EZR

Summary

EZR (ezrin, HGNC:12691) is a protein-coding gene on chromosome 6q25.3, encoding Ezrin (P15311). Probably involved in connections of major cytoskeletal structures to the plasma membrane.

The cytoplasmic peripheral membrane protein encoded by this gene functions as a protein-tyrosine kinase substrate in microvilli. As a member of the ERM protein family, this protein serves as an intermediate between the plasma membrane and the actin cytoskeleton. This protein plays a key role in cell surface structure adhesion, migration and organization, and it has been implicated in various human cancers. A pseudogene located on chromosome 3 has been identified for this gene. Alternatively spliced variants have also been described for this gene.

Source: NCBI Gene 7430 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal recessive non-syndromic intellectual disability (Supportive, GenCC)
• GWAS associations: 6
• Clinical variants (ClinVar): 133 total
• Druggable target: yes
• MANE Select transcript: NM_001111077

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12691
Approved symbol	EZR
Name	ezrin
Location	6q25.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000092820
Ensembl biotype	protein_coding
OMIM	123900
Entrez	7430

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 25 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000337147, ENST00000367075, ENST00000476189, ENST00000852603, ENST00000852604, ENST00000852605, ENST00000852606, ENST00000852607, ENST00000852608, ENST00000852609, ENST00000852610, ENST00000852611, ENST00000852612, ENST00000852613, ENST00000852614, ENST00000923500, ENST00000923501, ENST00000923502, ENST00000923503, ENST00000923504, ENST00000923505, ENST00000923506, ENST00000945662, ENST00000945663, ENST00000945664, ENST00000945665

RefSeq mRNA: 2 — MANE Select: NM_001111077 NM_001111077, NM_003379

CCDS: CCDS5258

Canonical transcript exons

ENST00000367075 — 14 exons

Exon	Start	End
ENSE00000894187	158769326	158769418
ENSE00001028540	158769784	158769944
ENSE00001028543	158783520	158783666
ENSE00001028545	158770764	158770894
ENSE00001316323	158767261	158767512
ENSE00001443426	158819317	158819368
ENSE00001927159	158765748	158767078
ENSE00002333652	158771244	158771407
ENSE00002491581	158776408	158776504
ENSE00003527117	158787108	158787203
ENSE00003532760	158789288	158789371
ENSE00003648714	158784644	158784727
ENSE00003678887	158818082	158818166
ENSE00003679609	158785309	158785583

Expression profiles

Bgee: expression breadth ubiquitous, 291 present calls, max score 99.47.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 99.5074 / max 1334.0617, expressed in 1815 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
76421	56.1614	1805
76419	30.7515	1735
76422	4.2146	1504
76420	4.1556	1211
76409	1.4886	768
76410	1.1841	632
76398	0.6379	398
76407	0.3879	186
76408	0.3100	142
76399	0.2158	69

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	99.47	gold quality
bronchial epithelial cell	CL:0002328	99.46	gold quality
epithelium of bronchus	UBERON:0002031	99.44	gold quality
ganglionic eminence	UBERON:0004023	99.42	gold quality
nasal cavity epithelium	UBERON:0005384	99.38	gold quality
bronchus	UBERON:0002185	99.36	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	99.36	gold quality
mucosa of paranasal sinus	UBERON:0005030	99.29	gold quality
nasal cavity mucosa	UBERON:0001826	99.15	gold quality
tendon of biceps brachii	UBERON:0008188	99.04	gold quality
right adrenal gland cortex	UBERON:0035827	98.94	gold quality
right adrenal gland	UBERON:0001233	98.88	gold quality
right uterine tube	UBERON:0001302	98.87	gold quality
lower esophagus mucosa	UBERON:0035834	98.86	gold quality
jejunal mucosa	UBERON:0000399	98.78	gold quality
left adrenal gland	UBERON:0001234	98.73	gold quality
calcaneal tendon	UBERON:0003701	98.67	gold quality
esophagus mucosa	UBERON:0002469	98.64	gold quality
left adrenal gland cortex	UBERON:0035825	98.62	gold quality
adrenal cortex	UBERON:0001235	98.60	gold quality
right lung	UBERON:0002167	98.57	gold quality
adrenal gland	UBERON:0002369	98.49	gold quality
upper lobe of lung	UBERON:0008948	98.42	gold quality
upper lobe of left lung	UBERON:0008952	98.42	gold quality
skin of abdomen	UBERON:0001416	98.41	gold quality
placenta	UBERON:0001987	98.41	gold quality
oral cavity	UBERON:0000167	98.37	gold quality
skin of leg	UBERON:0001511	98.32	gold quality
pigmented layer of retina	UBERON:0001782	98.32	gold quality
tendon	UBERON:0000043	98.30	gold quality

