Na(+)/H(+) exchange regulatory cofactor NHE-RF1 (SLC9A3R1)
The protein contains 358 amino acids for an estimated molecular weight of 38868 Da.
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. Necessary for recycling of internalized ADRB2. Was first known to play a role in the regulation of the activity and subcellular location of SLC9A3. Necessary for cAMP-mediated phosphorylation and inhibition of SLC9A3. May enhance Wnt signaling. May participate in HTR4 targeting to microvilli (By similarity). Involved in the regulation of phosphate reabsorption in the renal proximal tubules. Involved in sperm capacitation. May participate in the regulation of the chloride and bicarbonate homeostasis in spermatozoa. (updated: Oct. 10, 2018)
Protein identification was indicated in the following studies:
- Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
This protein is annotated as membranous in UniProt.
No binding partner found
Biological Process
Actin cytoskeleton organization
Adenylate cyclase-activating dopamine receptor signaling pathway
Auditory receptor cell stereocilium organization
Bile acid secretion
CAMP-mediated signaling
Cellular phosphate ion homeostasis
Cerebrospinal fluid circulation
Cilium organization
Establishment of epithelial cell apical/basal polarity
Establishment of Golgi localization
Gamma-aminobutyric acid import
Gland morphogenesis
Glutathione transport
Import across plasma membrane
Maintenance of epithelial cell apical/basal polarity
Microvillus assembly
Morphogenesis of an epithelium
Negative regulation of canonical Wnt signaling pathway
Negative regulation of cell migration
Negative regulation of cell population proliferation
Negative regulation of ERK1 and ERK2 cascade
Negative regulation of mitotic cell cycle
Negative regulation of phosphatidylinositol 3-kinase signaling
Negative regulation of platelet-derived growth factor receptor signaling pathway
Negative regulation of protein kinase B signaling
Negative regulation of sodium:proton antiporter activity
Nuclear migration
Phospholipase C-activating dopamine receptor signaling pathway
Plasma membrane organization
Positive regulation of intrinsic apoptotic signaling pathway
Positive regulation of ion transmembrane transport
Protein localization to plasma membrane
Protein-containing complex assembly
Regulation of cell shape
Regulation of cell size
Regulation of excretion
Regulation of protein kinase activity
Regulation of sodium:proton antiporter activity
Renal absorption
Renal phosphate ion absorption
Renal sodium ion transport
Sensory perception of sound
Transport across blood-brain barrier
Wnt signaling pathway
Cellular Component
Actin cytoskeleton
Apical plasma membrane
Brush border membrane
Cell periphery
Cytoplasm
Endomembrane system
Extracellular exosome
Filopodium
Membrane
Membrane raft
Microvillus
Microvillus membrane
Obsolete cell
Perinuclear region of cytoplasm
Plasma membrane protein complex
Ruffle
Sperm midpiece
Stereocilium tip
Vesicle
Molecular Function
Beta-2 adrenergic receptor binding
Beta-catenin binding
Chloride channel regulator activity
Dopamine receptor binding
Gamma-aminobutyric acid transmembrane transporter activity
Growth factor receptor binding
Molecular adaptor activity
Myosin II binding
PDZ domain binding
Phosphatase binding
Protein N-terminus binding
Protein self-association
Protein-containing complex binding
Protein-membrane adaptor activity
Signaling receptor binding
Type 2 metabotropic glutamate receptor binding
Type 3 metabotropic glutamate receptor binding
The reference OMIM entry for this protein is 604990
Solute carrier family 9, member 3, regulator 1; slc9a3r1
Sodium/hydrogen exchanger regulatory factor 1; nherf1
Erm-binding phosphoprotein, 50-kd; ebp50
DESCRIPTION
NHERF1 is a cytoplasmic adaptor protein that recruits various signaling proteins, cellular receptors, ion transporters, and other proteins to the plasma membrane of epithelia and other cell types (Wang et al., 2008).CLONING
Members of the ezrin (VIL2; 123900)-radixin (RDX; 179410)-moesin (MSN; 309845) (ERM) family of membrane-cytoskeletal linking proteins have N- and C-terminal domains that associate with the plasma membrane and the actin cytoskeleton, respectively. Using affinity chromatography with the immobilized N termini of ERM proteins to capture ERM-binding proteins in membrane, Reczek et al. (1997) isolated polypeptides from placenta that migrated at 50 kD after phosphatase treatment. By micropeptide sequence analysis of these polypeptides, followed by searching an EST database, they identified a cDNA encoding SLC9A3R1, which they called EBP50. The predicted 358-amino acid SLC9A3R1 protein shares high homology with the rabbit sodium/hydrogen exchanger regulatory factor (Nherf) and contains 2 N-terminal PDZ domains of approximately 90 amino acids. SDS-PAGE and blot overlay analyses showed that recombinant SLC9A3R1 is expressed as a 50-kD protein. Immunoblot analysis detected SLC9A3R1 expression in all tissues tested except heart and skeletal muscle, with the most abundant expression detected in tissues with polarized epithelia, including kidney, small intestine, placenta, and liver. Immunofluorescence microscopy demonstrated that SLC9A3R1 colocalizes with actin in areas with abundant microvilli in placenta and intestinal brush border; the pattern of SLC9A3R1 staining was very similar to that seen for ezrin. Immunoprecipitation analysis showed that SLC9A3R1 and ezrin associate in vivo. Murthy et al. (1998) isolated SLC9A3R1, which they termed NHERF, by screening a fetal frontal cortex cDNA library using a yeast 2-hybrid system with merlin (NF2; 607379) as bait. Northern blot analysis revealed that SLC9A3R1 was ubiquitously expressed, with highest levels in kidney, liver, and pancreas. Immunocytochemistry demonstrated that SLC9A3R1 colocalized with moesin at the ruffling membrane, microvilli, and filopodia in HeLa cells. By deletion and mutation analyses, Murthy et al. (1998) showed that SLC9A3R1 associated with the N terminus but not with the C terminus of merlin. SLC9A3R1 was also shown to bind to moesin and radixin at the N terminus, the region with the most homology to merlin. Bonilha and Rodriguez-Boulan (2001) identified EBP50 and SAP97 (601014) as binding partners for ezrin, an actin-binding protein crucial for morphogenesis of apical microvilli and basolateral infoldings in retinal pigment epithelial (RPE) cells. Immunofluorescence microscopy detected a polarized distribution of EBP50 at apical microvilli and of SAP97 at the basolateral surface of RPE cells, which overlapped with ezrin.GENE FUNCTION
PTEN (601728) is a dual-specificity phosphatase that is targeted to the plasma membrane and antagonizes the PI3 kinase (PI3K, see PIK3CA 171834)/AKT (AKT1; 164730) signaling cascade involved in cell survival, growth, proliferation and other processes. Takahashi et al. (2006) found that PTEN interacts with NHERF1 and NHERF2 (SLC9A3R2; 606553) adaptor proteins. A ternary complex was formed between PTEN, NHERF proteins and PDGFR (see PDGFRA, 173490), resulting in activation of the PI3K pathway upon PDGF (see PDGFA, 173430) binding. In Nherf1 -/- mouse embryonic fibroblasts, activation ... More on the omim web site
June 30, 2020: Protein entry updated
Automatic update: OMIM entry 604990 was added.
Oct. 19, 2018: Additional information
Initial protein addition to the database. This entry was referenced in Bryk and co-workers. (2017).