Affinage

NHERF1

Na(+)/H(+) exchange regulatory cofactor NHE-RF1 · UniProt O14745

Length
358 aa
Mass
38.9 kDa
Annotated
2026-06-10
100 papers in source corpus 45 papers cited in narrative 45 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NHERF1 (EBP50) is a two-PDZ-domain scaffolding phosphoprotein that organizes apical membrane signaling and transport complexes in polarized epithelia by physically coupling membrane proteins to the actin cytoskeleton through activated ERM proteins (PMID:9314537, PMID:9660814). Its C-terminal EB region binds the N-terminal domains of ezrin and moesin, an interaction that is mutually exclusive with the ezrin intramolecular N/C-ERMAD clamp and therefore requires prior ezrin activation to expose the binding site (PMID:9660814), and that is required for microvillar assembly together with a functional PDZ1 domain (PMID:20937695, PMID:20237154). NHERF1 adopts an autoinhibited head-to-tail conformation in which the EB region occludes PDZ2 and masks ligand binding; ezrin association relieves this intramolecular block to license PDZ-mediated interactions (PMID:17242191, PMID:20042604). Through its PDZ domains NHERF1 assembles complexes containing the Na+/H+ exchanger NHE3, the renal sodium-phosphate cotransporter Npt2a, CFTR, Mrp2, and store-operated TRPC4/5 channels, and tethers them to ezrin-anchored kinases to control transporter trafficking and activity (PMID:9792717, PMID:10821685, PMID:12169661, PMID:20404332, PMID:27994151). A central function is hormonal signal transduction: NHERF1 is obligatory for cAMP/PKA-mediated and dopamine-mediated regulation of NHE3 and Npt2a, and forms an obligate Npt2a-NHERF1-ezrin ternary complex in which ezrin-anchored PKA phosphorylates NHERF1 to release Npt2a and inhibit phosphate transport (PMID:12586353, PMID:20200151, PMID:22628548). Reversible phosphorylation tunes this scaffolding: phosphorylation of PDZ1 Ser77 (by PKC/dopamine signaling) attenuates binding to β2-AR, PDGFR, CFTR, and Npt2a (PMID:17895247, PMID:20200151), while PTH drives dynamic Ser290 cycling between PP1α-mediated dephosphorylation and GRK6A-dependent rephosphorylation that is essential for PTH-sensitive phosphate transport (PMID:30696771), and Cdc2/CyclinB phosphorylation at Ser279/Ser301 governs actin reorganization and cytokinesis (PMID:23775624). NHERF1 also restrains GPCR internalization and desensitization, blocking β-arrestin2 binding and slowing arrestin recruitment to PTH1R and stabilizing receptors such as the kappa-opioid receptor (PMID:12920119, PMID:17884816, PMID:19188335, PMID:12004055). Beyond epithelial transport, NHERF1 modulates Wnt/β-catenin signaling and EGFR-driven epithelial-mesenchymal transition, and stabilizes partner proteins including BECN1 and GPER against ubiquitin-dependent degradation (PMID:12830000, PMID:20802536, PMID:21822312, PMID:26218645, PMID:27448983).

Mechanistic history

Synthesis pass · year-by-year structured walk · 28 steps
  1. 1997 High

    Established NHERF1/EBP50 as a physiological ezrin-binding PDZ protein, defining its core role as a physical link between membrane proteins and the apical actin cytoskeleton.

    Evidence Affinity chromatography, Co-IP from placental microvilli, and immunolocalization with actin/ezrin

    PMID:9314537

    Open questions at the time
    • Did not define which membrane cargoes the PDZ domains bind
    • Did not establish regulation of the ezrin interaction
  2. 1998 High

    Showed that NHERF1 binds only the activated (open) form of ezrin, establishing regulated ERM activation as a gate controlling scaffold assembly.

    Evidence Blot overlay and in-solution binding with ezrin/EBP50 truncation mutants and competition assays

    PMID:9660814

    Open questions at the time
    • Did not show the physiological trigger that opens ezrin in cells
  3. 1998 High

    Demonstrated NHERF1 simultaneously binds NHE3 and ezrin to position PKA near NHE3, defining its function in hormonally regulated transporter inhibition.

    Evidence Reciprocal Co-IP, in vivo phosphorylation, and intracellular pH Na+/H+ exchange assays

    PMID:9792717

    Open questions at the time
    • Did not separate the contributions of the PDZ versus ERM-binding regions to PKA-mediated inhibition
  4. 2000 High

    Established that both the NHE3-PDZ and the ezrin-ERM interactions are jointly required for cAMP-dependent NHE3 inhibition, proving the scaffold itself enables kinase access to substrate.

    Evidence Truncated NHERF (1-325) lacking the ezrin-binding domain in PS120/NHE3 cells with phosphorylation and activity assays

    PMID:10821685

    Open questions at the time
    • Did not address whether other transporters use the same dual-requirement logic
  5. 2000 High

    Extended the scaffolding repertoire to store-operated channels by showing PDZ1 binds Trp4/Trp5 and PLC-β isozymes, linking signaling enzymes to the cytoskeleton.

    Evidence Yeast two-hybrid, GST pulldown, and Co-IP from HEK293 and mouse brain

    PMID:10980202

    Open questions at the time
    • Did not define functional consequences on channel gating at this stage
  6. 2002 High

    Genetic knockout established a non-redundant, cargo-specific role: NHERF1 is required for apical retention of Npt2a but not NHE3, explaining renal phosphate wasting.

    Evidence Nherf1 knockout mouse with brush-border fractionation, immunocytochemistry, and urine electrolytes

    PMID:12169661

    Open questions at the time
    • Did not explain the molecular basis of selectivity over NHERF2
  7. 2002 High

    Showed NHERF1 controls GPCR trafficking, protecting the kappa-opioid receptor from agonist-induced downregulation by promoting recycling.

    Evidence Co-IP in CHO cells, radioligand binding, flow cytometry, and receptor/NHERF1 domain mutagenesis

    PMID:12004055

    Open questions at the time
    • Did not generalize the recycling mechanism to other GPCRs
  8. 2003 High

    Defined NHERF1 as the non-redundant transducer of cAMP/PKA signals to NHE3 in native renal membranes, showing NHERF2 cannot compensate.

    Evidence Brush-border vesicles from Nherf1-/- mice with Na+/H+ exchange and NHE3 phosphorylation assays

    PMID:12586353

    Open questions at the time
    • Did not map the NHERF1 phosphosites driving this isoform specificity
  9. 2003 High

    Extended GPCR regulation to PTH1R, showing NHERF1 blocks arrestin-independent receptor internalization in an actin- and ERM-dependent manner.

    Evidence Live-cell confocal imaging of fluorescent PTH1R, dominant-negatives, and actin depolymerization

    PMID:12920119

    Open questions at the time
    • Did not resolve how NHERF1 selects between endocytic pathways
  10. 2007 High

    Provided the regulatory mechanism for cargo binding: NHERF1 is autoinhibited by an EB-PDZ2 head-to-tail interaction that ezrin binding relieves, distinguishing it from NHERF2.

    Evidence In vitro binding, mutagenesis, and Co-IP in polarized epithelial cells with PTEN/β-catenin ligands

    PMID:17242191

    Open questions at the time
    • Did not provide atomic structural detail of the autoinhibited state
  11. 2007 High

    Mapped Ser77 in PDZ1 as a phosphorylation switch that attenuates binding to β2-AR, PDGFR, CFTR, and Npt2a, linking kinase signaling to scaffold disassembly.