Single-cell (SCXA)

Detected in 30 experiment(s), a significant marker in 22.

Experiment	Marker?	Max mean expression
E-MTAB-9388	yes	3001.05
E-GEOD-81547	yes	2751.61
E-MTAB-8530	yes	1374.76
E-GEOD-135922	yes	1221.09
E-GEOD-149689	yes	1194.39
E-CURD-122	yes	1167.72
E-MTAB-8495	yes	1147.24
E-MTAB-10018	yes	837.80
E-HCAD-4	yes	121.37
E-MTAB-6701	yes	47.98
E-HCAD-5	yes	42.86
E-CURD-112	yes	42.04
E-MTAB-10287	yes	40.16
E-MTAB-9467	yes	33.45
E-HCAD-10	yes	30.30

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
ICAM1	Activation

Upstream regulators (CollecTRI, top): AP1, AR, FOS, FOXJ1, JUN, MYC, NFKB, SIX1, SP1

miRNA regulators (miRDB)

71 targeting EZR, 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-3613-3P	100.00	76.36	7965
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-205-5P	99.81	70.05	1557
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-548AG	99.77	69.25	1492
HSA-MIR-548A-3P	99.76	70.58	3524

Literature-anchored findings (GeneRIF, showing 40)

• A2BR binds to Ezrin upon agonist stimulation. (PMID:12080047)
• evaluated the role of Lck tyrosine kinase, an early effector of T cell activation, in regulation of the membrane-cytoskeleton linker protein ezrin; results identify ezrin as the first cytoskeletal substrate for Lck (PMID:12560083)
• Although ezrin is excluded from the inhibitory, i.e., noncytolytic, NK cell immune synapse (IS), it is homogeneously distributed across the IS of activating conjugates. (PMID:12626536)
• Review.CD44 and ezrin and their respective complex have properties suggesting that they may be important in the process of tumour-endothelium interactions, cell migrations, cell adhesion, tumour progression and metastasis. (PMID:12711360)
• amino-terminal domains of the ezrin, radixin, and moesin (ERM) proteins bind advanced glycation end products and have a role in diabetes (PMID:12734202)
• The upregulated ezrin expression is one of the important factors that are possibly associated with the invasive phenotype formation in malignantly transformed esophageal epithelial cells (ezrin) (PMID:12800220)
• Ezrin N-terminal domain binds to the syndecan-2 cytoplasmic domain with an estimated K(D) of 0.71 microM and without the requirement of other proteins (PMID:12860416)
• a major role of ezrin is to connect CD95 to actin, thus allowing the CD95 polarization on the cells and the occurrence of the following multiple cascades of the CD95 pathway (PMID:14676203)
• Data show that ezrin and the homeodomain-containing transcription factor Six-1 (sine oculis-related homeobox-1 homolog) had essential roles in determining the metastatic fate of rhabdomyosarcoma cells. (PMID:14704789)
• results report a significant association between high ezrin expression and poor outcome in pediatric osteosarcoma patients (PMID:14704791)
• pka phosphorylation of merlin serine 518 promotes heterodimerization between merlin and ezrin, an event suggested to convert merlin from a growth-suppressive to a growth-permissive state (PMID:14981079)
• ezrin/radixin/moesin proteins are recruited by NHE1 Na+/H+ exchanger and have roles in regulating Akt-dependent cell survival (PMID:15096511)
• All three ERM family members can localise to the nucleus; a specific nuclear localisation sequence, which is conserved and functional in all ERM family members, is identified, implying specific regulated nuclear import. (PMID:15149851)
• results suggest that ezrin-radixin-moesin proteins are required for microvillar positioning of L-selectin and that this is important both for leukocyte tethering and L-selectin shedding (PMID:15178693)
• Ezrin, radixin and moesin are ADP-ribosylated by Pseudomonas aeruginosa ExoS (PMID:15252013)
• Akt2-dependent ezrin phosphorylation leads to NHE3 translocation and activation (PMID:15531580)
• Src phosphorylates ezrin at tyrosine 477 (PMID:15623525)
• Src-dependent ezrin phosphorylation has a role in adhesion-mediated events in epithelial cells (PMID:15647376)
• Data show that the integrity of ezrin is essential for parietal cell activation and provide evidence that ezrin interacts with PALS1, an evolutionarily conserved PDZ and SH3 domain-containing protein. (PMID:15677456)
