NHERF1

Summary

NHERF1 (NHERF family PDZ scaffold protein 1, HGNC:11075) is a protein-coding gene on chromosome 17q25.1, encoding Na(+)/H(+) exchange regulatory cofactor NHE-RF1 (O14745). 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.

This gene encodes a sodium/hydrogen exchanger regulatory cofactor. The protein interacts with and regulates various proteins including the cystic fibrosis transmembrane conductance regulator and G-protein coupled receptors such as the beta2-adrenergic receptor and the parathyroid hormone 1 receptor. The protein also interacts with proteins that function as linkers between integral membrane and cytoskeletal proteins. The protein localizes to actin-rich structures including membrane ruffles, microvilli, and filopodia. Mutations in this gene result in hypophosphatemic nephrolithiasis/osteoporosis type 2, and loss of heterozygosity of this gene is implicated in breast cancer.

Source: NCBI Gene 9368 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypophosphatemic nephrolithiasis/osteoporosis 2 (Moderate, GenCC) — +1 more curated relationship
• GWAS associations: 10
• Clinical variants (ClinVar): 209 total
• Phenotypes (HPO): 8
• Druggable target: yes
• MANE Select transcript: NM_004252

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11075
Approved symbol	NHERF1
Name	NHERF family PDZ scaffold protein 1
Location	17q25.1
Locus type	gene with protein product
Status	Approved
Aliases	NHERF, EBP50, NHERF-1, NHE-RF
Ensembl gene	ENSG00000109062
Ensembl biotype	protein_coding
OMIM	604990
Entrez	9368

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 9 protein_coding, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000262613, ENST00000413388, ENST00000578958, ENST00000581356, ENST00000583369, ENST00000851800, ENST00000851801, ENST00000851802, ENST00000851803, ENST00000851804, ENST00000967136

RefSeq mRNA: 1 — MANE Select: NM_004252 NM_004252

CCDS: CCDS11705

Canonical transcript exons

ENST00000262613 — 6 exons

Exon	Start	End
ENSE00001196813	74762012	74762173
ENSE00002698726	74768468	74769353
ENSE00002928526	74763367	74763520
ENSE00003566520	74768147	74768236
ENSE00003598187	74766936	74766976
ENSE00003842038	74748628	74749287

Expression profiles

Bgee: expression breadth ubiquitous, 284 present calls, max score 99.08.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 30.4622 / max 381.7081, expressed in 1790 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
162654	24.7003	1685
162655	3.5406	1483
162663	0.8058	383
162664	0.4852	253
162657	0.4103	237
162656	0.3311	194
162658	0.1710	78
162662	0.0179	8

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	99.08	gold quality
lower esophagus mucosa	UBERON:0035834	99.05	gold quality
esophagus mucosa	UBERON:0002469	98.80	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	98.62	gold quality
mucosa of transverse colon	UBERON:0004991	98.60	gold quality
right adrenal gland	UBERON:0001233	98.58	gold quality
ileal mucosa	UBERON:0000331	98.49	gold quality
right adrenal gland cortex	UBERON:0035827	98.37	gold quality
right lobe of liver	UBERON:0001114	98.32	gold quality
jejunal mucosa	UBERON:0000399	98.09	gold quality
left adrenal gland	UBERON:0001234	98.08	gold quality
left adrenal gland cortex	UBERON:0035825	98.08	gold quality
minor salivary gland	UBERON:0001830	97.82	gold quality
saliva-secreting gland	UBERON:0001044	97.78	gold quality
mouth mucosa	UBERON:0003729	97.73	gold quality
duodenum	UBERON:0002114	97.48	gold quality
esophagus squamous epithelium	UBERON:0006920	97.37	gold quality
adult mammalian kidney	UBERON:0000082	97.36	gold quality
gall bladder	UBERON:0002110	97.35	gold quality
parotid gland	UBERON:0001831	97.33	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.30	gold quality
adrenal cortex	UBERON:0001235	97.24	gold quality
cerebellar hemisphere	UBERON:0002245	97.15	gold quality
nasal cavity epithelium	UBERON:0005384	97.12	gold quality
cerebellar cortex	UBERON:0002129	97.11	gold quality
endometrium epithelium	UBERON:0004811	96.84	gold quality
epithelium of esophagus	UBERON:0001976	96.80	gold quality
gingival epithelium	UBERON:0001949	96.71	gold quality
squamous epithelium	UBERON:0006914	96.71	gold quality
gingiva	UBERON:0001828	96.66	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-CURD-114	yes	72.22
E-CURD-122	yes	46.14
E-MTAB-10287	yes	44.77
E-HCAD-10	yes	29.75
E-GEOD-93593	yes	14.03
E-MTAB-9388	yes	11.91
E-GEOD-84465	yes	11.79
E-GEOD-106540	no	1610.77
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

53 targeting NHERF1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-3059-5P	99.70	69.93	2491
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-17-3P	99.55	66.77	1311
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-766-5P	99.47	67.91	2225
HSA-MIR-149-5P	99.25	67.16	1315
HSA-MIR-6734-3P	99.15	66.27	1627
HSA-MIR-29A-5P	99.08	68.59	1813

Literature-anchored findings (GeneRIF, showing 40)