    Evidence Metabolic labeling, S77A/S77D mutagenesis, Co-IP, and confocal localization

    PMID:17895247

    Open questions at the time
    • Did not identify the physiological kinase acting on Ser77 at this stage
  12. 2007 High

    Quantified NHERF1 control of GPCR membrane dynamics, showing it reduces receptor diffusion and slows arrestin-dependent PTH1R internalization.

    Evidence FRAP, TIRF, image correlation spectroscopy, and live-cell imaging of β2AR/PTH1R

    PMID:17599914 PMID:17884816

    Open questions at the time
    • Did not establish the structural interface with arrestin
  13. 2009 High

    Determined the NMR structure of PDZ2-CT, revealing a helix-turn-helix subdomain allosterically coupled to PDZ2 and ezrin-released intramolecular contacts, and linked PDZ2 disease mutations to destabilization.

    Evidence NMR with SAXS/SANS constraints and R153Q/E225K mutagenesis

    PMID:20042604

    Open questions at the time
    • Did not capture the full-length autoinhibited conformation structurally
  14. 2009 High

    Generalized the scaffold-to-secretion paradigm, establishing NHERF1 as the obligatory linker for β2-AR stimulation of CFTR-dependent bicarbonate secretion in vivo.

    Evidence Nherf1-/-, Nherf2-/-, Pdzk1-/- mice with HCO3- secretion and colocalization measurements

    PMID:19221439

    Open questions at the time
    • Did not define the phosphoregulation of the β2-AR/CFTR complex
  15. 2009 High

    Defined NHERF1 as a desensitization brake forming a ternary complex with PTH1R and β-arrestin2 and preventing PTH-induced Gαs dissociation.

    Evidence Adenylyl cyclase assays, inducible NHERF1, shRNA, Co-IP, and FRET

    PMID:19188335

    Open questions at the time
    • Did not resolve the kinetic basis of arrestin exclusion
  16. 2009 High

    Extended scaffold function to immune signaling, showing the ezrin-EBP50-PAG complex positions PKA near Csk to mediate cAMP inhibition of IL-2 production in T cells.

    Evidence KD determination (58 nM), peptide competition (EBP50pep) in T cells, and IL-2 assays

    PMID:19857202

    Open questions at the time
    • Did not test whether other ERM-anchored kinase complexes share this architecture
  17. 2010 High

    Established a structural cell-biology role: NHERF1 is necessary for microvillar assembly, requiring functional PDZ1 and the ezrin-binding site, and is inactivated by Cdc2/PKC phosphomimetics.

    Evidence RNAi with rescue by phospho-mutant EBP50 and microvilli quantification

    PMID:20237154 PMID:20937695

    Open questions at the time
    • Did not fully separate the microvillar and transport-scaffolding functions
  18. 2010 Medium

    Connected NHERF1 to oncogenic signaling, showing it restrains Wnt/β-catenin via Frizzled binding and that loss enhances Wnt-dependent mammary proliferation.

    Evidence Co-IP, reporter assays, and NHERF1 knockout mouse mammary gland analysis

    PMID:20802536

    Open questions at the time
    • Single lab; did not define which Frizzled receptors are bound
    • Mechanism connecting Frizzled binding to β-catenin levels not resolved
  19. 2010 High

    Demonstrated post-transcriptional control of canalicular transport, showing NHERF1 binds Mrp2 and is required for its membrane expression and glutathione-dependent bile flow.

    Evidence Co-IP with PDZ-motif mutagenesis and Nherf1-/- mice with bile flow/glutathione assays

    PMID:20404332

    Open questions at the time
    • Did not define the degradation pathway stabilized by NHERF1
  20. 2010 High

    Identified the kinase context for Ser77, showing dopamine signaling phosphorylates PDZ1 Ser77 to release Npt2a and inhibit renal phosphate transport.

    Evidence Co-IP, phosphate transport in WT/KO cells, cAMP/PKC assays, adenoviral rescue, and 32P labeling

    PMID:20200151

    Open questions at the time
    • Did not integrate dopamine and PTH phosphoregulation of the same scaffold
  21. 2010 Medium

    Documented dynamic, arrestin-dependent recruitment, showing NHERF1 switches from direct P2Y12R binding to arrestin-scaffolded recruitment upon agonist stimulation.

    Evidence Co-IP, PDZ-motif mutagenesis, and internalization assays

    PMID:20656684 PMID:21325834 PMID:22610101

    Open questions at the time
    • Single lab for P2Y12R; mechanism of the binding mode switch not structurally defined
  22. 2012 High

    Resolved the core phosphate-regulatory mechanism: NHERF1 forms an obligate Npt2a-ezrin ternary complex in which ezrin-anchored PKA phosphorylates NHERF1 to release Npt2a, and disease mutations stabilize an inactive PKA-refractory conformation.

    Evidence In vitro kinase assays, disease-variant mutagenesis, compensatory mutagenesis rescue, and phosphate transport assays

    PMID:22628548

    Open questions at the time
    • Did not identify the specific NHERF1 residue phosphorylated to disassemble the complex
  23. 2013 Medium

    Defined cell-cycle control of the cytoskeletal function, showing Cdc2/CyclinB phosphorylation of Ser279/Ser301 regulates actin reorganization and cytokinesis.

    Evidence Phosphodeficient/phosphomimetic mutants in MDA-MB-231 with F-actin, DNA content, and adhesion assays plus knockdown rescue

    PMID:23775624

    Open questions at the time
    • Single lab; direct Cdc2 phosphorylation of these sites in vivo not fully established
  24. 2014 Medium

    Established NHERF1 as a determinant of epithelial polarity and lumen formation, anchoring PTEN at the membrane and restraining nuclear β-catenin, via a moesin-dependent mechanism.

    Evidence 3D gland morphogenesis with siRNA and domain-mutant expression

    PMID:24862762

    Open questions at the time
    • Single lab; did not reconcile the moesin versus ezrin dependence with earlier ezrin-centric data
  25. 2015 High

    Defined a gating role at TRPC4/5 channels, showing PIP2-triggered NHERF dissociation from the channel C-terminus is a prerequisite for DAG sensitivity.

    Evidence PDZ-motif mutagenesis, PKC inhibition, electrophysiology, and dynamic Co-IP

    PMID:27994151

    Open questions at the time
    • Did not define the upstream signal coordinating NHERF dissociation in vivo
  26. 2015 Medium

    Expanded NHERF1 function to controlling partner protein stability, showing it stabilizes BECN1 against ubiquitin-dependent degradation to promote autophagy and binds α-actinin-4 to promote its ubiquitination.

    Evidence Co-IP, ubiquitination assays, domain-deletion mutagenesis, and autophagy/F-actin readouts

    PMID:26218645 PMID:26432781

    Open questions at the time
    • Single-lab findings; the opposing stabilizing/destabilizing logic across partners not mechanistically unified
  27. 2019 High

    Resolved the full PTH phosphocycle, showing Ser290 is dephosphorylated by NHERF1-docked PP1α and rephosphorylated by a GRK6A cascade to drive PTH-sensitive phosphate transport.

    Evidence MS phosphosite mapping, Ala mutagenesis, PP1 inhibition, FLIM, and HDX-MS conformational analysis

    PMID:30696771

    Open questions at the time
    • Did not define the full GRK6A kinase cascade composition
  28. 2019 Medium

    Identified NHERF1 as a viral oncoprotein target, showing HPV E6 directs its E6AP-dependent degradation via the EB domain to activate Wnt/β-catenin signaling.

