Sodium-hydrogen exchange regulatory cofactor 2 explained

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.

Function

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]

Interactions

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

• Solute carrier family

Further reading

• Yun CH, Oh S, Zizak M, etal . cAMP-mediated inhibition of the epithelial brush border Na+/H+ exchanger, NHE3, requires an associated regulatory protein. . Proc. Natl. Acad. Sci. U.S.A. . 94 . 7 . 3010–5 . 1997 . 9096337 . 10.1073/pnas.94.7.3010 . 20313 . 1997PNAS...94.3010Y . free .
• Reczek D, Berryman M, Bretscher A . Identification of EBP50: A PDZ-containing phosphoprotein that associates with members of the ezrin-radixin-moesin family. . J. Cell Biol. . 139 . 1 . 169–79 . 1998 . 9314537 . 10.1083/jcb.139.1.169 . 2139813 .
• Yun CH, Lamprecht G, Forster DV, Sidor A . NHE3 kinase A regulatory protein E3KARP binds the epithelial brush border Na+/H+ exchanger NHE3 and the cytoskeletal protein ezrin. . J. Biol. Chem. . 273 . 40 . 25856–63 . 1998 . 9748260 . 10.1074/jbc.273.40.25856 . free .
• Imai K, Sarker AH, Akiyama K, etal . Genomic structure and sequence of a human homologue (NTHL1/NTH1) of Escherichia coli endonuclease III with those of the adjacent parts of TSC2 and SLC9A3R2 genes. . Gene . 222 . 2 . 287–95 . 1999 . 9831664 . 10.1016/S0378-1119(98)00485-5 .
• Zizak M, Lamprecht G, Steplock D, etal . cAMP-induced phosphorylation and inhibition of Na(+)/H(+) exchanger 3 (NHE3) are dependent on the presence but not the phosphorylation of NHE regulatory factor. . J. Biol. Chem. . 274 . 35 . 24753–8 . 1999 . 10455146 . 10.1074/jbc.274.35.24753 . free .
• Hwang JI, Heo K, Shin KJ, etal . Regulation of phospholipase C-beta 3 activity by Na+/H+ exchanger regulatory factor 2. . J. Biol. Chem. . 275 . 22 . 16632–7 . 2000 . 10748023 . 10.1074/jbc.M001410200 . free .
• Sun F, Hug MJ, Lewarchik CM, etal . E3KARP mediates the association of ezrin and protein kinase A with the cystic fibrosis transmembrane conductance regulator in airway cells. . J. Biol. Chem. . 275 . 38 . 29539–46 . 2000 . 10893422 . 10.1074/jbc.M004961200 . free .
• Kanai F, Marignani PA, Sarbassova D, etal . TAZ: a novel transcriptional co-activator regulated by interactions with 14-3-3 and PDZ domain proteins. . EMBO J. . 19 . 24 . 6778–91 . 2001 . 11118213 . 10.1093/emboj/19.24.6778 . 305881 .
• Reczek D, Bretscher A . Identification of EPI64, a TBC/rabGAP domain-containing microvillar protein that binds to the first PDZ domain of EBP50 and E3KARP. . J. Cell Biol. . 153 . 1 . 191–206 . 2001 . 11285285 . 10.1083/jcb.153.1.191 . 2185518 .
• Takeda T, McQuistan T, Orlando RA, Farquhar MG . Loss of glomerular foot processes is associated with uncoupling of podocalyxin from the actin cytoskeleton. . J. Clin. Invest. . 108 . 2 . 289–301 . 2001 . 11457882 . 10.1172/JCI12539 . 203027 .
• Yun CC, Chen Y, Lang F . Glucocorticoid activation of Na(+)/H(+) exchanger isoform 3 revisited. The roles of SGK1 and NHERF2. . J. Biol. Chem. . 277 . 10 . 7676–83 . 2002 . 11751930 . 10.1074/jbc.M107768200 . free .
• DeMarco SJ, Chicka MC, Strehler EE . Plasma membrane Ca2+ ATPase isoform 2b interacts preferentially with Na+/H+ exchanger regulatory factor 2 in apical plasma membranes. . J. Biol. Chem. . 277 . 12 . 10506–11 . 2002 . 11786550 . 10.1074/jbc.M111616200 . free .
• Ingraffea J, Reczek D, Bretscher A . Distinct cell type-specific expression of scaffolding proteins EBP50 and E3KARP: EBP50 is generally expressed with ezrin in specific epithelia, whereas E3KARP is not. . Eur. J. Cell Biol. . 81 . 2 . 61–8 . 2002 . 11893083 . 10.1078/0171-9335-00218 .
• Kim JH, Lee-Kwon W, Park JB, etal . 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. . 277 . 26 . 23714–24 . 2002 . 11948184 . 10.1074/jbc.M200835200 . free .
• Li Y, Li J, Straight SW, Kershaw DB . PDZ domain-mediated interaction of rabbit podocalyxin and Na(+)/H(+) exchange regulatory factor-2. . Am. J. Physiol. Renal Physiol. . 282 . 6 . F1129–39 . 2002 . 11997330 . 10.1152/ajprenal.00131.2001 .
• Mahon MJ, Donowitz M, Yun CC, Segre GV . Na(+)/H(+) exchanger regulatory factor 2 directs parathyroid hormone 1 receptor signalling. . Nature . 417 . 6891 . 858–61 . 2002 . 12075354 . 10.1038/nature00816 . 2002Natur.417..858M . 4379134 .
• Sitaraman SV, Wang L, Wong M, etal . The adenosine 2b receptor is recruited to the plasma membrane and associates with E3KARP and Ezrin upon agonist stimulation. . J. Biol. Chem. . 277 . 36 . 33188–95 . 2002 . 12080047 . 10.1074/jbc.M202522200 . free .
• Lamprecht G, Heil A, Baisch S, etal . 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. . Biochemistry . 41 . 41 . 12336–42 . 2002 . 12369822 . 10.1021/bi0259103 .