• Ezrin accumulates at Listeria protrusions, which plays a role in the Listeria cell-to-cell spread during infection. (PMID:15729356)
• Results strongly support the conformational activation model of ezrin, elucidate the basis for dimer formation, and reveal that a mutant generally considered to be fully activated is not. (PMID:15751968)
• Fibronectin and ezrin were upregulated in primary laryngeal carcinoma. (PMID:15835821)
• Ezrin is a novel substrate of GRK2 (PMID:15843435)
• 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)
• High expressions of ezrin is associated with development of distant metastasis of soft tissue sarcomas (PMID:16144921)
• Ezrin was expressed in the majority of prostate cancers and correlated with adverse prognostic factors (PMID:16230228)
• Ezrin directly interacts with the alpha1b-adrenergic receptor and plays a role in receptor recycling. (PMID:16352594)
• Protein Kinase A-mediated phosphorylation of ezrin is essential and sufficient for the apical localization of WW domain containing oxidoreductase (WWOX) protein as disruption of ezrin-WWOX interaction eliminated the apical localization of WWOX (PMID:16438931)
• a change in ezrin localization from the apical membrane to either the complete membrane or to the cytoplasm may have a role in dedifferentiation in invasive breast tumors (PMID:16538541)
• Elevated ezrin expression is a new independent prognostic marker in FIGO stage I endometrioid carcinoma, and thus provides further evidence for an important role of ezrin in tumor progression. (PMID:16554733)
• data imply that ezrin is necessary for tumor cell invasion, and the better prognosis of ovarian carcinomas lacking ezrin is probably related to their impaired invasion (PMID:16633060)
• the release of ezrin from lipid rafts acts as a critical trigger that regulates lipid raft dynamics during B cell antigen receptor signaling. (PMID:16648854)
• Ezrin appears to play a role in the progression of tumors, such as the metastasis of osteosarcoma. (PMID:16677779)
• Over-expression of ezrin and cytoskeleton protein gamma-actin are associated with the process of metastasis of hepatocellular carcinoma cells. (PMID:16867268)
• Hormonal regulation of ezrin phosphorylation is required for androgen-induced cell invasion. (PMID:16873375)
• Expression of ExoS in HeLa cells led to a loss of phosphorylation of Ezrin/radixin/moesin proteins that was dependent upon the expression of ADP-ribosyltransferase activity. (PMID:16889625)
• the action of ezrin in Ewing’s sarcoma is dependent on the AKT/mTOR signal transduction cascade, but not MAP Kinase. (PMID:17028919)
• increased CD44, ezrin, radixin, and moesin phosphorylation represents a key molecular abnormality that guides T cell adhesion and migration in SLE patients. (PMID:17237445)
• identification of PTHrP and ezrin as important regulators of lung cancer bone metastasis offers new mechanistic insights into the metastasis of lung cancer and provides potential targets for the prevention and treatment of lung cancer metastasis (PMID:17370040)
• data support a role for ezrin in the biology of human cancers and the need for additional studies in breast cancer and sarcoma patients that may validate ezrin as a marker of cancer progression and as a potential target for cancer therapy (PMID:17370041)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ezra	ENSDARG00000020944
danio_rerio	ezrb	ENSDARG00000025091
mus_musculus	Ezr	ENSMUSG00000052397
rattus_norvegicus	Ezr	ENSRNOG00000018524

Paralogs (6): FRMD4B (ENSG00000114541), ERMN (ENSG00000136541), RDX (ENSG00000137710), MSN (ENSG00000147065), FRMD4A (ENSG00000151474), NF2 (ENSG00000186575)

Protein

Protein identifiers

Ezrin — P15311 (reviewed: P15311)

Alternative names: Cytovillin, Villin-2, p81

All UniProt accessions (1): P15311

UniProt curated annotations — full annotation on UniProt →

Function. Probably involved in connections of major cytoskeletal structures to the plasma membrane. In epithelial cells, required for the formation of microvilli and membrane ruffles on the apical pole. Along with PLEKHG6, required for normal macropinocytosis.