    Evidence E6AP and NHERF1 domain mutagenesis, proteasome inhibition, and Wnt reporter assays

    PMID:31002735

    Open questions at the time
    • Single lab; in vivo relevance during HPV-driven transformation not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple phosphorylation switches (Ser77, Ser290, Ser279/Ser301), the autoinhibited conformation, and ERM activation are integrated to coordinate distinct cargoes in a single cell remains unresolved.
  • No unified model of combinatorial phosphocode-to-cargo selectivity
  • No full-length structure of NHERF1 in its autoinhibited versus ezrin-activated states
  • Mechanism distinguishing stabilizing versus destabilizing effects on partner proteins unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 6 GO:0098772 molecular function regulator activity 5 GO:0008092 cytoskeletal protein binding 4
Localization
GO:0005856 cytoskeleton 5 GO:0005886 plasma membrane 5 GO:0005777 peroxisome 1
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-382551 Transport of small molecules 5 R-HSA-9609507 Protein localization 5
Partners
CFTREZRMRP2NHE3NPT2APP1ΑPTH1RTRPC5
Complex memberships
Npt2a-NHERF1-ezrin ternary complexPDZK1-EBP50-ezrin microvillar complexPTH1R-NHERF1-β-arrestin2 ternary complexezrin-EBP50-PAG T-cell scaffold