Notes and References

1. Poulat F, de Santa Barbara P, Desclozeaux M, Soullier S, Moniot B, Bonneaud N, Boizet B, Berta P . The human testis determining factor SRY binds a nuclear factor containing PDZ protein interaction domains . J. Biol. Chem. . 272 . 11 . 7167–72 . March 1997 . 9054412 . 10.1074/jbc.272.11.7167 . free .
2. Hall RA, Ostedgaard LS, Premont RT, Blitzer JT, Rahman N, Welsh MJ, Lefkowitz RJ . 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 . July 1998 . 9671706 . 21104 . 10.1073/pnas.95.15.8496. 1998PNAS...95.8496H . free .
3. Web site: Entrez Gene: SLC9A3R2 solute carrier family 9 (sodium/hydrogen exchanger), member 3 regulator 2.
4. Chun . Jaesun . Kwon Taegun . Lee Eunjung . Suh Pann-Ghill . 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. . 298 . 2 . 207–15 . United States. 0006-291X. 12387817 . 10.1016/S0006-291X(02)02428-2 .
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. . 277 . 10 . 7676–83 . United States. 0021-9258. 11751930 . 10.1074/jbc.M107768200 . free .
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. . 277 . 26 . 23714–24 . United States. 0021-9258. 11948184 . 10.1074/jbc.M200835200 . free .
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 . . 417 . 6891 . 858–61 . England. 0028-0836. 12075354 . 10.1038/nature00816 . 2002Natur.417..858M . 4379134 .
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. . 273 . 40 . 25856–63 . UNITED STATES. 0021-9258. 9748260 . 10.1074/jbc.273.40.25856 . free .
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. . 277 . 36 . 33188–95 . United States. 0021-9258. 12080047 . 10.1074/jbc.M202522200 . free .
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. . 168 . 2 . 303–13 . United States. 0021-9525. 15642748 . 10.1083/jcb.200407072 . 2171597 .
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. . 108 . 2 . 289–301 . United States. 0021-9738. 11457882 . 10.1172/JCI12539 . 203027 .
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. . 282 . 6 . F1129–39 . United States. 0363-6127. 11997330 . 10.1152/ajprenal.00131.2001 .
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. . 275 . 38 . 29539–46 . UNITED STATES. 0021-9258. 10893422 . 10.1074/jbc.M004961200 . free .
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. . 275 . 22 . 16632–7 . UNITED STATES. 0021-9258. 10748023 . 10.1074/jbc.M001410200 . free .