Sodium-hydrogen exchange regulatory cofactor 2

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Sodium-hydrogen exchange regulatory cofactor NHE-RF2 (NHERF-2) also known as tyrosine kinase activator protein 1 (TKA-1) or SRY-interacting protein 1 (SIP-1) is a protein that in humans is encoded by the SLC9A3R2 (solute carrier family 9 isoform A3 regulatory factor 2) gene.[1][2]

NHERF-2) 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 and to regulate their surface expression. It is necessary for cAMP-mediated phosphorylation and inhibition of SLC9A3. In addition, it may also act as scaffold protein in the nucleus.


This regulatory protein (factor) interacts with a sodium/hydrogen exchanger NHE3 (SLC9A3) in the brush border membrane of the proximal tubule, small intestine, and colon that plays a major role in transepithelial sodium absorption. SLC9A3R2, as well as SLC9A3R1 and protein kinase A phosphorylation, may play a role in NHE3 regulation.[3]


Sodium-hydrogen exchange regulatory cofactor 2 has been shown to interact with SGK,[4][5] Actinin alpha 4,[6] Parathyroid hormone receptor 1,[7] Phosphoinositide-dependent kinase-1,[4] EZR,[8][9] PODXL,[10][11][12] Cystic fibrosis transmembrane conductance regulator[13] and PLCB3.[14]

See also


  1. Poulat F, de Santa Barbara P, Desclozeaux M, Soullier S, Moniot B, Bonneaud N, Boizet B, Berta P (March 1997). "The human testis determining factor SRY binds a nuclear factor containing PDZ protein interaction domains". J. Biol. Chem. 272 (11): 7167–72. doi:10.1074/jbc.272.11.7167. PMID 9054412.
  2. Hall RA, Ostedgaard LS, Premont RT, Blitzer JT, Rahman N, Welsh MJ, Lefkowitz RJ (July 1998). "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". Proc. Natl. Acad. Sci. U.S.A. 95 (15): 8496–501. doi:10.1073/pnas.95.15.8496. PMC 21104. PMID 9671706.
  3. "Entrez Gene: SLC9A3R2 solute carrier family 9 (sodium/hydrogen exchanger), member 3 regulator 2".
  4. 4.0 4.1 Chun, Jaesun; Kwon Taegun; Lee Eunjung; Suh Pann-Ghill; Choi Eui-Ju; Sun Kang Sang (October 2002). "The Na(+)/H(+) exchanger regulatory factor 2 mediates phosphorylation of serum- and glucocorticoid-induced protein kinase 1 by 3-phosphoinositide-dependent protein kinase 1". Biochem. Biophys. Res. Commun. United States. 298 (2): 207–15. doi:10.1016/S0006-291X(02)02428-2. ISSN 0006-291X. PMID 12387817.
  5. Yun, C Chris; Chen Yueping; Lang Florian (March 2002). "Glucocorticoid activation of Na(+)/H(+) exchanger isoform 3 revisited. The roles of SGK1 and NHERF2". J. Biol. Chem. United States. 277 (10): 7676–83. doi:10.1074/jbc.M107768200. ISSN 0021-9258. PMID 11751930.
  6. Kim JH, Lee-Kwon W, Park JB, Ryu SH, Yun CH, Donowitz M (June 2002). "Ca(2+)-dependent inhibition of Na+/H+ exchanger 3 (NHE3) requires an NHE3-E3KARP-alpha-actinin-4 complex for oligomerization and endocytosis". J. Biol. Chem. United States. 277 (26): 23714–24. doi:10.1074/jbc.M200835200. ISSN 0021-9258. PMID 11948184.
  7. Mahon, Matthew J; Donowitz Mark; Yun C Chris; Segre Gino V (June 2002). "Na(+)/H(+ ) exchanger regulatory factor 2 directs parathyroid hormone 1 receptor signalling". Nature. England. 417 (6891): 858–61. doi:10.1038/nature00816. ISSN 0028-0836. PMID 12075354.
  8. Yun, C H; Lamprecht G; Forster D V; Sidor A (October 1998). "NHE3 kinase A regulatory protein E3KARP binds the epithelial brush border Na+/H+ exchanger NHE3 and the cytoskeletal protein ezrin". J. Biol. Chem. UNITED STATES. 273 (40): 25856–63. doi:10.1074/jbc.273.40.25856. ISSN 0021-9258. PMID 9748260.
  9. Sitaraman, Shanthi V; Wang Lixin; Wong Michelle; Bruewer Matthias; Hobert Michael; Yun C-H; Merlin Didier; Madara James L (September 2002). "The adenosine 2b receptor is recruited to the plasma membrane and associates with E3KARP and Ezrin upon agonist stimulation". J. Biol. Chem. United States. 277 (36): 33188–95. doi:10.1074/jbc.M202522200. ISSN 0021-9258. PMID 12080047.
  10. Meder, Doris; Shevchenko Anna; Simons Kai; Füllekrug Joachim (January 2005). "Gp135/podocalyxin and NHERF-2 participate in the formation of a preapical domain during polarization of MDCK cells". J. Cell Biol. United States. 168 (2): 303–13. doi:10.1083/jcb.200407072. ISSN 0021-9525. PMC 2171597. PMID 15642748.
  11. Takeda, T; McQuistan T; Orlando R A; Farquhar M G (July 2001). "Loss of glomerular foot processes is associated with uncoupling of podocalyxin from the actin cytoskeleton". J. Clin. Invest. United States. 108 (2): 289–301. doi:10.1172/JCI12539. ISSN 0021-9738. PMC 203027. PMID 11457882.
  12. Li, Yong; Li Jian; Straight Samuel W; Kershaw David B (June 2002). "PDZ domain-mediated interaction of rabbit podocalyxin and Na(+)/H(+) exchange regulatory factor-2". Am. J. Physiol. Renal Physiol. United States. 282 (6): F1129–39. doi:10.1152/ajprenal.00131.2001. ISSN 0363-6127. PMID 11997330.
  13. Sun, F; Hug M J; Lewarchik C M; Yun C H; Bradbury N A; Frizzell R A (September 2000). "E3KARP mediates the association of ezrin and protein kinase A with the cystic fibrosis transmembrane conductance regulator in airway cells". J. Biol. Chem. UNITED STATES. 275 (38): 29539–46. doi:10.1074/jbc.M004961200. ISSN 0021-9258. PMID 10893422.
  14. Hwang, J I; Heo K; Shin K J; Kim E; Yun C; Ryu S H; Shin H S; Suh P G (June 2000). "Regulation of phospholipase C-beta 3 activity by Na+/H+ exchanger regulatory factor 2". J. Biol. Chem. UNITED STATES. 275 (22): 16632–7. doi:10.1074/jbc.M001410200. ISSN 0021-9258. PMID 10748023.

Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.