Evidence

Reading pass · 45 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 EBP50/NHERF1 was identified as a PDZ-containing phosphoprotein that directly binds the N-terminal domains of ezrin and moesin (N-ERMADs) via affinity chromatography. It colocalizes with actin and ezrin in apical microvilli of epithelial cells and can be co-immunoprecipitated with ezrin from human placental microvilli, establishing it as a physiologically relevant ezrin-binding protein that links membrane proteins to the actin cytoskeleton through its PDZ domains. Affinity chromatography, co-immunoprecipitation, immunofluorescence microscopy, immunoelectron microscopy, recombinant protein binding assays The Journal of cell biology High 9314537
1998 The C-terminal 30 residues of EBP50 are sufficient to bind ezrin residues 1-286, but EBP50 does not bind full-length ezrin because the EBP50-binding site is masked by intramolecular N/C-ERMAD association. Binding of EBP50 and the C-ERMAD to the ezrin N-terminal domain is mutually exclusive, with C-ERMAD having higher affinity, establishing a model of regulated ezrin activation to expose the EBP50 binding site. Blot overlays, in-solution binding assays, truncation/deletion mutagenesis of EBP50 and ezrin The Journal of biological chemistry High 9660814
1998 NHERF/EBP50 and the related E3KARP function as scaffold adapters that bind both NHE3 and ezrin simultaneously, linking NHE3 to ezrin to localize PKA type II near NHE3 and enable PKA-mediated phosphorylation and inhibition of NHE3. NHERF is a phosphoprotein under basal conditions but does not change phosphorylation state after cAMP treatment; E3KARP is not phosphorylated. Co-immunoprecipitation, in vivo phosphorylation studies, intracellular pH measurement of Na+/H+ exchange activity, cAMP analog pharmacology The Journal of biological chemistry High 9792717
1999 EBP50 PDZ domain 1 binds CFTR and PDZ domain 2 binds YAP65, localizing YAP65 to the apical membrane of airway epithelial cells. The EBP50-YAP65 interaction recruits the nonreceptor tyrosine kinase c-Yes into apical EBP50 protein complexes. Mutant YAP65 lacking the EBP50-interaction motif is mislocalized when expressed in airway epithelial cells. Co-immunoprecipitation, immunofluorescence, expression of mutant proteins, confocal microscopy The Journal of cell biology High 10562288
2000 NHERF1 PDZ domain 1 interacts with murine Trp4, Trp5, and phospholipase C-β1 and β2. Co-immunoprecipitation confirmed the Trp4-NHERF1 and PLC-β1-NHERF1 association in HEK293 cells expressing Trp4 and in adult mouse brain, establishing that NHERF1 scaffolds store-operated channels with PLC isozymes and links them to the actin cytoskeleton via ERM proteins. Yeast two-hybrid, GST pulldown, co-immunoprecipitation from HEK293 cells and mouse brain lysates The Journal of biological chemistry High 10980202
2000 NHERF associations with both NHE3 (via PDZ domains) and ezrin (via C-terminal ERM-binding domain) are both required for cAMP-mediated phosphorylation and inhibition of NHE3. Truncated NHERF lacking the ezrin-binding domain (NHERF 1-325) bound NHE3 but failed to support cAMP-mediated NHE3 inhibition or NHE3 phosphorylation, demonstrating that the NHERF-ezrin scaffold is essential for PKA access to NHE3. Stable transfection of truncated NHERF constructs in PS120/NHE3 cells, co-immunoprecipitation, Na+/H+ exchange activity assays, in vivo phosphorylation Biochemistry High 10821685
2001 NHERF-1 PDZ domains can oligomerize; oligomerization of NHERF-1 (but not NHERF-2) is facilitated by ligand binding to its PDZ domains (e.g., β2-adrenergic receptor or PDGFR C-termini). Phosphomimetic mutation S289D enhances NHERF-1 homo- and hetero-oligomerization, while S289A reduces it. NHERF-1 and NHERF-2 form homo- and hetero-oligomers in cells. Purified PDZ domain association assays, co-immunoprecipitation with differentially tagged constructs, phosphomimetic/phosphodeficient mutagenesis Biochemistry High 11456497
2002 Targeted disruption of NHERF-1 in mice causes internalization of the renal sodium-phosphate cotransporter Npt2 away from the brush-border membrane, resulting in renal phosphate wasting. NHE3 localization at the apical surface is unaffected, demonstrating a unique and specific role for NHERF-1 in apical targeting/retention of Npt2 that is not shared by NHERF-2. Gene knockout mouse model, immunocytochemistry, brush-border membrane fractionation, urine electrolyte analysis Proceedings of the National Academy of Sciences of the United States of America High 12169661
2002 EBP50/NHERF1 PDZ domain 1 binds the human kappa opioid receptor (hKOR) C-terminus; agonist treatment enhances this association. NHERF1 expression (requiring its ERM-binding domain) blocks U50,488H-induced hKOR down-regulation by increasing receptor recycling rate, without affecting agonist binding, G-protein signaling, desensitization, or internalization. C-terminal mutations in hKOR that prevent NHERF1 binding abolish this protective effect. Co-immunoprecipitation in CHO cells, radioligand binding, flow cytometry, mutagenesis of receptor C-terminus and NHERF1 domains The Journal of biological chemistry High 12004055
2003 NHERF-1 uniquely transduces cAMP signals that inhibit NHE3 in mouse renal brush-border membranes. In NHERF-1(-/-) BBMs, cAMP-activated PKA failed to inhibit NHE3 activity and failed to phosphorylate NHE3, despite normal levels of NHE3, NHERF-2, PKA, and ezrin, demonstrating that NHERF-2 cannot compensate for NHERF-1 in this signaling context. Isolated brush-border membrane vesicles from NHERF-1 knockout mice, Na+/H+ exchange activity assays, NHE3 phosphorylation by immunoprecipitation FEBS letters High 12586353
2003 NHERF1 (EBP50) inhibits activation-independent, arrestin-independent PTH1R internalization. In cells lacking NHERF1, PTH antagonists (PTH 7-34, PTH 7-84) induce dynamin-dependent but β-arrestin-independent PTH1R endocytosis. NHERF1 expression blocked this endocytosis; dominant-negative NHERF1 conferred internalization sensitivity to cells normally expressing NHERF1. Both the PTH1R PDZ-binding motif and NHERF1 ERM domain are required; actin polymerization is necessary for NHERF1-mediated retention. Radioligand binding, live-cell confocal microscopy of fluorescent PTH1R, dominant-negative constructs, PDZ-binding motif mutagenesis, actin depolymerization experiments The Journal of biological chemistry High 12920119
2003 EBP50 interacts with β-catenin through its C-terminal PDZ domain both in vitro and in vivo. Over-expression of EBP50 enhances β-catenin/TCF-dependent transcription in a dose-dependent manner in hepatocellular carcinoma and colorectal cancer cells, but only when β-catenin is already stabilized. Protein interaction screening, GST pulldown, co-immunoprecipitation, luciferase reporter assays, Northern/RT-PCR, immunohistochemistry Hepatology Medium 12830000
2003 NHERF-1 is required for PTH regulation of Na-K ATPase in renal proximal tubule cells. Wild-type NHERF-1 supported PTH-induced inhibition of Na-K ATPase and increased serine phosphorylation of its α-subunit; NHERF-1 lacking the ezrin-binding domain (1-325) blunted α-subunit phosphorylation and reversed the response to stimulation. Basal sodium-dependent phosphate transport was lower in cells expressing the truncation. Stable transfection of NHERF-1 truncation mutants in opossum kidney cells, ouabain-sensitive ATPase activity assays, phosphorylation assays Journal of the American Society of Nephrology Medium 12819230
2004 Podocalyxin activates RhoA and induces apical actin redistribution through NHERF (NHERF2) and ezrin in MDCK cells. Full-length podocalyxin, but not a mutant lacking the NHERF binding site, connects to actin, activates RhoA, and redistributes actin apically. Ezrin was found to bind directly to the juxtamembrane cytoplasmic region of podocalyxin. Stable cell lines expressing full-length or PDZ-binding-deficient podocalyxin, pulldown assays, RhoA activity assays, immunofluorescence Journal of the American Society of Nephrology Medium 15339978
2004 NHERF-1/EBP50 PDZ domain 1 directly binds the hKOR C-tail (but not μ or δ opioid receptor C-tails), and this interaction enhances NHERF-1 oligomerization. In OK cells expressing endogenous NHERF-1, kappa opioid receptor stimulation increases Na+/H+ exchange in a pertussis toxin-independent manner; in OKH cells (NHERF-1-deficient), this effect is absent and restored by NHERF-1 transfection, establishing that NHERF-1 mediates KOR-stimulated NHE3 activity. GST pulldown with purified proteins, co-immunoprecipitation, intracellular pH/Na+/H+ exchange assays, NHERF-1 stable transfection in OKH cells The Journal of biological chemistry High 15070904
