi, J.W., Kim, H.S., Seo, S.W., Kang, K.O., Hwang, J.I., Heo, K., Kim, S.H., Kim, Y.H., Kim, I.H., Kim, J.H., Banno, Y., Ryu, S.H., Suh, P.G. Mol. Cell. Biol. (2004) [Pubmed]
  9. 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]
  10. Distinct 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., Reczek, D., Bretscher, A. Eur. J. Cell Biol. (2002) [Pubmed]
  11. The Na(+)/H(+) exchanger regulatory factor 2 mediates phosphorylation of serum- and glucocorticoid-induced protein kinase 1 by 3-phosphoinositide-dependent protein kinase 1. Chun, J., Kwon, T., Lee, E., Suh, P.G., Choi, E.J., Sun Kang, S. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  12. Regulation of albumin endocytosis by PSD95/Dlg/ZO-1 (PDZ) scaffolds. Interaction of Na+-H+ exchange regulatory factor-2 with ClC-5. Hryciw, D.H., Ekberg, J., Ferguson, C., Lee, A., Wang, D., Parton, R.G., Pollock, C.A., Yun, C.C., Poronnik, P. J. Biol. Chem. (2006) [Pubmed]
  13. 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]
  14. The adenosine 2b receptor is recruited to the plasma membrane and associates with E3KARP and Ezrin upon agonist stimulation. Sitaraman, S.V., Wang, L., Wong, M., Bruewer, M., Hobert, M., Yun, C.H., Merlin, D., Madara, J.L. J. Biol. Chem. (2002) [Pubmed]
  15. Plasma membrane Ca2+ ATPase isoform 2b interacts preferentially with Na+/H+ exchanger regulatory factor 2 in apical plasma membranes. DeMarco, S.J., Chicka, M.C., Strehler, E.E. J. Biol. Chem. (2002) [Pubmed]
  16. Regulation of phospholipase C-beta 3 activity by Na+/H+ exchanger regulatory factor 2. Hwang, J.I., Heo, K., Shin, K.J., Kim, E., Yun, C., Ryu, S.H., Shin, H.S., Suh, P.G. J. Biol. Chem. (2000) [Pubmed]
  17. Stimulation of renal Na+ dicarboxylate cotransporter 1 by Na+/H+ exchanger regulating factor 2, serum and glucocorticoid inducible kinase isoforms, and protein kinase B. Boehmer, C., Embark, H.M., Bauer, A., Palmada, M., Yun, C.H., Weinman, E.J., Endou, H., Cohen, P., Lahme, S., Bichler, K.H., Lang, F. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  18. Hierarchy of merlin and ezrin N- and C-terminal domain interactions in homo- and heterotypic associations and their relationship to binding of scaffolding proteins EBP50 and E3KARP. Nguyen, R., Reczek, D., Bretscher, A. J. Biol. Chem. (2001) [Pubmed]
  19. Acute regulation of NHE3 by protein kinase A requires a multiprotein signal complex. Weinman, E.J., Steplock, D., Shenolikar, S. Kidney Int. (2001) [Pubmed]
  20. Ca2+-dependent inhibition of NHE3 requires PKC alpha which binds to E3KARP to decrease surface NHE3 containing plasma membrane complexes. Lee-Kwon, W., Kim, J.H., Choi, J.W., Kawano, K., Cha, B., Dartt, D.A., Zoukhri, D., Donowitz, M. Am. J. Physiol., Cell Physiol. (2003) [Pubmed]
  21. NHE3 kinase A regulatory protein E3KARP binds the epithelial brush border Na+/H+ exchanger NHE3 and the cytoskeletal protein ezrin. Yun, C.H., Lamprecht, G., Forster, D.V., Sidor, A. J. Biol. Chem. (1998) [Pubmed]
  22. E3KARP mediates the association of ezrin and protein kinase A with the cystic fibrosis transmembrane conductance regulator in airway cells. Sun, F., Hug, M.J., Lewarchik, C.M., Yun, C.H., Bradbury, N.A., Frizzell, R.A. J. Biol. Chem. (2000) [Pubmed]
  23. Lysophosphatidic acid induces exocytic trafficking of Na(+)/H(+) exchanger 3 by E3KARP-dependent activation of phospholipase C. Choi, J.W., Lee-Kwon, W., Jeon, E.S., Kang, Y.J., Kawano, K., Kim, H.S., Suh, P.G., Donowitz, M., Kim, J.H. Biochim. Biophys. Acta (2004) [Pubmed]
  24. Na(+)-H(+) exchanger regulatory factor 1 is a PDZ scaffold for the astroglial glutamate transporter GLAST. Lee, A., Rayfield, A., Hryciw, D.H., Ma, T.A., Wang, D., Pow, D., Broer, S., Yun, C., Poronnik, P. Glia (2007) [Pubmed]
  25. The PDZ Scaffold NHERF-2 Interacts with mGluR5 and Regulates Receptor Activity. Paquet, M., Asay, M.J., Fam, S.R., Inuzuka, H., Castleberry, A.M., Oller, H., Smith, Y., Yun, C.C., Traynelis, S.F., Hall, R.A. J. Biol. Chem. (2006) [Pubmed]
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