• structural determinants in interaction of beta 2 adrenergic and platelet-derived growth factor receptors (PMID:11882663)
• Epithelial cells expressing ezrin generally co-express EBP50. These results document a preference for co-expression of EBP50 with ezrin in polarized epithelia. (PMID:11893083)
• Protein kinase C epsilon-dependent regulation of cystic fibrosis transmembrane regulator involves binding to a receptor for activated C kinase (RACK1) and RACK1 binding to Na+/H+ exchange regulatory factor (PMID:11956211)
• EBP50/NHERF binds to the C terminus of FLAG-hkor and blocks the down-regulation of FLAG-hkor (PMID:12004055)
• epithelial iNOS binds to EPB50 which directs vectorial nitric oxide output (PMID:12080081)
• Estrogen receptor inducibility of the human Na+/H+ exchanger regulatory factor/ezrin-radixin-moesin binding protein 50 (NHE-RF/EBP50) gene involving multiple half-estrogen response elements. (PMID:12145337)
• role in regulating GTP-binding protein alpha q signaling (PMID:12193606)
• EBP50 has the capacity to inhibit receptor endocytosis (PMID:12626493)
• Na+/H+ exchanger regulatory factor has a role in the functional expression of cystic fibrosis transmembrane conductance regulator in nonpolarized cells and epithelia (PMID:12651858)
• the EBP50/beta-catenin complex promotes Wnt signaling, and over-expression of EBP50 may work cooperatively with beta-catenin in the development of liver cancer. (PMID:12830000)
• NHERF1 acts as a molecular switch that legislates the conditional efficacy of PTH fragments (PMID:12920119)
• A putative RUNX1 binding site variant of SLC9A3R1 is associated with susceptibility to psoriasis (PMID:14608357)
• binding of the KOR to NHERF-1/EBP50 facilitates oligomerization of NHERF-1/EBP50, leading to stimulation of NHE3. (PMID:15070904)
• NHERF links the betaPDGFR to the actin cytoskeleton through its interaction with MERM proteins and regulates cell spreading and migration (PMID:15161943)
• NHERF to be a candidate tumor suppressor gene in human breast carcinoma that may be interconnected to the SYK and MERLIN suppressors (PMID:15467753)
• results, using both endogenous and overexpressed cellular models, indicate a novel function for NHERF-1 and RAMP3 in the internalization of the adrenomedullin receptor and suggest additional regulatory mechanisms for receptor trafficking (PMID:15805108)
• ezrin binding activates the second PDZ domain of NHERF to interact with the cytoplasmic tails of CFTR (C-CFTR), so as to form a specific 2:1:1 (C-CFTR)(2).NHERF.ezrin ternary complex (PMID:16129695)
• analysis of NHERF recognition by ERM proteins (PMID:16615918)
• the tumour suppressor activity of NHERF1 in breast may be related to its regulatory effect on the cell cycle to suppress cell proliferation. (PMID:17078868)
• Modulation of the expression of CFTR (cystic fibrosis transmembrane conductance regulator) protein partners, like NHE-RF1, can rescue sequence-deleted CFTR activity. (PMID:17237149)
• An intramolecular conformation of NHERF1/EBP50 (ERM-binding phosphoprotein 50) in which the C-terminal EB region binds to the PDZ2 domain is described. (PMID:17242191)
• NHERF1 overexpression enhances the invasive phenotype in breast cancer cells, both alone and in synergy with exposure to the tumor microenvironment, via the coordination of PKA-gated RhoA/p38 signaling. (PMID:17332506)
• Oestrogen-responsive EBP50 may play an important role in tumour progression and might be a potential marker of invasiveness for breast cancer. (PMID:17593079)
• The interaction of PDZ proteins with hOAT4 may be cell-specific. In placenta, a different set of interacting proteins from PDZK1 and NHERF1 may be required to modulate hOAT4 activity. (PMID:17602283)
• C-terminal domain of NHERF functions as an intramolecular switch that regulates the binding capability of PDZ2, and thus controls the stoichiometry of NHERF to assemble protein complexes. (PMID:17613530)
• that NHERF1 inhibits endocytosis without affecting PTH1R recycling (PMID:17884816)
• serine 77 phosphorylation plays a key role in modulating NHERF-1 association with plasma membrane targets (PMID:17895247)
• Acts as a scaffold that assembles the cyclic AMP pathway in lipid rafts of the cell membrane during T cell activation. (PMID:17911601)
• These results indicate that NHERF1 plays a role in the turnover of CFTR at the cell surface, and that rDeltaF508 CFTR at the cell surface remains highly susceptible to degradation. (PMID:17982258)
• Beta-oestradiol-dependent up-regulation of NHERF1 significantly increases F508CFTR functional expression in CFBE41o(-) cells. (PMID:18184109)
• Relatively high level of expression of mRNA for SLC9A3RI was detected wheres lower level of S100A7 and GPRA were found. (PMID:18588753)
• Affinity of the cystic fibrosis transmembrane conductance regulator (CFTR) PDZ domain for the CFTR C-terminus is much weaker than that of the NHERF1/NHERF2 domains, enabling wild-type CFTR to avoid premature entrapment in the lysosomal pathway. (PMID:18754678)
• We identified three distinct mutations in seven patients with a low TmP/GFR value. The mutants expressed in cultured renal cells increased the generation of cyclic AMP (cAMP) by parathyroid hormone (PTH) and inhibited phosphate transport. (PMID:18784102)
• This protein has been found differentially expressed in the temporal lobe from patients with schizophrenia. (PMID:19034380)
• These data establish NHERF1 as a major determinant of MRP4 trafficking to apical membranes of mammalian kidney cells. (PMID:19073137)
• While the presence of forskolin results in an increase in OCTN2 protein expression, the increase in uptake capacity may be compensated by the decreased expression of PDZK1, NHERF1 or NHERF2. (PMID:19091402)
• no evidence was found for association of SNPs mapping to the NAT9, SLC9A3R1 and RAPTOR loci with susceptibility to psoriatic arthritis (PMID:19139211)
• Using shotgun mass spectrometry, we found this protein differentially expressed in the dorsolateral prefrontal cortex from patients with schizophrenia. (PMID:19165527)
• The tail of PDZK1 interacts with the PDZ domains of EBP50, and this interaction is negatively regulated by the intramolecular association of the tail of PDZK1 with its first PDZ domain. (PMID:19173579)
• NHERF1 inhibited beta-arrestin2 binding to wtPTH1R but had no effect on beta-arrestin2 association with pdPTH1R. Such an effect may protect against PTH resistance or PTH1R down-regulation in cells harboring NHERF1. (PMID:19188335)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	nherf1a	ENSDARG00000000068
		ENSDARG00000102503
mus_musculus	Nherf1	ENSMUSG00000020733
rattus_norvegicus	Nherf1	ENSRNOG00000003232
drosophila_melanogaster	CG10939	FBGN0010620

Paralogs (3): NHERF2 (ENSG00000065054), NHERF4 (ENSG00000172367), PDZK1 (ENSG00000174827)

Protein

Protein identifiers

Na(+)/H(+) exchange regulatory cofactor NHE-RF1 — O14745 (reviewed: O14745)

Alternative names: Ezrin-radixin-moesin-binding phosphoprotein 50, Regulatory cofactor of Na(+)/H(+) exchanger, Sodium-hydrogen exchanger regulatory factor 1, Solute carrier family 9 isoform A3 regulatory factor 1

All UniProt accessions (3): O14745, J3QRA3, J3QRP6

UniProt curated annotations — full annotation on UniProt →

Function. 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. 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.