2005 NHERF-1 inhibits agonist-induced internalization of the adrenomedullin AM2 receptor complex (CRLR/RAMP3) by tethering it to the actin cytoskeleton via the ERM-binding domain of NHERF-1. NHERF-1 interaction is RAMP3-isoform specific (not RAMP1 or RAMP2). RAMP3 and NHERF-1 interact via a PDZ type I domain on NHERF-1. siRNA knockdown of RAMP3 or NHERF-1 in human proximal tubule cells enabled agonist-induced internalization. Co-immunoprecipitation, overlay assays, mutational analysis, siRNA knockdown, internalization assays in HEK293T and primary proximal tubule cells The Journal of biological chemistry High 15805108
2007 NHERF1 adopts a head-to-tail autoinhibited conformation in which the C-terminal EB region binds the PDZ2 domain, masking both PDZ domains from interacting with ligands such as PTEN and β-catenin. Prior association of ezrin with the EB region disrupts this intramolecular interaction, releasing PDZ domain accessibility. NHERF2 does not exhibit this regulatory conformation. In vitro binding assays, mutagenesis, co-immunoprecipitation, confocal microscopy in polarized epithelial cells Molecular and cellular biology High 17242191
2007 Phosphorylation of NHERF-1 PDZ1 domain at serine 77 attenuates its binding to physiological targets including β2-adrenergic receptor, PDGFR, CFTR, and Npt2a. Phosphatase inhibitors enhance NHERF-1 phosphorylation and inhibit its dimerization. S77A mutation abolishes PDZ1 phosphorylation and increases NHERF-1 localization at the cell periphery; S77D reduces colocalization with cortical actin. Metabolic labeling, phosphatase inhibitor treatment, mutagenesis (S77A/S77D), co-immunoprecipitation, confocal microscopy The Journal of biological chemistry High 17895247
2007 NHERF-1 and the actin cytoskeleton regulate the distribution and trafficking of GPCRs. NHERF-1 expression reduces diffusion of β2AR and PTH1R, forms receptor bundles along stress fibers for β2AR, and reduces ligand-induced internalization rate of PTH1R by slowing arrestin recruitment. CaSR does not interact with the cytoskeleton via NHERF-1. FRAP, TIRF microscopy, image correlation spectroscopy, live-cell confocal imaging of fluorescent receptors The Journal of biological chemistry High 17599914
2007 NHERF1 inhibits PTH1R endocytosis and delays PTH1R recycling. Both the PDZ-binding domain and MERM domain of NHERF1, as well as the PTH1R C-terminal PDZ recognition motif, are required for inhibition of endocytosis. NHERF1-mediated effects involve β-arrestin and dynamin. shRNA knockdown of NHERF1 in HEK-293 cells augmented PTH1R endocytosis. Radioligand binding, confocal microscopy of fluorescent PTH1R, tetracycline-inducible NHERF1 expression, PDZ-domain mutagenesis, shRNA knockdown The Journal of biological chemistry High 17884816
2009 NHERF1 is an obligatory linker for β2-adrenergic receptor stimulation of CFTR-dependent HCO3- secretion in mouse duodenum. NHERF1 ablation strongly reduced basal and FSK-stimulated HCO3- secretion and blocked β2-AR stimulation; colocalization of β2-AR and CFTR was reduced in NHERF1-null mice. NHERF2 confers inhibitory signals by coupling LPA receptor to CFTR. Knockout mouse models (Nherf1-/-, Nherf2-/-, Pdzk1-/-), HCO3- secretion measurements, laser microdissection/qPCR, immunofluorescence colocalization The Journal of clinical investigation High 19221439
2009 NHERF1 inhibits PTH1R desensitization by blocking β-arrestin2 binding to the receptor. NHERF1 prevents PTH-induced dissociation of PTH1R from Gαs. Both PDZ-binding and MERM domains of NHERF1 are required. NHERF1 forms a ternary complex with PTH1R and β-arrestin2 in cells; NHERF1 modulates the kinetics of β-arrestin2 recruitment to the PTH1R. Adenylyl cyclase activity assays, tetracycline-inducible NHERF1, shRNA knockdown, mutagenesis, co-immunoprecipitation, FRET imaging Molecular pharmacology High 19188335
2009 The NMR structure of the NHERF1 PDZ2-CT domain reveals weak intramolecular interactions between the disordered CT domain and the PDZ ligand binding site, and a novel helix-turn-helix subdomain allosterically coupled to PDZ2. Binding of ezrin releases these intramolecular domain-domain interactions as demonstrated by NMR and SANS. Disease-causing mutations R153Q and E225K in PDZ2 significantly reduce protein stability. High-resolution NMR, small-angle X-ray scattering (SAXS), small-angle neutron scattering (SANS), mutagenesis of disease variants The Journal of biological chemistry High 20042604
2009 EBP50/NHERF1, as part of the ezrin-EBP50-PAG scaffold in T cells, positions PKA type I near its substrate Csk at the TCR. The ezrin-EBP50 interaction has a KD of 58 nM. Disruption of the ezrin-EBP50 interaction by a competing peptide (EBP50pep) delocalizes ezrin, and reverses cAMP-mediated inhibition of IL-2 production, demonstrating a required role for EBP50 in cAMP immunomodulation in T cells. Binding kinetics (KD determination), peptide competition assays, T-cell loading with competing peptide, IL-2 production assays The Biochemical journal High 19857202
2010 EBP50/NHERF1 is necessary for microvillar assembly in epithelial cells. RNAi depletion of EBP50 reduces microvilli. This requires both a functional PDZ1 domain and the ezrin-binding site. Phosphomimetic mutations at Cdc2 or PKC phosphorylation sites render EBP50 nonfunctional in microvillar assembly. PKC activation causes EBP50 phosphorylation-dependent loss of microvillar organization. RNAi knockdown, expression of phosphomimetic/phosphodeficient EBP50 mutants, biochemical analysis of PDZ domain accessibility The Journal of cell biology High 20937695
2010 NHERF1 directly interacts with a subset of Frizzled (Fzd) receptors via one of its PDZ domains, maintaining low Wnt/β-catenin signaling. Loss of NHERF1 in breast cancer cell lines enhances canonical Wnt signaling and Wnt-dependent proliferation. NHERF1-knockout mouse mammary glands exhibit increased duct density, proliferation, and β-catenin activity. Co-immunoprecipitation, reporter assays, NHERF1 knockout mice, cell proliferation assays Oncogene Medium 20802536
2010 NHERF-1 binds to Mrp2 (via Mrp2's PDZ-binding motif) in co-transfected HEK293 cells and in mouse liver. In NHERF-1(-/-) mice, Mrp2 protein is reduced ~50% in whole cell lysates and ~70% in membrane fractions (post-transcriptional regulation), bile flow is reduced ~30%, and glutathione excretion is reduced ~50%, demonstrating a critical role for NHERF-1 in canalicular Mrp2 expression and glutathione-dependent bile flow. Co-immunoprecipitation, NHERF-1 knockout mice, Western blotting, membrane fractionation, bile collection/bile flow measurement, GS-MF fluorescence assay The Journal of biological chemistry High 20404332
2010 NHERF-1 transduces dopamine inhibition of renal phosphate transport. NHERF-1 associates with D1-like receptors (Co-IP). Dopamine stimulated cAMP and PKC activity in wild-type proximal tubule cells but not in NHERF-1 null cells; adenoviral re-expression of NHERF-1 rescued these responses. Dopamine increased NHERF-1 phosphorylation at Ser77 (PDZ1), attenuating Npt2a binding. Co-immunoprecipitation, phosphate transport assays in WT and KO cells, cAMP/PKC activity assays, adenoviral rescue, 32P metabolic labeling The Journal of biological chemistry High 20200151
2010 NHERF-1 controls the amplitude and duration of PKD1/PKD2 signaling at the membrane scaffold. The first PDZ domain of NHERF-1 interacts with PDZ-binding motifs of PKD1 and PKD2. FRET-based live-cell imaging reveals that PKD activation at the NHERF-1 scaffold is rapid and sustained but blunted in magnitude compared with cytosolic or bulk membrane PKD activity. PDZ domain proteomic array, FRET-based PKD activity reporter, FRET translocation assay in live cells The Journal of biological chemistry Medium 19581308
2010 NHERF-1 forms a ternary complex with β-arrestin2 and PTH1R. NHERF1 binds constitutively to PTH1R while β-arrestin2 binding is agonist-promoted. NHERF1 interacts directly with β-arrestin2 without using PTH1R as an interface. NHERF1 modulates the kinetics of PTH1R/β-arrestin2 interactions as shown by FRET. Co-immunoprecipitation, BRET/FRET imaging, confocal microscopy, biochemical binding assays The Journal of biological chemistry High 20656684