Subunit / interactions. Monomer. Homodimer. Interacts with PALS1 and NHERF2. Found in a complex with EZR, PODXL and NHERF2. Interacts with MCC, PLEKHG6, PODXL, SCYL3/PACE1, NHERF1 and TMEM8B. Interacts (when phosphorylated) with FES/FPS. Interacts with dimeric S100P, the interaction may be activating through unmasking of F-actin binding sites. Identified in complexes that contain VIM, EZR, AHNAK, BFSP1, BFSP2, ANK2, PLEC, PRX and spectrin. Detected in a complex composed of at least EZR, AHNAK, PPL and PRX. Interacts with PDPN (via cytoplasmic domain); activates RHOA and promotes epithelial-mesenchymal transition. Interacts with SPN/CD43 cytoplasmic tail, CD44 and ICAM2. Interacts with SLC9A3; interaction targets SLC9A3 to the apical membrane. Interacts with SLC9A1; regulates interactions of SLC9A1 with cytoskeletal and promotes stress fiber formation. Interacts with CLIC5; may work together in a complex which also includes RDX and MYO6 to stabilize linkages between the plasma membrane and subjacent actin cytoskeleton at the base of stereocilia.

Subcellular location. Apical cell membrane. Cell projection. Microvillus membrane. Ruffle membrane. Cytoplasm. Cell cortex. Cytoskeleton. Microvillus.

Tissue specificity. Expressed in cerebral cortex, basal ganglia, hippocampus, hypophysis, and optic nerve. Weakly expressed in brain stem and diencephalon. Stronger expression was detected in gray matter of frontal lobe compared to white matter (at protein level). Component of the microvilli of intestinal epithelial cells. Preferentially expressed in astrocytes of hippocampus, frontal cortex, thalamus, parahippocampal cortex, amygdala, insula, and corpus callosum. Not detected in neurons in most tissues studied.

Post-translational modifications. Phosphorylated by tyrosine-protein kinases. Phosphorylation by ROCK2 suppresses the head-to-tail association of the N-terminal and C-terminal halves resulting in an opened conformation which is capable of actin and membrane-binding. S-nitrosylation is induced by interferon-gamma and oxidatively-modified low-densitity lipoprotein (LDL(ox)) possibly implicating the iNOS-S100A8/9 transnitrosylase complex.

Activity regulation. A head-to-tail association, of the N-terminal and C-terminal halves results in a closed conformation (inactive form) which is incapable of actin or membrane-binding.

Domain organisation. Has three main structural domains: an N-terminal FERM domain, a central alpha-helical domain and a C-terminal actin-binding domain. The FERM domain is organized in a clover-shaped structure that comprises three subdomains identified as F1 (residues 2-82), F2 (residues 96-198), and F3 (residues 204-296). In the active form, the subdomain F3 adopts two mutually exclusive conformational isomers where a row of four phenylalanine side chains (Phe250, Phe255, Phe267 and Phe269) must point in the same direction. In the autoinhibited form, the F3 subdomain interacts with the C-terminal domain (residues 516-586) and stabilizes the structure, selecting only one possible arrangement of phenylalanine side chains. The FERM domain mediates binding to membrane lipids and signaling molecules. The central alpha-helical domain is composed of two alpha helices (residues 326-406 and 417-466) connected by a linker. It protrudes from the FERM domain forming a coiled coil structure where the linker can have either a loop or a helix conformation. The monomer is predicted to form an intra-molecular helix-loop-helix coiled coil structure. Whereas the dimer adopts an elongated dumbbell-shaped configuration where continuous alpha helices from each protomer are organized in a antiparallel coiled coil structure that connect FERM:C-terminal domain swapped complex at each end. The dimer is predicted to link actin filaments parallel to the plasma membrane. The [IL]-x-C-x-x-[DE] motif is a proposed target motif for cysteine S-nitrosylation mediated by the iNOS-S100A8/A9 transnitrosylase complex.