Subunit / interactions. Homodimer, and heterodimer with NHERF2. Binds the N-termini of EZR, RDX and MSN. Binds the C-termini of PDGFRA, PDGFRB, ADRB2, NOS2 and CFTR. Binds ARHGAP17, EPI64, RACK1, OPRK1, GNAQ, CTNNB1 and PLCB3. Binds PDZK1. Interacts with CLCN3. Binds the C-terminus of PAG1. In resting T-cells, part of a PAG1-NHERF1-MSN complex which is disrupted upon TCR activation. Forms a complex with CFTR and SLC4A7. Forms a complex with SLC4A7 and ATP6V1B1. Interacts with TRPC4 (via the PDZ-binding domain). Directly interacts with HTR4. Interacts (via the PDZ 1 domain) with PODXL (via the C-terminal PDZ-binding motif DTHL); interaction is not detected in glomerular epithelium cells. Interacts (via the PDZ 1 domain) with PODXL (via the C-terminal PDZ-binding motif DTHL); the interaction take place early in the secretory pathway and is necessary for its apical membrane sorting. Interacts with SLC26A3. Interacts with MCC. Interacts with SLC34A1. Interacts (via the PDZ domains) with SLC26A6 isoform 4 and isoform 5. Interacts (via PDZ domains) with ACE2 (via PDZ-binding motif); the interaction may enhance ACE2 membrane residence.

Subcellular location. Cytoplasm. Apical cell membrane. Endomembrane system. Cell projection. Filopodium. Ruffle. Microvillus.

Tissue specificity. Detected in liver, kidney, pancreas, prostate, spleen, small intestine and placenta, in particular in the syncytiotrophoblast.

Post-translational modifications. Phosphorylated on serine residues.

Disease relevance. Nephrolithiasis/osteoporosis, hypophosphatemic, 2 (NPHLOP2) [MIM:612287] A disease characterized by decreased renal phosphate absorption, renal phosphate wasting, hypophosphatemia, hyperphosphaturia, hypercalciuria, nephrolithiasis and osteoporosis. The disease is caused by variants affecting the gene represented in this entry.

Induction. By estrogen.

Isoforms (2)

UniProt ID	Names	Canonical?
O14745-1	1	yes
O14745-2	2

RefSeq proteins (1): NP_004243* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001478	PDZ	Domain
IPR015098	EBP50_C	Domain
IPR017300	NHERF-1/NHERF-2	Family
IPR036034	PDZ_sf	Homologous_superfamily
IPR041489	PDZ_6	Domain
IPR051067	NHER	Family

Pfam: PF00595, PF09007, PF17820

UniProt features (65 total): strand 16, modified residue 12, helix 12, compositionally biased region 5, turn 5, sequence variant 4, mutagenesis site 4, domain 2, region of interest 2, initiator methionine 1, chain 1, splice variant 1

Structure

Experimental structures (PDB)

22 structures.

PDB	Method	Resolution (Å)
4N6X	X-RAY DIFFRACTION	1.05
4MPA	X-RAY DIFFRACTION	1.1
4LMM	X-RAY DIFFRACTION	1.1
4JL7	X-RAY DIFFRACTION	1.16
9RXT	X-RAY DIFFRACTION	1.36
9RXQ	X-RAY DIFFRACTION	1.38
4Q3H	X-RAY DIFFRACTION	1.44
4PQW	X-RAY DIFFRACTION	1.47
1G9O	X-RAY DIFFRACTION	1.5
2OZF	X-RAY DIFFRACTION	1.5
1I92	X-RAY DIFFRACTION	1.7
1GQ4	X-RAY DIFFRACTION	1.9
1GQ5	X-RAY DIFFRACTION	2.2
6RQR	X-RAY DIFFRACTION	2.2
2D10	X-RAY DIFFRACTION	2.5
1SGH	X-RAY DIFFRACTION	3.5
2JXO	SOLUTION NMR
2KJD	SOLUTION NMR
2KRG	SOLUTION NMR
2M0T	SOLUTION NMR
2M0U	SOLUTION NMR
2M0V	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14745-F1	73.02	0.10

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (12): 2, 2, 46, 162, 269, 280, 290, 291, 293, 294, 299, 302

Mutagenesis-validated functional residues (4):

Position	Phenotype
24–26	loss of interaction with ace2.
164–166	loss of interaction with ace2.
355	loss of msx binding.
358	reduces msx binding.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 514 (showing top): GOBP_PLATELET_DERIVED_GROWTH_FACTOR_RECEPTOR_SIGNALING_PATHWAY, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_EXCRETION, GOBP_NEGATIVE_REGULATION_OF_ERK1_AND_ERK2_CASCADE, MODULE_52, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_MONOPOLAR_CELL_POLARITY, GOBP_ACID_SECRETION, GOBP_GLAND_MORPHOGENESIS, TSENG_IRS1_TARGETS_UP, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GOBP_NEGATIVE_REGULATION_OF_SODIUM_ION_TRANSPORT, GOBP_CIRCULATORY_SYSTEM_PROCESS

GO Biological Process (45): morphogenesis of an epithelium (GO:0002009), renal sodium ion transport (GO:0003096), plasma membrane organization (GO:0007009), nuclear migration (GO:0007097), adenylate cyclase-activating dopamine receptor signaling pathway (GO:0007191), sensory perception of sound (GO:0007605), negative regulation of cell population proliferation (GO:0008285), regulation of cell shape (GO:0008360), regulation of cell size (GO:0008361), negative regulation of platelet-derived growth factor receptor signaling pathway (GO:0010642), fibroblast migration (GO:0010761), negative regulation of fibroblast migration (GO:0010764), negative regulation of sodium ion transport (GO:0010766), Wnt signaling pathway (GO:0016055), gland morphogenesis (GO:0022612), microvillus assembly (GO:0030033), actin cytoskeleton organization (GO:0030036), intracellular phosphate ion homeostasis (GO:0030643), bile acid secretion (GO:0032782), glutathione transport (GO:0034635), cilium organization (GO:0044782), establishment of epithelial cell apical/basal polarity (GO:0045198), maintenance of epithelial cell apical/basal polarity (GO:0045199), regulation of protein kinase activity (GO:0045859), negative regulation of mitotic cell cycle (GO:0045930), establishment of Golgi localization (GO:0051683), negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051898), gamma-aminobutyric acid import (GO:0051939), auditory receptor cell stereocilium organization (GO:0060088), phospholipase C-activating dopamine receptor signaling pathway (GO:0060158), protein-containing complex assembly (GO:0065003), renal absorption (GO:0070293), negative regulation of ERK1 and ERK2 cascade (GO:0070373), protein localization to plasma membrane (GO:0072659), negative regulation of canonical Wnt signaling pathway (GO:0090090), cerebrospinal fluid circulation (GO:0090660), renal phosphate ion absorption (GO:0097291), import across plasma membrane (GO:0098739), transport across blood-brain barrier (GO:0150104), regulation of renal phosphate excretion (GO:1903402)