2010 PDZK1 and EBP50 form a regulated ternary complex with ezrin in apical microvilli. Ezrin positively influences the PDZK1/EBP50 interaction (cooperativity). PDZK1 shuttles from nucleus to microvilli upon cell confluence, regulating complex formation. Knockdown of EBP50 reduces microvilli; this phenotype can be rescued by a PDZK1 chimera targeted directly to ezrin. In vitro binding assays, co-immunoprecipitation, RNAi knockdown, confocal microscopy of PDZK1 redistribution Molecular biology of the cell High 20237154
2010 Arrestin scaffolds NHERF1 to the P2Y12 receptor to regulate internalization. Prior to agonist stimulation, NHERF1 interacts directly with the P2Y12R C-tail via the intact PDZ-binding motif. Upon receptor stimulation, NHERF1 no longer binds the receptor directly but instead is recruited via arrestin as an adaptor, facilitating NHERF1-dependent P2Y12R internalization. Co-immunoprecipitation in vitro and in cells, PDZ-binding motif mutagenesis, internalization assays The Journal of biological chemistry Medium 22610101
2011 EBP50 depletion in biliary cancer cells increases EGFR surface expression and causes sustained EGFR activation (ERK1/2, STAT3) under basal and EGF-stimulated conditions. Loss of EBP50 induces epithelial-mesenchymal transition features (loss of E-cadherin/CK19, induction of S100A4/Slug, loss of polarity, lamellipodia formation). These effects are reversed by EGFR tyrosine kinase inhibition with gefitinib. siRNA knockdown of EBP50, Western blotting for signaling proteins, cell migration/invasion assays, immunofluorescence for junction proteins, gefitinib rescue Oncogene Medium 21822312
2012 NHERF1 forms an obligate ternary complex with Npt2a and the PKA-anchoring protein ezrin to facilitate PTH-responsive phosphate transport. Ezrin-anchored PKA phosphorylates NHERF1 to disassemble this complex and release Npt2a, thereby inhibiting phosphate transport. Loss-of-function NHERF1 mutations stabilize an inactive conformation refractory to PKA phosphorylation and impair ternary complex assembly. Co-immunoprecipitation, in vitro kinase assays, mutagenesis of disease-associated NHERF1 variants, phosphate transport assays, compensatory mutagenesis rescue The Journal of biological chemistry High 22628548
2012 NHERF-1 mediates P2Y12 receptor internalization via the PDZ binding motif of the receptor prior to agonist stimulation, and via arrestin scaffolding upon agonist activation. Additionally, PDZ2 of NHERF1 binds megalin directly and via an internal (non-C-terminal) PDZ binding motif in megalin; NHERF1 silencing increases megalin expression in proximal tubule cells. Immunoprecipitation from rat kidney lysate, GST fusion protein binding, peptide studies, confocal colocalization, siRNA knockdown Cellular physiology and biochemistry Medium 21325834
2012 NHERF1 PDZ1 domain is required for ANG II-mediated forward trafficking and activation of NHE3. NHERF1 mediates ANG II-induced increase in NHERF1-NHE3 and NHERF1-IRBIT interactions. IRBIT is indispensable for ANG II-provoked NHERF1-NHE3 interactions; phosphorylation of IRBIT at Ser68 is necessary for assembly of the NHERF1-IRBIT-NHE3 complex. Co-immunoprecipitation, dominant-negative PDZ1 construct, adenoviral YFP-NHERF1 expression, NHE3 apical membrane trafficking assays, IRBIT siRNA American journal of physiology. Renal physiology Medium 27279487
2013 EBP50 targets iNOS to peroxisomes in hepatocytes. siRNA knockdown of PEX7 reduced iNOS colocalization with the peroxisomal marker PMP70. Proteomic/MALDI-MS identified iNOS association with EBP50; confocal and immunoelectron microscopy confirmed co-localization. EBP50 associates with peroxisomes in a PEX5/PEX7-dependent manner, and iNOS peroxisomal localization was contingent on EBP50 expression in LPS-treated mice. siRNA knockdown, MALDI-MS proteomics, confocal microscopy, immunoelectron microscopy, in vivo LPS model Nitric oxide : biology and chemistry Medium 23474170
2013 EBP50 phosphorylation by Cdc2/CyclinB at Ser279 and Ser301 regulates actin cytoskeleton reorganization. Phosphodeficient (S279A/S301A) EBP50 significantly increased F-actin content, enhanced cell-matrix adhesion, caused cytokinesis defects (multinucleation, heteroploid DNA, giant cells), and had weaker actin binding. Phosphomimetic (S279D/S301D) did not cause these defects. Knockdown of EBP50 in AA cells rescued cytokinesis failure. Stable transfection of phosphodeficient/phosphomimetic mutants in MDA-MB-231, F-actin staining, DNA content analysis, cell adhesion assays, EBP50 knockdown rescue Molecules and cells Medium 23775624
2014 NHERF1 depletion in human intestinal epithelial cells in 3D culture disrupts apical-basal polarity and prevents lumen formation. NHERF1 concentrates at the apical membrane from the two-cell stage. NHERF1 depletion displaces PTEN from the membrane and causes nuclear β-catenin translocation. Moesin (but not ezrin) depletion reproduces the NHERF1 loss phenotype. NHERF1 ERM-binding and PDZ-domain mutants fail to localize apically and impair gland formation. 3D gland morphogenesis assay, siRNA knockdown, confocal microscopy, domain-mutant expression Neoplasia Medium 24862762
2015 NHERF1 interaction with TRPC4 and TRPC5 (via their C-terminal PDZ-binding motif) regulates channel gating: dynamic dissociation of NHERF1/2 from the TRPC5 C-terminus upon PIP2 depletion is a prerequisite for DAG sensitivity. PKC inhibition or mutation of the PDZ-binding motif in TRPC4/5 conferred DAG sensitivity to the channel. PIP2 depletion evokes a C-terminal conformational change in TRPC5 leading to NHERF dissociation. PDZ-binding motif mutagenesis, PKC inhibition, electrophysiology, Co-immunoprecipitation, conformational change assays Proceedings of the National Academy of Sciences of the United States of America High 27994151
2015 NHERF1 interacts with α-actinin-4 via NHERF1's PDZ domain and the α-actinin-4 C-terminal region. The NHERF1/α-actinin-4 interaction increases α-actinin-4 ubiquitination and decreases its expression, resulting in actin cytoskeleton disassembly. NHERF1 loss-of-function/gain-of-function experiments show that NHERF1 disorganizes polymerized F-actin in HeLa cells. 2D-DIGE proteomics/MALDI-TOF identification, GST pulldown, co-immunoprecipitation, siRNA/overexpression, ubiquitination assay, F-actin staining FASEB journal Medium 26432781
2015 NHERF1 binds BECN1 via its C-terminal domain, blocks ubiquitin-dependent BECN1 degradation, and thereby stabilizes BECN1 to stimulate autophagy. NHERF1 attenuates the BECN1-BCL2 interaction. Deletion of the NHERF1 C-terminal domain abolishes BECN1 binding, reduces BECN1 levels, and prevents autophagy induction. Co-immunoprecipitation, ubiquitination assay, autophagy flux assays, C-terminal domain deletion mutagenesis Autophagy Medium 26218645
2016 NHERF1 interacts with GPER via NHERF1's PDZ2 domain and the GPER C-terminal PDZ binding motif in breast cancer cells. NHERF1 stabilizes GPER protein by inhibiting its degradation through the ubiquitin-proteasome pathway in an interaction-dependent manner. Co-immunoprecipitation, domain mutagenesis (PDZ2), ubiquitin-proteasome inhibitor experiments, protein stability assays Oncotarget Medium 27448983
2019 HPV E6 proteins (both high- and low-risk) degrade NHERF1 in an E6AP ubiquitin ligase-dependent manner, independent of PDZ interactions. E6 binding requires a novel structural domain of E6 (independent of the p53-recognition domain) and the NHERF1 EB domain. NHERF1 degradation by E6 activates canonical Wnt/β-catenin signaling. E6AP mutagenesis, NHERF1 domain deletion constructs, proteasome inhibitor experiments, Wnt/β-catenin reporter assays PLoS pathogens Medium 31002735
2019 PTH initiates dynamic NHERF1 phosphorylation cycling at Ser290: Ser290 is rapidly dephosphorylated by protein phosphatase 1α (PP1α, which binds NHERF1 via a VPF PP1-docking motif at residues 257-259) and then rephosphorylated by a GRK6A-containing kinase cascade. S290A substitution abolishes PTH-dependent phosphate transport. PP1α inhibition or mutation of the VPF motif blocks dephosphorylation and abrogates PTH-sensitive phosphate transport. Hydrogen-deuterium exchange MS reveals PTH-induced conformational changes in NHERF1 PDZ domains. Tandem MS phosphorylation site mapping, Ala-substitution mutagenesis, tautomycetin (PP1 inhibitor), FLIM, hydrogen-deuterium exchange MS, PP1α binding domain mutagenesis (VPF→Ala) The Journal of biological chemistry High 30696771

