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Protein-coding gene in the species Homo sapiens
SLC9A3R2 Identifiers Aliases SLC9A3R2 External IDs OMIM : 606553 ; MGI : 1890662 ; HomoloGene : 56962 ; GeneCards : SLC9A3R2 ; OMA :SLC9A3R2 - orthologs Wikidata
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 .[ 5] [ 6]
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.[ 7]
Sodium-hydrogen exchange regulatory cofactor 2 has been shown to interact with SGK ,[ 8] [ 9] Actinin alpha 4 ,[ 10] Parathyroid hormone receptor 1 ,[ 11] Phosphoinositide-dependent kinase-1 ,[ 8] EZR ,[ 12] [ 13] PODXL ,[ 14] [ 15] [ 16] Cystic fibrosis transmembrane conductance regulator [ 17] PLCB3 .[ 18]
^ a b c GRCh38: Ensembl release 89: ENSG00000065054 – Ensembl , May 2017^ a b c GRCm38: Ensembl release 89: ENSMUSG00000002504 – Ensembl , May 2017^ "Human PubMed Reference:" . National Center for Biotechnology Information, U.S. National Library of Medicine .^ "Mouse PubMed Reference:" . National Center for Biotechnology Information, U.S. National Library of Medicine .^ 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 . ^ 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. Bibcode :1998PNAS...95.8496H . doi :10.1073/pnas.95.15.8496 PMC 21104 PMID 9671706 . ^ "Entrez Gene: SLC9A3R2 solute carrier family 9 (sodium/hydrogen exchanger), member 3 regulator 2" .^ a b Chun J, 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 . 298 (2). United States: 207–15. doi :10.1016/S0006-291X(02)02428-2 . ISSN 0006-291X . PMID 12387817 . ^ Yun CC, 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). United States: 7676–83. doi :10.1074/jbc.M107768200 ISSN 0021-9258 . PMID 11751930 . ^ 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). United States: 23714–24. doi :10.1074/jbc.M200835200 ISSN 0021-9258 . PMID 11948184 . ^ Mahon MJ, Donowitz Mark, Yun C Chris, Segre Gino V (June 2002). "Na(+)/H(+ ) exchanger regulatory factor 2 directs parathyroid hormone 1 receptor signalling". Nature 417 (6891). England: 858–61. Bibcode :2002Natur.417..858M . doi :10.1038/nature00816 . ISSN 0028-0836 . PMID 12075354 . S2CID 4379134 . ^ Yun CH, 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). UNITED STATES: 25856–63. doi :10.1074/jbc.273.40.25856 ISSN 0021-9258 . PMID 9748260 . ^ Sitaraman SV, 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). United States: 33188–95. doi :10.1074/jbc.M202522200 ISSN 0021-9258 . PMID 12080047 . ^ Meder D, 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). United States: 303–13. doi :10.1083/jcb.200407072 . ISSN 0021-9525 . PMC 2171597 PMID 15642748 . ^ 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). United States: 289–301. doi :10.1172/JCI12539 . ISSN 0021-9738 . PMC 203027 PMID 11457882 . ^ Li Y, 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). United States: F1129–39. doi :10.1152/ajprenal.00131.2001 . ISSN 0363-6127 . PMID 11997330 . ^ 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). UNITED STATES: 29539–46. doi :10.1074/jbc.M004961200 ISSN 0021-9258 . PMID 10893422 . ^ Hwang JI, 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). UNITED STATES: 16632–7. doi :10.1074/jbc.M001410200 ISSN 0021-9258 . PMID 10748023 .