GO Molecular Function (16): signaling receptor binding (GO:0005102), beta-catenin binding (GO:0008013), chloride channel regulator activity (GO:0017081), phosphatase binding (GO:0019902), PDZ domain binding (GO:0030165), beta-2 adrenergic receptor binding (GO:0031698), type 2 metabotropic glutamate receptor binding (GO:0031799), type 3 metabotropic glutamate receptor binding (GO:0031800), identical protein binding (GO:0042802), protein-membrane adaptor activity (GO:0043495), dopamine receptor binding (GO:0050780), growth factor receptor binding (GO:0070851), channel activator activity (GO:0099103), protein binding (GO:0005515), gamma-aminobutyric acid transmembrane transporter activity (GO:0015185), molecular adaptor activity (GO:0060090)

GO Cellular Component (21): ruffle (GO:0001726), cytoplasm (GO:0005737), microvillus (GO:0005902), endomembrane system (GO:0012505), actin cytoskeleton (GO:0015629), membrane (GO:0016020), apical plasma membrane (GO:0016324), filopodium (GO:0030175), brush border membrane (GO:0031526), microvillus membrane (GO:0031528), vesicle (GO:0031982), stereocilium tip (GO:0032426), perinuclear region of cytoplasm (GO:0048471), extracellular exosome (GO:0070062), cell periphery (GO:0071944), sperm midpiece (GO:0097225), plasma membrane protein complex (GO:0098797), plasma membrane (GO:0005886), stereocilium (GO:0032420), cell projection (GO:0042995), apical part of cell (GO:0045177)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	8
protein binding	3
actin-based cell projection	3
sodium ion transport	2
G protein-coupled glutamate receptor binding	2
binding	2
plasma membrane	2
cell projection membrane	2
tissue morphogenesis	1
epithelium development	1
renal system process	1
endomembrane system organization	1
membrane organization	1
intracellular transport	1
nucleus localization	1
establishment of organelle localization	1
adenylate cyclase-activating G protein-coupled receptor signaling pathway	1
G protein-coupled dopamine receptor signaling pathway	1
sensory perception of mechanical stimulus	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
regulation of cell morphogenesis	1
regulation of biological quality	1
regulation of cellular component size	1
negative regulation of signal transduction	1
regulation of platelet-derived growth factor receptor signaling pathway	1
platelet-derived growth factor receptor signaling pathway	1
ameboidal-type cell migration	1
fibroblast migration	1
regulation of fibroblast migration	1
negative regulation of cell migration	1
regulation of sodium ion transport	1
negative regulation of monoatomic ion transport	1
cell surface receptor signaling pathway	1
animal organ morphogenesis	1
gland development	1
microvillus organization	1
plasma membrane bounded cell projection assembly	1
cytoskeleton organization	1

Protein interactions and networks

STRING

1974 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NHERF1	EZR	P15311	999
NHERF1	RDX	P35241	998
NHERF1	MSN	P26038	997
NHERF1	CFTR	P13569	996
NHERF1	SLC9A3	P48764	992
NHERF1	ADRB2	P07550	989
NHERF1	PODXL	O00592	957
NHERF1	SLC26A3	P40879	939
NHERF1	TRPC4	Q9UBN4	920
NHERF1	PTEN	P60484	905
NHERF1	TBC1D10A	Q9BXI6	884
NHERF1	NF2	P35240	870
NHERF1	CTNNB1	P35222	866
NHERF1	GOPC	Q9HD26	866
NHERF1	EGFR	P00533	854

IntAct

337 interactions, top by confidence:

A	B	Type	Score
CFTR	NHERF1	psi-mi:“MI:0407”(direct interaction)	0.940
CFTR	NHERF1	psi-mi:“MI:0914”(association)	0.940
NHERF1	CFTR	psi-mi:“MI:0915”(physical association)	0.940
NHERF1	EZR	psi-mi:“MI:0407”(direct interaction)	0.850
NHERF1	EZR	psi-mi:“MI:0403”(colocalization)	0.850
EZR	NHERF1	psi-mi:“MI:0914”(association)	0.850
NHERF1	EZR	psi-mi:“MI:0915”(physical association)	0.850
PTEN	NHERF1	psi-mi:“MI:0915”(physical association)	0.830
PHLPP2	NHERF1	psi-mi:“MI:0915”(physical association)	0.760
PHLPP2	NHERF1	psi-mi:“MI:0407”(direct interaction)	0.760
NHERF1	PHLPP2	psi-mi:“MI:0915”(physical association)	0.760
PHLPP2	NHERF1	psi-mi:“MI:0914”(association)	0.760
NHERF1	TBC1D10A	psi-mi:“MI:0407”(direct interaction)	0.730
PDGFRB	NHERF1	psi-mi:“MI:2364”(proximity)	0.730
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710

BioGRID (288): SLC9A3R1 (Affinity Capture-Western), ABCC4 (Affinity Capture-Western), SLC9A3R1 (Reconstituted Complex), SLC9A3R1 (Reconstituted Complex), SKP2 (Affinity Capture-Western), SLC9A3R1 (Far Western), SKP2 (Protein-peptide), AKT1 (Affinity Capture-Western), SLC9A3R1 (Biochemical Activity), IREB2 (Co-fractionation), SLC9A3R1 (Co-fractionation), SLC9A3R1 (Affinity Capture-MS), SLC4A7 (Reconstituted Complex), PRKCA (Reconstituted Complex), SLC9A3R1 (Affinity Capture-MS)

ESM2 similar proteins: A1A5G4, A2ALK8, A8MUH7, A9CB74, F1M386, F1MSG6, F1PBJ0, O14745, O14907, O14936, O70589, P19878, P26045, P70290, P70441, P70600, Q00013, Q09506, Q14289, Q17QN6, Q28619, Q3SZK8, Q3T0X8, Q4L1J4, Q4R6G4, Q570Y9, Q5F488, Q5RCF7, Q5RDW4, Q5T2W1, Q5TCQ9, Q5ZIJ9, Q5ZJ00, Q60629, Q62915, Q69ZS7, Q6RHR9, Q865P3, Q8CHG7, Q8TB45