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Identification of EBP50: A PDZ-containing phosphoprotein that associates with members of the ezrin-radixin-moesin family. The Journal of cell biology 513 9314537
2000 ERM-Merlin and EBP50 protein families in plasma membrane organization and function. Annual review of cell and developmental biology 319 11031232
2009 Differential roles of NHERF1, NHERF2, and PDZK1 in regulating CFTR-mediated intestinal anion secretion in mice. The Journal of clinical investigation 303 19221439
2002 Targeted disruption of the mouse NHERF-1 gene promotes internalization of proximal tubule sodium-phosphate cotransporter type IIa and renal phosphate wasting. Proceedings of the National Academy of Sciences of the United States of America 256 12169661
2003 A putative RUNX1 binding site variant between SLC9A3R1 and NAT9 is associated with susceptibility to psoriasis. Nature genetics 234 14608357
2000 Association of mammalian trp4 and phospholipase C isozymes with a PDZ domain-containing protein, NHERF. The Journal of biological chemistry 195 10980202
1998 The role of NHERF and E3KARP in the cAMP-mediated inhibition of NHE3. The Journal of biological chemistry 178 9792717
1998 The carboxyl-terminal region of EBP50 binds to a site in the amino-terminal domain of ezrin that is masked in the dormant molecule. The Journal of biological chemistry 176 9660814
1999 Yes-associated protein 65 localizes p62(c-Yes) to the apical compartment of airway epithelia by association with EBP50. The Journal of cell biology 163 10562288
2006 The association of NHERF adaptor proteins with g protein-coupled receptors and receptor tyrosine kinases. Annual review of physiology 146 16460281
2001 NHERF: targeting and trafficking membrane proteins. American journal of physiology. Renal physiology 143 11181400
2001 Expanding the role of NHERF, a PDZ-domain containing protein adapter, to growth regulation. Oncogene 143 11607833
2003 EBP50, a beta-catenin-associating protein, enhances Wnt signaling and is over-expressed in hepatocellular carcinoma. Hepatology (Baltimore, Md.) 131 12830000
2003 Activation-independent parathyroid hormone receptor internalization is regulated by NHERF1 (EBP50). The Journal of biological chemistry 131 12920119
2000 NHERF associations with sodium-hydrogen exchanger isoform 3 (NHE3) and ezrin are essential for cAMP-mediated phosphorylation and inhibition of NHE3. Biochemistry 118 10821685
2001 Differential renal distribution of NHERF isoforms and their colocalization with NHE3, ezrin, and ROMK. American journal of physiology. Cell physiology 115 11121391
2004 Podocalyxin activates RhoA and induces actin reorganization through NHERF1 and Ezrin in MDCK cells. Journal of the American Society of Nephrology : JASN 107 15339978
2009 Downregulation of sodium transporters and NHERF proteins in IBD patients and mouse colitis models: potential contributors to IBD-associated diarrhea. Inflammatory bowel diseases 100 18942765
2002 Ezrin-radixin-moesin-binding phosphoprotein-50/Na+/H+ exchanger regulatory factor (EBP50/NHERF) blocks U50,488H-induced down-regulation of the human kappa opioid receptor by enhancing its recycling rate. The Journal of biological chemistry 100 12004055
2001 Oligomerization of NHERF-1 and NHERF-2 PDZ domains: differential regulation by association with receptor carboxyl-termini and by phosphorylation. Biochemistry 100 11456497
2000 Signal complex regulation of renal transport proteins: NHERF and regulation of NHE3 by PKA. American journal of physiology. Renal physiology 100 10966919
2016 Dynamic NHERF interaction with TRPC4/5 proteins is required for channel gating by diacylglycerol. Proceedings of the National Academy of Sciences of the United States of America 96 27994151
2003 Localization and interaction of NHERF isoforms in the renal proximal tubule of the mouse. American journal of physiology. Cell physiology 90 12917102
2008 Roles of NHERF1/EBP50 in cancer. Current molecular medicine 87 18781953
2007 NHERF1/EBP50 head-to-tail intramolecular interaction masks association with PDZ domain ligands. Molecular and cellular biology 86 17242191
2005 P2Y1 receptor signaling is controlled by interaction with the PDZ scaffold NHERF-2. Proceedings of the National Academy of Sciences of the United States of America 79 15901899
2007 NHERF1 regulates parathyroid hormone receptor membrane retention without affecting recycling. The Journal of biological chemistry 76 17884816
2010 NHERF1/EBP50 is a new marker in colorectal cancer. Neoplasia (New York, N.Y.) 73 21170265
2004 NHERF (Na+/H+ exchanger regulatory factor) gene mutations in human breast cancer. Oncogene 73 15467753
2017 Role of the PDZ-scaffold protein NHERF1/EBP50 in cancer biology: from signaling regulation to clinical relevance. Oncogene 71 28068322
2009 The role of the NHERF family of PDZ scaffolding proteins in the regulation of salt and water transport. Annals of the New York Academy of Sciences 70 19538313
2012 Participation of the Cl-/HCO(3)- exchangers SLC26A3 and SLC26A6, the Cl- channel CFTR, and the regulatory factor SLC9A3R1 in mouse sperm capacitation. Biology of reproduction 69 21976599
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. European journal of cell biology 68 11893083
2015 PTEN inhibits macrophage polarization from M1 to M2 through CCL2 and VEGF-A reduction and NHERF-1 synergism. Cancer biology & therapy 67 25756512
2007 NHERF-1 and the cytoskeleton regulate the traffic and membrane dynamics of G protein-coupled receptors. The Journal of biological chemistry 65 17599914
2007 Phosphorylation of PDZ1 domain attenuates NHERF-1 binding to cellular targets. The Journal of biological chemistry 62 17895247
2003 NHERF-1 uniquely transduces the cAMP signals that inhibit sodium-hydrogen exchange in mouse renal apical membranes. FEBS letters 61 12586353
2009 NHERF-1: modulator of glioblastoma cell migration and invasion. Neoplasia (New York, N.Y.) 60 19308292
2010 The scaffolding protein EBP50 regulates microvillar assembly in a phosphorylation-dependent manner. The Journal of cell biology 59 20937695
2009 NHERF1 regulates parathyroid hormone receptor desensitization: interference with beta-arrestin binding. Molecular pharmacology 57 19188335
2005 Receptor activity-modifying protein (RAMP) isoform-specific regulation of adrenomedullin receptor trafficking by NHERF-1. The Journal of biological chemistry 56 15805108
2010 MAGI-3 competes with NHERF-2 to negatively regulate LPA2 receptor signaling in colon cancer cells. Gastroenterology 53 21134377
2011 Loss of EBP50 stimulates EGFR activity to induce EMT phenotypic features in biliary cancer cells. Oncogene 51 21822312
2010 A regulated complex of the scaffolding proteins PDZK1 and EBP50 with ezrin contribute to microvillar organization. Molecular biology of the cell 51 20237154
2019 E6 proteins from high-risk HPV, low-risk HPV, and animal papillomaviruses activate the Wnt/β-catenin pathway through E6AP-dependent degradation of NHERF1. PLoS pathogens 50 31002735
2006 The PDZ scaffold NHERF-2 interacts with mGluR5 and regulates receptor activity. The Journal of biological chemistry 50 16891310
2010 NHERF1 and NHERF2 are necessary for multiple but usually separate aspects of basal and acute regulation of NHE3 activity. American journal of physiology. Cell physiology 49 21191106
2009 A conformational switch in the scaffolding protein NHERF1 controls autoinhibition and complex formation. The Journal of biological chemistry 47 20042604
2003 Role of NHERF-1 in regulation of the activity of Na-K ATPase and sodium-phosphate co-transport in epithelial cells. Journal of the American Society of Nephrology : JASN 46 12819230
2010 NHERF-1 binds to Mrp2 and regulates hepatic Mrp2 expression and function. The Journal of biological chemistry 45 20404332
2003 NHERF-1 is required for renal adaptation to a low-phosphate diet. American journal of physiology. Renal physiology 44 12952857