Yun CH, Oh S, Zizak M, et al. (1997). "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. Bibcode :1997PNAS...94.3010Y . doi :10.1073/pnas.94.7.3010 PMC 20313 PMID 9096337 . Reczek D, Berryman M, Bretscher A (1998). "Identification of EBP50: A PDZ-containing phosphoprotein that associates with members of the ezrin-radixin-moesin family" . J. Cell Biol . 139 (1): 169–79. doi :10.1083/jcb.139.1.169 . PMC 2139813 PMID 9314537 . Yun CH, Lamprecht G, Forster DV, Sidor A (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. doi :10.1074/jbc.273.40.25856 PMID 9748260 . Imai K, Sarker AH, Akiyama K, et al. (1999). "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. doi :10.1016/S0378-1119(98)00485-5 . PMID 9831664 . Zizak M, Lamprecht G, Steplock D, et al. (1999). "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. doi :10.1074/jbc.274.35.24753 PMID 10455146 . Hwang JI, Heo K, Shin KJ, et al. (2000). "Regulation of phospholipase C-beta 3 activity by Na+/H+ exchanger regulatory factor 2" . J. Biol. Chem . 275 (22): 16632–7. doi :10.1074/jbc.M001410200 PMID 10748023 . Sun F, Hug MJ, Lewarchik CM, et al. (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. doi :10.1074/jbc.M004961200 PMID 10893422 . Kanai F, Marignani PA, Sarbassova D, et al. (2001). "TAZ: a novel transcriptional co-activator regulated by interactions with 14-3-3 and PDZ domain proteins" . EMBO J . 19 (24): 6778–91. doi :10.1093/emboj/19.24.6778 . PMC 305881 PMID 11118213 . Reczek D, Bretscher A (2001). "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. doi :10.1083/jcb.153.1.191 . PMC 2185518 PMID 11285285 . Takeda T, McQuistan T, Orlando RA, Farquhar MG (2001). "Loss of glomerular foot processes is associated with uncoupling of podocalyxin from the actin cytoskeleton" . J. Clin. Invest . 108 (2): 289–301. doi :10.1172/JCI12539 . PMC 203027 PMID 11457882 . Yun CC, Chen Y, Lang F (2002). "Glucocorticoid activation of Na(+)/H(+) exchanger isoform 3 revisited. The roles of SGK1 and NHERF2" . J. Biol. Chem . 277 (10): 7676–83. doi :10.1074/jbc.M107768200 PMID 11751930 . DeMarco SJ, Chicka MC, Strehler EE (2002). "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. doi :10.1074/jbc.M111616200 PMID 11786550 . Ingraffea J, Reczek D, Bretscher A (2002). "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. doi :10.1078/0171-9335-00218 . PMID 11893083 . Kim JH, Lee-Kwon W, Park JB, et al. (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. doi :10.1074/jbc.M200835200 PMID 11948184 . Li Y, Li J, Straight SW, Kershaw DB (2002). "PDZ domain-mediated interaction of rabbit podocalyxin and Na(+)/H(+) exchange regulatory factor-2". Am. J. Physiol. Renal Physiol . 282 (6): F1129–39. doi :10.1152/ajprenal.00131.2001 . PMID 11997330 . Mahon MJ, Donowitz M, Yun CC, Segre GV (2002). "Na(+)/H(+ ) exchanger regulatory factor 2 directs parathyroid hormone 1 receptor signalling". Nature . 417 (6891): 858–61. Bibcode :2002Natur.417..858M . doi :10.1038/nature00816 . PMID 12075354 . S2CID 4379134 . Sitaraman SV, Wang L, Wong M, et al. (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. doi :10.1074/jbc.M202522200 PMID 12080047 . Lamprecht G, Heil A, Baisch S, et al. (2002). "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. doi :10.1021/bi0259103 . PMID 12369822 .
Overview of all the structural information available in the PDB for UniProt : Q15599 PDBe-KB . This article incorporates text from the United States National Library of Medicine , which is in the public domain .
PDB gallery
2he4 : The crystal structure of the second PDZ domain of human NHERF-2 (SLC9A3R2) interacting with a mode 1 PDZ binding motif
2ocs : The crystal structure of the first PDZ domain of human NHERF-2 (SLC9A3R2)
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