Diamond homologs: A0A1D5P556, A0A8C0TYJ0, A4D2P6, A5PKA5, A8MUH7, B7WN72, G5ECY0, O08774, O14745, O14924, O15085, O60879, P31007, P31016, P70175, P70441, P78352, P97879, Q09506, Q0D5P3, Q0QWG9, Q12959, Q13425, Q15599, Q15700, Q28619, Q28C55, Q3T0X8, Q3UHD6, Q4R6G4, Q5PYH5, Q5PYH6, Q5PYH7, Q5RCF7, Q5T2W1, Q5ZM14, Q61085, Q61235, Q62108, Q62696

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
GRK6	“down-regulates activity”	SLC9A3R1	phosphorylation
RPS6KA1	“up-regulates activity”	SLC9A3R1	phosphorylation
CDK1	“down-regulates activity”	SLC9A3R1	phosphorylation
SLC9A3R1	“up-regulates activity”	ADRB2	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 109 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Neurexins and neuroligins	7	17.9×	6e-05
Assembly and cell surface presentation of NMDA receptors	5	16.5×	1e-03
Sensory processing of sound by outer hair cells of the cochlea	5	13.2×	2e-03
Sensory processing of sound by inner hair cells of the cochlea	5	10.6×	5e-03
RAF/MAP kinase cascade	8	6.3×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	6	36.3×	6e-06
regulation of postsynaptic membrane neurotransmitter receptor levels	5	25.8×	2e-04
negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	5	13.7×	3e-03
negative regulation of ERK1 and ERK2 cascade	5	11.2×	6e-03
phosphatidylinositol 3-kinase/protein kinase B signal transduction	5	11.0×	6e-03
establishment of localization in cell	6	10.0×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

209 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	129
Likely benign	47
Benign	10

Top pathogenic / likely-pathogenic (0)

SpliceAI

955 predictions. Top by Δscore:

Variant	Effect	Δscore
17:74749287:GGT:G	donor_loss	1.0000
17:74749288:G:GA	donor_loss	1.0000
17:74749289:T:A	donor_loss	1.0000
17:74762011:GC:G	acceptor_gain	1.0000
17:74762171:G:GT	donor_gain	1.0000
17:74763362:TGCA:T	acceptor_loss	1.0000
17:74763363:GCA:G	acceptor_loss	1.0000
17:74763365:AGGTG:A	acceptor_loss	1.0000
17:74763516:GAATG:G	donor_gain	1.0000
17:74763520:GGTA:G	donor_loss	1.0000
17:74763521:G:GG	donor_gain	1.0000
17:74766930:GCCTA:G	acceptor_loss	1.0000
17:74766931:CCTAG:C	acceptor_loss	1.0000
17:74766932:CTAGG:C	acceptor_loss	1.0000
17:74766933:TAGGT:T	acceptor_loss	1.0000
17:74766934:AGGT:A	acceptor_loss	1.0000
17:74768141:T:TA	acceptor_gain	1.0000
17:74768142:GCCA:G	acceptor_loss	1.0000
17:74768145:A:AG	acceptor_gain	1.0000
17:74768145:AG:A	acceptor_gain	1.0000
17:74768146:G:A	acceptor_loss	1.0000
17:74768146:G:GG	acceptor_gain	1.0000
17:74768146:GG:G	acceptor_gain	1.0000
17:74768146:GGA:G	acceptor_gain	1.0000
17:74768233:GGAG:G	donor_gain	1.0000
17:74768234:GAGG:G	donor_gain	1.0000
17:74768235:AG:A	donor_loss	1.0000
17:74768236:GG:G	donor_loss	1.0000
17:74768238:T:A	donor_loss	1.0000
17:74768463:TACA:T	acceptor_loss	1.0000

AlphaMissense

2340 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:74748923:T:C	F26S	1.000
17:74748922:T:C	F26L	0.999
17:74748924:C:A	F26L	0.999
17:74748924:C:G	F26L	0.999
17:74748925:C:G	H27D	0.999
17:74748929:T:C	L28P	0.999
17:74749060:C:G	H72D	0.999
17:74762066:T:C	F166L	0.999
17:74762067:T:C	F166S	0.999
17:74762068:C:A	F166L	0.999
17:74762068:C:G	F166L	0.999
17:74762133:C:A	A188D	0.999
17:74763446:T:C	L228P	0.999
17:74748920:G:A	G25D	0.998
17:74748929:T:A	L28Q	0.998
17:74748962:T:A	I39N	0.998
17:74748989:C:A	A48D	0.998
17:74749062:C:A	H72Q	0.998
17:74749062:C:G	H72Q	0.998
17:74749082:T:C	I79T	0.998
17:74762064:G:A	G165D	0.998
17:74762073:T:A	L168Q	0.998
17:74762073:T:C	L168P	0.998
17:74762126:T:C	S186P	0.998
17:74762148:T:A	L193H	0.998
17:74762148:T:C	L193P	0.998
17:74762163:G:C	R198P	0.998
17:74762166:T:A	I199N	0.998
17:74763419:T:A	I219N	0.998
17:74763449:T:C	L229P	0.998

dbSNP variants (sampled 300 via entrez): RS1000283277 (17:74769427 A>G), RS1000290319 (17:74763672 T>C), RS1000441266 (17:74753174 A>T), RS1000511810 (17:74747521 G>C,T), RS1000627543 (17:74762634 T>C), RS1000658984 (17:74769674 A>G), RS1000919519 (17:74767381 G>A,T), RS1000928222 (17:74759534 A>G), RS1001083910 (17:74765782 C>T), RS1001183162 (17:74757205 TG>T), RS1001218417 (17:74752771 C>A,T), RS1001332094 (17:74752118 T>C), RS1001535255 (17:74765527 C>T), RS1001688878 (17:74747169 G>A,C), RS1001737054 (17:74747611 T>C)

Disease associations

OMIM: gene MIM:604990 | disease phenotypes: MIM:612287

GenCC curated gene-disease

Disease	Classification	Inheritance
hypophosphatemic nephrolithiasis/osteoporosis 2	Moderate	Autosomal dominant
dominant hypophosphatemia with nephrolithiasis or osteoporosis	Supportive	Autosomal dominant

Mondo (5): hypophosphatemic nephrolithiasis/osteoporosis 2 (MONDO:0012851), chronic kidney disease (MONDO:0005300), hypophosphatemia (MONDO:0000313), nephrolithiasis (MONDO:0008171), (MONDO:0016579)

Orphanet (1): Dominant hypophosphatemia with nephrolithiasis or osteoporosis (Orphanet:244305)

