Sodium-hydrogen exchange regulatory cofactor 2

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]

SLC9A3R2
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2D11, 2HE4, 2OCS, 4P0C
Identifiers
Aliases	SLC9A3R2, E3KARP, NHE3RF2, NHERF-2, NHERF2, OCTS2, SIP-1, SIP1, TKA-1, Sodium-hydrogen exchange regulatory cofactor 2, SLC9A3 regulator 2
External IDs	OMIM: 606553; MGI: 1890662; HomoloGene: 56962; GeneCards: SLC9A3R2; OMA:SLC9A3R2 - orthologs
Gene location (Human) Chr. Chromosome 16 (human)[1] Band 16p13.3 Start 2,025,356 bp[1] End 2,039,026 bp[1]
Gene location (Mouse) Chr. Chromosome 17 (mouse)[2] Band 17|17 A3.3 Start 24,858,260 bp[2] End 24,869,301 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in apex of heart right lung right lobe of liver upper lobe of left lung right lobe of thyroid gland right auricle right coronary artery left lobe of thyroid gland left uterine tube left coronary artery Top expressed in external carotid artery aortic valve motor neuron internal carotid artery ascending aorta right lung right lung lobe carotid body left lung right ventricle More reference expression data BioGPS More reference expression data
Gene ontology Molecular function molecular adaptor activity phosphatase binding beta-catenin binding signaling receptor binding protein C-terminus binding protein binding cadherin binding Cellular component plasma membrane extracellular exosome apical plasma membrane membrane endomembrane system nucleus focal adhesion Biological process protein-containing complex assembly Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 9351 65962 Ensembl ENSG00000065054 ENSMUSG00000002504 UniProt Q15599 Q9JHL1 RefSeq (mRNA) NM_001130012 NM_001252073 NM_001252075 NM_001252076 NM_004785 NM_023055 NM_023449 NM_001357796 RefSeq (protein) NP_001123484 NP_001239002 NP_001239004 NP_001239005 NP_004776 NP_075542 NP_075938 NP_001344725 Location (UCSC) Chr 16: 2.03 – 2.04 Mb Chr 17: 24.86 – 24.87 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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.^[7]

Interactions

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] and PLCB3.^[18]

See also

• Solute carrier family

References

1. GRCh38: Ensembl release 89: ENSG00000065054 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000002504 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. 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.
6. 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.
7. "Entrez Gene: SLC9A3R2 solute carrier family 9 (sodium/hydrogen exchanger), member 3 regulator 2".
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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.
18. 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.

Further reading

• 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.

External links

• Overview of all the structural information available in the PDB for UniProt: Q15599 (Na(+)/H(+) exchange regulatory cofactor NHE-RF2) at the PDBe-KB.

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