2010 Direct interaction between NHERF1 and Frizzled regulates β-catenin signaling. Oncogene 41 20802536
2009 Ezrin-radixin-moesin-binding phosphoprotein (EBP50), an estrogen-inducible scaffold protein, contributes to biliary epithelial cell proliferation. The American journal of pathology 39 19234136
2009 The protein scaffold NHERF-1 controls the amplitude and duration of localized protein kinase D activity. The Journal of biological chemistry 39 19581308
2015 SLC9A3R1 stimulates autophagy via BECN1 stabilization in breast cancer cells. Autophagy 37 26218645
2012 Ezrin-anchored protein kinase A coordinates phosphorylation-dependent disassembly of a NHERF1 ternary complex to regulate hormone-sensitive phosphate transport. The Journal of biological chemistry 36 22628548
2012 EBP50 inhibits EGF-induced breast cancer cell proliferation by blocking EGFR phosphorylation. Amino acids 35 22476347
2008 The epithelial brush border Na+/H+ exchanger NHE3 associates with the actin cytoskeleton by binding to ezrin directly and via PDZ domain-containing Na+/H+ exchanger regulatory factor (NHERF) proteins. Clinical and experimental pharmacology & physiology 35 18430067
2014 NHERF1/EBP50 controls morphogenesis of 3D colonic glands by stabilizing PTEN and ezrin-radixin-moesin proteins at the apical membrane. Neoplasia (New York, N.Y.) 34 24862762
2012 NHE3 regulatory factor 1 (NHERF1) modulates intestinal sodium-dependent phosphate transporter (NaPi-2b) expression in apical microvilli. The Journal of biological chemistry 34 22904329
2005 Beyond the brush border: NHERF4 blazes new NHERF turf. The Journal of physiology 34 15994182
2010 Sodium-hydrogen exchanger regulatory factor 1 (NHERF-1) transduces signals that mediate dopamine inhibition of sodium-phosphate co-transport in mouse kidney. The Journal of biological chemistry 33 20200151
2018 HPV16 E6 promotes cervical cancer cell migration and invasion by downregulation of NHERF1. International journal of cancer 32 30230542
2012 Arrestin scaffolds NHERF1 to the P2Y12 receptor to regulate receptor internalization. The Journal of biological chemistry 31 22610101
2010 Role of NHERF and scaffolding proteins in proximal tubule transport. Urological research 31 20632170
2011 Na+-H+ exchanger regulatory factor 1 (NHERF1) PDZ scaffold binds an internal binding site in the scavenger receptor megalin. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 30 21325834
2014 The scaffolding protein NHERF1 sensitizes EGFR-dependent tumor growth, motility and invadopodia function to gefitinib treatment in breast cancer cells. International journal of oncology 29 25530180
2012 NHERF-1 and the regulation of renal phosphate reabsoption: a tale of three hormones. American journal of physiology. Renal physiology 29 22535796
2010 Formation of a ternary complex among NHERF1, beta-arrestin, and parathyroid hormone receptor. The Journal of biological chemistry 29 20656684
2010 NHERF1/EBP50 in Breast Cancer: Clinical Perspectives. Breast care (Basel, Switzerland) 29 21048827
2009 The adaptor protein EBP50 is important for localization of the protein kinase A-Ezrin complex in T-cells and the immunomodulating effect of cAMP. The Biochemical journal 29 19857202
2004 Expression of TRPC4 channel protein that interacts with NHERF-2 in rat descending vasa recta. American journal of physiology. Cell physiology 29 15590898
2015 NHERF1/EBP50 is an organizer of polarity structures and a diagnostic marker in ependymoma. Acta neuropathologica communications 28 25775275
2015 NHERF1 regulates actin cytoskeleton organization through modulation of α-actinin-4 stability. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 28 26432781
2014 PDZK1 and NHERF1 regulate the function of human organic anion transporting polypeptide 1A2 (OATP1A2) by modulating its subcellular trafficking and stability. PloS one 28 24728453
2012 Na+/H+ exchanger regulatory factor 1 (NHERF1) directly regulates osteogenesis. The Journal of biological chemistry 28 23109343
2009 EBP50 exerts tumor suppressor activity by promoting cell apoptosis and retarding extracellular signal-regulated kinase activity. Amino acids 28 20012548
2004 kappa Opioid receptor interacts with Na(+)/H(+)-exchanger regulatory factor-1/Ezrin-radixin-moesin-binding phosphoprotein-50 (NHERF-1/EBP50) to stimulate Na(+)/H(+) exchange independent of G(i)/G(o) proteins. The Journal of biological chemistry 28 15070904
2012 Aberrant nuclear localization of EBP50 promotes colorectal carcinogenesis in xenotransplanted mice by modulating TCF-1 and β-catenin interactions. The Journal of clinical investigation 27 22466651
2005 NHERF and regulation of the renal sodium-hydrogen exchanger NHE3. Pflugers Archiv : European journal of physiology 25 15742180
2013 Ezrin-radixin-moesin-binding phosphoprotein 50 (EBP50) and nuclear factor-κB (NF-κB): a feed-forward loop for systemic and vascular inflammation. The Journal of biological chemistry 24 24196963
2006 Adenoviral expression of NHERF-1 in NHERF-1 null mouse renal proximal tubule cells restores Npt2a regulation by low phosphate media and parathyroid hormone. American journal of physiology. Renal physiology 24 16705152
2019 Parathyroid hormone initiates dynamic NHERF1 phosphorylation cycling and conformational changes that regulate NPT2A-dependent phosphate transport. The Journal of biological chemistry 23 30696771
2018 NHERF1 inhibits beta-catenin-mediated proliferation of cervical cancer cells through suppression of alpha-actinin-4 expression. Cell death & disease 23 29867145
2017 Roles of NHERF Family of PDZ-Binding Proteins in Regulating GPCR Functions. Advances in immunology 22 28950951
2017 NHERF1 Enhances Cisplatin Sensitivity in Human Cervical Cancer Cells. International journal of molecular sciences 21 28085111
2016 The NHERF1 PDZ1 domain and IRBIT interact and mediate the activation of Na+/H+ exchanger 3 by ANG II. American journal of physiology. Renal physiology 21 27279487
2013 PEX7 and EBP50 target iNOS to the peroxisome in hepatocytes. Nitric oxide : biology and chemistry 21 23474170
2012 Involvement of nuclear NHERF1 in colorectal cancer progression. Oncology reports 21 22766563
2016 NHERF1, a novel GPER associated protein, increases stability and activation of GPER in ER-positive breast cancer. Oncotarget 20 27448983
2013 EBP50 phosphorylation by Cdc2/Cyclin B kinase affects actin cytoskeleton reorganization and regulates functions of human breast cancer cell line MDA-MB-231. Molecules and cells 20 23775624
2010 Spatiotemporal control of cyclic AMP immunomodulation through the PKA-Csk inhibitory pathway is achieved by anchoring to an Ezrin-EBP50-PAG scaffold in effector T cells. FEBS letters 20 20420835
2002 NHE3 and NHERF are targeted to the basolateral membrane in proximal tubules of colchicine-treated rats. Kidney international 20 11918742
2002 Expression of NHERF-1, NHERF-2, PDGFR-alpha, and PDGFR-beta in normal human kidneys and in renal transplant rejection. Pathobiology : journal of immunopathology, molecular and cellular biology 20 12865627
2018 Wnt signaling pathway upregulates DNMT1 to trigger NHERF1 promoter hypermethylation in colon cancer. Oncology reports 19 29901158
2017 The scaffolding protein NHERF1 regulates the stability and activity of the tyrosine kinase HER2. The Journal of biological chemistry 19 28235801
2016 NHERF1/EBP50 Suppresses Wnt-β-Catenin Pathway-Driven Intestinal Neoplasia. Neoplasia (New York, N.Y.) 19 27566107
2010 Dopamine regulation of Na+-K+-ATPase requires the PDZ-2 domain of sodium hydrogen regulatory factor-1 (NHERF-1) in opossum kidney cells. American journal of physiology. Cell physiology 19 21160026
2008 Novel regulatory function for NHERF-1 in Npt2a transcription. American journal of physiology. Renal physiology 19 18216150
2018 NHERF1 Between Promises and Hopes: Overview on Cancer and Prospective Openings. Translational oncology 18 29455084

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