RefSeq proteins (2): NP_001104547, NP_003370 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000299	FERM_domain	Domain
IPR000798	Ez/rad/moesin-like	Family
IPR008954	Moesin_tail_sf	Homologous_superfamily
IPR011174	ERM	Family
IPR011259	ERM_C_dom	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR014352	FERM/acyl-CoA-bd_prot_sf	Homologous_superfamily
IPR018979	FERM_N	Domain
IPR018980	FERM_PH-like_C	Domain
IPR019747	FERM_CS	Conserved_site
IPR019748	FERM_central	Domain
IPR019749	Band_41_domain	Domain
IPR029071	Ubiquitin-like_domsf	Homologous_superfamily
IPR035963	FERM_2	Homologous_superfamily
IPR041789	ERM_FERM_C	Domain
IPR046810	ERM_helical	Domain

Pfam: PF00373, PF00769, PF09379, PF09380, PF20492

UniProt features (56 total): helix 17, strand 14, modified residue 7, compositionally biased region 4, turn 4, sequence variant 3, region of interest 3, chain 1, domain 1, coiled-coil region 1, short sequence motif 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
7T1K	X-RAY DIFFRACTION	1.25
7T1L	X-RAY DIFFRACTION	1.35
4RMA	X-RAY DIFFRACTION	1.75
4RM8	X-RAY DIFFRACTION	1.9
4RM9	X-RAY DIFFRACTION	2
8XZ0	X-RAY DIFFRACTION	2.04
1NI2	X-RAY DIFFRACTION	2.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P15311-F1	88.16	0.69

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 (7): 60, 146, 354, 366, 478, 535, 567

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-373752	Netrin-1 signaling
R-HSA-437239	Recycling pathway of L1
R-HSA-9662360	Sensory processing of sound by inner hair cells of the cochlea
R-HSA-9662361	Sensory processing of sound by outer hair cells of the cochlea

MSigDB gene sets: 545 (showing top): GOBP_REGULATION_OF_T_CELL_RECEPTOR_SIGNALING_PATHWAY, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_ENDOTHELIAL_CELL_DEVELOPMENT, VERHAAK_AML_WITH_NPM1_MUTATED_DN, GOBP_REGULATION_OF_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOBP_DIGESTION, GOBP_NEGATIVE_REGULATION_OF_ERK1_AND_ERK2_CASCADE, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_CYTOPLASMIC_MICROTUBULE_ORGANIZATION, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_MONOPOLAR_CELL_POLARITY, GOBP_ACTIN_FILAMENT_BUNDLE_ORGANIZATION, GOBP_GLAND_MORPHOGENESIS, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY

GO Biological Process (35): negative regulation of transcription by RNA polymerase II (GO:0000122), intestinal D-glucose absorption (GO:0001951), sphingosine-1-phosphate receptor signaling pathway (GO:0003376), leukocyte cell-cell adhesion (GO:0007159), regulation of cell shape (GO:0008360), positive regulation of gene expression (GO:0010628), obsolete protein kinase A signaling (GO:0010737), membrane to membrane docking (GO:0022614), microvillus assembly (GO:0030033), actin cytoskeleton organization (GO:0030036), astral microtubule organization (GO:0030953), protein-containing complex localization (GO:0031503), receptor internalization (GO:0031623), regulation of microvillus length (GO:0032532), negative regulation of interleukin-2 production (GO:0032703), establishment or maintenance of apical/basal cell polarity (GO:0035088), positive regulation of multicellular organism growth (GO:0040018), cortical microtubule organization (GO:0043622), positive regulation of protein catabolic process (GO:0045732), filopodium assembly (GO:0046847), negative regulation of T cell receptor signaling pathway (GO:0050860), actin filament bundle assembly (GO:0051017), establishment of centrosome localization (GO:0051660), establishment of endothelial barrier (GO:0061028), negative regulation of ERK1 and ERK2 cascade (GO:0070373), cellular response to cAMP (GO:0071320), protein localization to plasma membrane (GO:0072659), protein localization to cell cortex (GO:0072697), postsynaptic actin cytoskeleton organization (GO:0098974), regulation of organelle assembly (GO:1902115), terminal web assembly (GO:1902896), positive regulation of protein localization to early endosome (GO:1902966), positive regulation of protein localization to plasma membrane (GO:1903078), negative regulation of p38MAPK cascade (GO:1903753), positive regulation of early endosome to late endosome transport (GO:2000643)