HPO phenotypes

8 total (8 of 8 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000117	Renal phosphate wasting
HP:0000787	Nephrolithiasis
HP:0000938	Osteopenia
HP:0000939	Osteoporosis
HP:0002148	Hypophosphatemia
HP:0002659	Increased susceptibility to fractures
HP:0003109	Hyperphosphaturia

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST000368_4	Fibrinogen	8.000000e-11
GCST004609_85	Monocyte percentage of white cells	7.000000e-10
GCST004625_199	Monocyte count	3.000000e-17
GCST009266_15	Dental caries (decayed and filled deciduous tooth surfaces)	4.000000e-07
GCST009269_18	Dental caries (decayed and filled deciduous teeth)	5.000000e-06
GCST90002388_506	Lymphocyte count	1.000000e-11
GCST90002394_413	Monocyte percentage of white cells	2.000000e-21
GCST90002398_311	Neutrophil count	9.000000e-14
GCST90002407_148	White blood cell count	8.000000e-11
GCST90002407_149	White blood cell count	6.000000e-19

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007989	monocyte percentage of leukocytes
EFO:0005091	monocyte count
EFO:0004587	lymphocyte count
EFO:0004833	neutrophil count

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D017674	Hypophosphatemia	C18.452.750.400
D007676	Kidney Failure, Chronic	C12.050.351.968.419.780.750.500; C12.200.777.419.780.750.500; C12.950.419.780.750.500; C23.550.291.500.906.500
D053040	Nephrolithiasis	C12.050.351.968.419.600; C12.050.351.968.967.249; C12.200.777.419.600; C12.200.777.967.249; C12.950.419.600; C12.950.967.249
C567362	Nephrolithiasis-Osteoporosis, Hypophosphatemic, 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523125 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

8 potent at pChembl≥5 of 41 total, top 8 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.48	Kd	330	nM	CHEMBL4763464
6.11	Kd	780	nM	CHEMBL4756359
5.79	Kd	1640	nM	CHEMBL4756115
5.40	Kd	3970	nM	CHEMBL4789294
5.30	IC50	5000	nM	CHEMBL4449346
5.10	IC50	8000	nM	CHEMBL4539177
5.10	IC50	8000	nM	CHEMBL4584542
5.00	IC50	1e+04	nM	CHEMBL4527356

PubChem BioAssay actives

19 with measured affinity, of 58 total; 12 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2R)-2-[[(2S)-3-(1-benzothiophen-3-yl)-2-[[(2S)-2-[[(2S)-5-carbamimidamido-2-[[(2S)-5-carbamimidamido-2-[[(2R)-5-carbamimidamido-2-[[(2R)-2-[[2-[2-[2-[(3’,6’-dihydroxy-3-oxospiro[2-benzofuran-1,9’-xanthene]-5-carbonyl)amino]ethoxy]ethoxy]acetyl]amino]-3-sulfanylpropanoyl]amino]pentanoyl]amino]pentanoyl]amino]pentanoyl]amino]-3-naphthalen-2-ylpropanoyl]amino]propanoyl]amino]-3-methyl-3-sulfanylbutanoyl]amino]-3,3-dimethylbutanoyl]amino]-3-hydroxybutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3,3-dimethylbutanoic acid	1701513: Binding affinity to NHERF1 PDZ1 domain (unknown origin) expressed in Escherichia coli BL21 incubated for 1 hr by fluorescence polarization based competition assay	kd	0.3300	uM
(4S)-4-[[(2S)-5-amino-2-[[(2S)-2-[(3’,6’-dihydroxy-3-oxospiro[2-benzofuran-1,9’-xanthene]-5-yl)carbamothioylamino]-4-methylpentanoyl]amino]-5-oxopentanoyl]amino]-5-[[(2S)-4-carboxy-1-[[(2S)-1-[[(2S)-4-carboxy-1-[[(2S,3R)-1-[[(2S)-1-[[(1S)-1-carboxy-3-methylsulfanylpropyl]amino]-3-methyl-1-oxobutan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-oxobutan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxobutan-2-yl]amino]-5-oxopentanoic acid	1802842: Fluorescent Polarization Competition Assay from Article 10.1021/acs.biochem.7b00078: “Origins of PDZ Binding Specificity. A Computational and Experimental Study Using NHERF1 and the Parathyroid Hormone Receptor.”	kd	0.4000	uM
(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2R)-2-[[(2S)-1-[(2S)-3-(1-benzothiophen-3-yl)-2-[[(2S)-2-[[(2S)-5-carbamimidamido-2-[[(2S)-5-carbamimidamido-2-[[(2R)-5-carbamimidamido-2-[[(2R)-2-[[2-[2-[2-[(3’,6’-dihydroxy-3-oxospiro[2-benzofuran-1,9’-xanthene]-5-yl)carbamothioylamino]ethoxy]ethoxy]acetyl]amino]-3-sulfanylpropanoyl]amino]pentanoyl]amino]pentanoyl]amino]pentanoyl]amino]-3-naphthalen-2-ylpropanoyl]amino]propanoyl]piperidine-2-carbonyl]amino]-3-methyl-3-sulfanylbutanoyl]amino]-3-hydroxybutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3,3-dimethylbutanoic acid	1701513: Binding affinity to NHERF1 PDZ1 domain (unknown origin) expressed in Escherichia coli BL21 incubated for 1 hr by fluorescence polarization based competition assay	kd	0.7800	uM
(4S)-4-[[(2S)-5-amino-2-[[(2S)-2-amino-4-methylpentanoyl]amino]-5-oxopentanoyl]amino]-5-[[(2S)-4-carboxy-1-[[(2S)-1-[[(2S)-4-carboxy-1-[[(2S,3R)-1-[[(2S)-1-[[(1S)-1-carboxy-3-methylsulfanylpropyl]amino]-3-methyl-1-oxobutan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-oxobutan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxobutan-2-yl]amino]-5-oxopentanoic acid	1802842: Fluorescent Polarization Competition Assay from Article 10.1021/acs.biochem.7b00078: “Origins of PDZ Binding Specificity. A Computational and Experimental Study Using NHERF1 and the Parathyroid Hormone Receptor.”	ki	1.4000	uM
5-[[3-[[(2R)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-5-amino-1-[[(2R)-1-[[(2S,3R)-1-[[(2S)-5-carbamimidamido-1-[[(1S)-1-carboxy-2,2-dimethylpropyl]amino]-1-oxopentan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-3-methyl-1-oxo-3-sulfanylbutan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-3-naphthalen-2-yl-1-oxopropan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1-oxo-3-sulfanylpropan-2-yl]amino]-3-oxopropyl]carbamothioylamino]-2-(3-hydroxy-6-oxoxanthen-9-yl)benzoic acid	1701513: Binding affinity to NHERF1 PDZ1 domain (unknown origin) expressed in Escherichia coli BL21 incubated for 1 hr by fluorescence polarization based competition assay	kd	1.6400	uM
(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2R)-2-[[(2S)-1-[(2S)-3-(1-benzothiophen-3-yl)-2-[[(2S)-2-[[(2S)-5-carbamimidamido-2-[[(2S)-5-carbamimidamido-2-[[(2R)-5-carbamimidamido-2-[[(2R)-2-[[2-[2-[2-[(3’,6’-dihydroxy-3-oxospiro[2-benzofuran-1,9’-xanthene]-5-yl)carbamothioylamino]ethoxy]ethoxy]acetyl]amino]-3-sulfanylpropanoyl]amino]pentanoyl]amino]pentanoyl]amino]pentanoyl]amino]-3-naphthalen-2-ylpropanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-3-methyl-3-sulfanylbutanoyl]amino]-3-hydroxybutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3,3-dimethylbutanoic acid	1701513: Binding affinity to NHERF1 PDZ1 domain (unknown origin) expressed in Escherichia coli BL21 incubated for 1 hr by fluorescence polarization based competition assay	kd	3.9700	uM
5-chloro-N-[2-(hydroxymethyl)phenyl]-1H-indole-3-carboxamide	1542935: Inhibition of NHERF1 in human Ls174T cells stably transfected with Dox-inducible shRNA for beta-catenin (Ls174Tsh-beta-Cat) assessed as inhibition of cell growth incubated for 72 hrs by presence of doxycycline by MTT assay	ic50	5.0000	uM
(4S)-4-[[(2S)-1-[(2R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[5-[(3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-carboxypropanoyl]amino]-4-carboxybutanoyl]amino]-4-carboxybutanoyl]amino]propanoyl]amino]-3-hydroxypropanoyl]amino]-3-sulfanylpropanoyl]pyrrolidine-2-carbonyl]amino]-5-[[(2S)-1-[(2S)-2-[(2S)-2-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-5-amino-1-[[(2S)-4-carboxy-1-[[(2S)-4-carboxy-1-[[(2S)-1-[[(2S)-4-carboxy-1-[[(2S,3R)-1-[[(2S)-1-[[(1S)-1-carboxy-3-methylsulfanylpropyl]amino]-3-methyl-1-oxobutan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-oxobutan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxobutan-2-yl]amino]-1-oxobutan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]carbamoyl]pyrrolidine-1-carbonyl]pyrrolidin-1-yl]-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-oxopentanoic acid	1802842: Fluorescent Polarization Competition Assay from Article 10.1021/acs.biochem.7b00078: “Origins of PDZ Binding Specificity. A Computational and Experimental Study Using NHERF1 and the Parathyroid Hormone Receptor.”	ki	7.0000	uM
3-benzyl-5-chloro-N-[4-(hydroxymethyl)phenyl]-1H-indole-2-carboxamide	1542935: Inhibition of NHERF1 in human Ls174T cells stably transfected with Dox-inducible shRNA for beta-catenin (Ls174Tsh-beta-Cat) assessed as inhibition of cell growth incubated for 72 hrs by presence of doxycycline by MTT assay	ic50	8.0000	uM
5-chloro-N-[3-(hydroxymethyl)phenyl]-1H-indole-3-carboxamide	1542935: Inhibition of NHERF1 in human Ls174T cells stably transfected with Dox-inducible shRNA for beta-catenin (Ls174Tsh-beta-Cat) assessed as inhibition of cell growth incubated for 72 hrs by presence of doxycycline by MTT assay	ic50	8.0000	uM
(4S)-5-[[(2S)-4-carboxy-1-[[(2S)-1-[[(2S)-4-carboxy-1-[[(2S,3R)-1-[[(2S)-1-[[(1S)-1-carboxy-3-methylsulfanylpropyl]amino]-3-methyl-1-oxobutan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-oxobutan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxobutan-2-yl]amino]-4-[[(2S)-2,5-diamino-5-oxopentanoyl]amino]-5-oxopentanoic acid	1802844: Isothermal Titration Calorimetry (ITC) from Article 10.1021/acs.biochem.7b00078: “Origins of PDZ Binding Specificity. A Computational and Experimental Study Using NHERF1 and the Parathyroid Hormone Receptor.”	kd	9.7000	uM
5-chloro-N-[[4-(hydroxymethyl)phenyl]methyl]-1H-indole-3-carboxamide	1542935: Inhibition of NHERF1 in human Ls174T cells stably transfected with Dox-inducible shRNA for beta-catenin (Ls174Tsh-beta-Cat) assessed as inhibition of cell growth incubated for 72 hrs by presence of doxycycline by MTT assay	ic50	10.0000	uM

CTD chemical–gene interactions

75 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Estradiol	decreases reaction, increases expression, affects binding, affects cotreatment, decreases expression	5
bisphenol A	increases expression, affects expression, decreases expression	3
Air Pollutants	decreases expression, affects cotreatment, increases abundance, increases oxidation	3
Valproic Acid	increases expression	3
Cyclosporine	decreases expression	3
Cisplatin	affects expression, affects cotreatment, increases expression	2
Smoke	decreases expression	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
Genistein	increases expression, increases reaction	2
FR900359	affects phosphorylation	1
2,4,6-tribromophenol	decreases expression	1
methylmercuric chloride	decreases expression	1
alpha-pinene	increases oxidation, increases abundance, affects cotreatment	1
titanium dioxide	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
decabromobiphenyl ether	decreases expression	1
sodium arsenite	increases expression	1
tetrabromobisphenol A	decreases expression	1
benzo(e)pyrene	decreases methylation	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
aflatoxin B2	decreases methylation	1
coumarin	decreases phosphorylation	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
beta-methylcholine	affects expression	1
tamibarotene	increases expression	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
14-deoxy-11,12-didehydroandrographolide	decreases expression	1
abrine	decreases expression	1

ChEMBL screening assays

5 unique, capped per target: 5 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4340092	Binding	Inhibition of NHERF1 in human Ls174T cells stably transfected with Dox-inducible shRNA for beta-catenin (Ls174Tsh-beta-Cat) assessed as inhibition of cell growth incubated for 72 hrs by absence of doxycycline by MTT assay	Drug Design and Synthesis of First in Class PDZ1 Targeting NHERF1 Inhibitors as Anticancer Agents. — ACS Med Chem Lett