GO Molecular Function (16): RNA binding (GO:0003723), actin binding (GO:0003779), microtubule binding (GO:0008017), protein domain specific binding (GO:0019904), protein kinase A catalytic subunit binding (GO:0034236), protein kinase A regulatory subunit binding (GO:0034237), identical protein binding (GO:0042802), S100 protein binding (GO:0044548), cadherin binding (GO:0045296), cell adhesion molecule binding (GO:0050839), actin filament binding (GO:0051015), protein kinase A binding (GO:0051018), ATPase binding (GO:0051117), disordered domain specific binding (GO:0097718), protein binding (GO:0005515), cytoskeletal protein binding (GO:0008092)

GO Cellular Component (33): fibrillar center (GO:0001650), ruffle (GO:0001726), immunological synapse (GO:0001772), uropod (GO:0001931), obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737), endosome (GO:0005768), cytosol (GO:0005829), actin filament (GO:0005884), plasma membrane (GO:0005886), microvillus (GO:0005902), brush border (GO:0005903), adherens junction (GO:0005912), focal adhesion (GO:0005925), actin cytoskeleton (GO:0015629), membrane (GO:0016020), basolateral plasma membrane (GO:0016323), apical plasma membrane (GO:0016324), filopodium (GO:0030175), cortical cytoskeleton (GO:0030863), microvillus membrane (GO:0031528), vesicle (GO:0031982), ruffle membrane (GO:0032587), protein-containing complex (GO:0032991), ciliary basal body (GO:0036064), cell projection (GO:0042995), plasma membrane raft (GO:0044853), apical part of cell (GO:0045177), perinuclear region of cytoplasm (GO:0048471), extracellular exosome (GO:0070062), cell periphery (GO:0071944), cytoskeleton (GO:0005856), cell cortex (GO:0005938)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Sensory processing of sound	2
Axon guidance	1
L1CAM interactions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	6
cellular anatomical structure	5
plasma membrane bounded cell projection assembly	2
cytoplasmic microtubule organization	2
protein kinase A binding	2
plasma membrane bounded cell projection	2
actin-based cell projection	2
apical part of cell	2
cytoskeleton	2
plasma membrane region	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
intestinal hexose absorption	1
G protein-coupled receptor signaling pathway	1
sphingolipid mediated signaling pathway	1
cell-cell adhesion	1
regulation of cell morphogenesis	1
regulation of biological quality	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
membrane docking	1
microvillus organization	1
cytoskeleton organization	1
actin filament-based process	1
spindle organization	1
macromolecule localization	1
receptor-mediated endocytosis	1
regulation of microvillus organization	1
regulation of cell projection size	1
negative regulation of cytokine production	1
interleukin-2 production	1
regulation of interleukin-2 production	1
establishment or maintenance of bipolar cell polarity	1
multicellular organism growth	1
regulation of multicellular organism growth	1
positive regulation of developmental growth	1
positive regulation of multicellular organismal process	1
cortical cytoskeleton organization	1

Protein interactions and networks

STRING

3648 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EZR	NHERF1	O14745	999
EZR	NHERF2	Q15599	995
EZR	CD44	P16070	993
EZR	PODXL	O00592	992
EZR	SLC9A1	P19634	985
EZR	RDX	P35241	984
EZR	PRKACA	P17612	983
EZR	PRKACG	P22612	983
EZR	PRKACB	P22694	983
EZR	MSN	P26038	983
EZR	ICAM1	P05362	980
EZR	VCL	P18206	977
EZR	SPN	P16150	966
EZR	ICAM2	P13598	963
EZR	HSP90AA1	P07900	952