Cellosaurus cell lines

6 cell lines: 6 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1E5	Abcam HCT 116 SLC9A3R1 KO	Cancer cell line	Male
CVCL_B2GE	Abcam HeLa SLC9A3R1 KO	Cancer cell line	Female
CVCL_LI03	GHOST(3)-CCR5 DRiP78 and NHERF1 knockdown	Cancer cell line	Female
CVCL_LI04	GHOST(3)-CXCR4 DRiP78 and NHERF1 knockdown	Cancer cell line	Female
CVCL_TP20	HAP1 SLC9A3R1 (-) 1	Cancer cell line	Male
CVCL_TP21	HAP1 SLC9A3R1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00073710	PHASE4	COMPLETED	Study to Evaluate the Effects of Zemplar Injection and Calcijex on Intestinal Absorption of Calcium
NCT00125593	PHASE4	COMPLETED	Study of Heart and Renal Protection
NCT00132431	PHASE4	COMPLETED	START: Sensipar Treatment Algorithm to Reach K/DOQI Targets in Chronic Kidney Disease Subjects With Secondary Hyperparathyroidism
NCT00155246	PHASE4	COMPLETED	Efficacy of Pentoxifylline on Chronic Kidney Disease
NCT00175149	PHASE4	TERMINATED	Active Vitamin D Effect on Left Ventricular Hypertrophy
NCT00184769	PHASE4	COMPLETED	Growth Hormone Treatment in Infants Aged 1 to 2 Years With Chronic Renal Insufficiency (CRI) and Growth Retardation.
NCT00190580	PHASE4	COMPLETED	Kanagawa Valsartan Trial (KVT): Effects of Valsartan on Renal and Cardiovascular Disease
NCT00194961	PHASE4	TERMINATED	Effect of Growth Hormone on Leptin, Cytokines and Body Composition of Children With Growth Failure Due to Chronic Kidney Disease
NCT00239642	PHASE4	COMPLETED	Safety and Efficacy of Iron Sucrose in Children
NCT00324571	PHASE4	COMPLETED	Dialysis Clinical Outcomes Revisited (DCOR) Trial
NCT00364884	PHASE4	UNKNOWN	Keto-/Amino Acid Supplemented Low Protein Diet in Patients With Chronic Kidney Disease
NCT00368901	PHASE4	COMPLETED	STAAR-2 Clinical Study
NCT00369733	PHASE4	COMPLETED	STAAR-3 Clinical Study
NCT00369772	PHASE4	COMPLETED	STAAR-1 Clinical Study
NCT00379899	PHASE4	COMPLETED	ADVANCE: Study to Evaluate Cinacalcet Plus Low Dose Vitamin D on Vascular Calcification in Subjects With Chronic Kidney Disease Receiving Hemodialysis
NCT00384618	PHASE4	TERMINATED	Anti-Oxidant Therapy In Chronic Renal Insufficiency (ATIC) Study
NCT00478543	PHASE4	COMPLETED	Loop Diuretics in Chronic Kidney Disease
NCT00632125	PHASE4	COMPLETED	Post-authorization Safety Study in CKD Subjects Receiving HX575 i.v.
NCT00644046	PHASE4	COMPLETED	Chronic Kidney Disease Prevention of An-Lo District, Keelung
NCT00719316	PHASE4	UNKNOWN	Aliskiren and Muscle Sympathetic Nerve Activity
NCT00725517	PHASE4	COMPLETED	Efficacy and Safety of a 7.5% Icodextrin Peritoneal Dialysis Solution in Once-Daily Long Dwell Exchange
NCT00741585	PHASE4	COMPLETED	Prognostic Value of the Circadian Pattern of Ambulatory Blood Pressure for Multiple Risk Assessment
NCT00749736	PHASE4	COMPLETED	The Role of Vitamin D in Immune Function in Patients With Chronic Kidney Disease (CKD) Stages 3 and 4.
NCT00752102	PHASE4	COMPLETED	Vitamin D and Coronary Calcification Study
NCT00756145	PHASE4	COMPLETED	The Use of Low Molecular Weight Heparin in Hemodiafiltration
NCT00768638	PHASE4	COMPLETED	Study of Atorvastatin Dose Dependent Reduction of Proteinuria
NCT00786136	PHASE4	COMPLETED	Rosuvastatin Prevent Contrast Induced Acute Kidney Injury in Patients With Diabetes
NCT00803712	PHASE4	COMPLETED	20070360 Incident Dialysis
NCT00812123	PHASE4	COMPLETED	Calcineurin Free Immunosuppression in Renal Transplant Recipients
NCT00823303	PHASE4	COMPLETED	Paricalcitol Versus Calcitriol for Efficacy and Safety in Stage 3/4 Chronic Kidney Disease (CKD) With Secondary Hyperparathyroidism (SHPT)
NCT00830037	PHASE4	TERMINATED	A Clinical Trial of Oral Versus IV Iron in Patients With Chronic Kidney Disease
NCT00852969	PHASE4	COMPLETED	Niacin and Endothelial Function in Early CKD
NCT00858299	PHASE4	UNKNOWN	The Change of Urinary Angiotensinogen Excretion After Valsartan Treatment in Patients With Persistent Proteinuria
NCT00860431	PHASE4	COMPLETED	Kremezin Study Against Renal Disease Progression in Korea
NCT00882401	PHASE4	COMPLETED	Vitamin D, Chronic Kidney Disease (CKD) and the Microcirculation
NCT00889629	PHASE4	COMPLETED	Pilot Study Evaluating Doxercalciferol Replacement Therapy in Kidney Transplant Recipients
NCT00892892	PHASE4	WITHDRAWN	Sympathetic Nerve Activity in Renal Failure
NCT00893425	PHASE4	COMPLETED	Effect of Renin Angiotensin System Blockade on the Fas Antigen (CD95) and Asymmetric Dimethylarginine (ADMA) Levels in Type-2 Diabetic Patients With Proteinuria
NCT00908310	PHASE4	COMPLETED	Post-marketing Safety Study in Patients With Moderate Renal Insufficiency Who Receive Omniscan for Contrast-enhanced Magnetic Resonance Imaging (MRI)
NCT00958451	PHASE4	COMPLETED	Vitamin D Deficiency in Chronic Kidney Disease (CKD) Patients