IntAct

230 interactions, top by confidence:

A	B	Type	Score
CFTR	NHERF1	psi-mi:“MI:0914”(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
EZR	EZR	psi-mi:“MI:0915”(physical association)	0.780
NHERF2	PODXL	psi-mi:“MI:0914”(association)	0.770
PHLPP2	NHERF1	psi-mi:“MI:0914”(association)	0.760
EZR	MSN	psi-mi:“MI:0914”(association)	0.740
EZR	MISP	psi-mi:“MI:0915”(physical association)	0.740
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
DCC	NTN1	psi-mi:“MI:0914”(association)	0.700
EZR	HTT	psi-mi:“MI:0915”(physical association)	0.670

BioGRID (748): EZR (Affinity Capture-MS), EZR (Affinity Capture-MS), VPS11 (Two-hybrid), VPS11 (Affinity Capture-Western), VPS11 (Reconstituted Complex), ACAA2 (Co-fractionation), AKR1B1 (Co-fractionation), ARHGDIA (Co-fractionation), CALR (Co-fractionation), CLIC4 (Co-fractionation), ECE2 (Co-fractionation), EIF5A2 (Co-fractionation), EIF5AL1 (Co-fractionation), ENO1 (Co-fractionation), ENO2 (Co-fractionation)

ESM2 similar proteins: B0DOB5, B0WYY2, H2KZZ6, O35346, O35763, O35889, P0C1G6, P15311, P26038, P26040, P26041, P26042, P26043, P26044, P31976, P31977, P35240, P35241, P36583, P46150, P46662, P52962, P55196, P59750, Q05397, Q12929, Q15057, Q170J7, Q18685, Q24564, Q29GR8, Q2HJ49, Q32LP2, Q3UU96, Q5R4H4, Q63648, Q66I42, Q6A028, Q6IVG4, Q7PGE8

Diamond homologs: B0WYY2, B2RYE5, O35763, O43491, O70318, P12264, P15311, P26038, P26040, P26041, P26042, P26043, P26044, P26045, P29074, P31976, P31977, P35240, P35241, P46150, P46662, P52962, P59750, P86232, Q12923, Q170J7, Q24564, Q29GR8, Q2HJ49, Q32LP2, Q58CU2, Q5FVG2, Q63648, Q66I42, Q7PS12, Q8BGS1, Q8HZQ5, Q8WY64, Q9H329, Q9HCM4

SIGNOR signaling

24 interactions.

A	Effect	B	Mechanism
AKT2	up-regulates	EZR	phosphorylation
SRC	up-regulates	EZR	phosphorylation
EGFR	up-regulates	EZR	phosphorylation
EGFR	unknown	EZR	phosphorylation
PRKCA	up-regulates	EZR	phosphorylation
GRK2	up-regulates	EZR	phosphorylation
EZR	up-regulates	FES	relocalization
PRKCI	up-regulates	EZR	phosphorylation
STK26	up-regulates	EZR	phosphorylation
ROCK1	up-regulates	EZR	phosphorylation
AKT	up-regulates	EZR	phosphorylation
PTP4A3	“down-regulates activity”	EZR	dephosphorylation
CDK5	“up-regulates activity”	EZR	phosphorylation
SIX1	“up-regulates quantity”	EZR	“transcriptional regulation”
EZR	up-regulates	Metastasis
VPS11	“up-regulates activity”	EZR	binding
RHOA	“up-regulates activity”	EZR	phosphorylation
EZR	up-regulates	Platelet_aggregation
STK10	“up-regulates activity”	EZR	phosphorylation
SYK	“up-regulates activity”	EZR	phosphorylation
LRRK2	“up-regulates activity”	EZR	phosphorylation
LCK	unknown	EZR	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 147 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
MyD88 cascade initiated on plasma membrane	5	10.6×	7e-03
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation	5	9.9×	8e-03
MyD88 dependent cascade initiated on endosome	5	9.9×	8e-03
Signaling by ALK fusions and activated point mutants	6	9.4×	3e-03
Constitutive Signaling by Aberrant PI3K in Cancer	7	9.2×	2e-03
PIP3 activates AKT signaling	13	9.0×	1e-06
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	8	8.1×	2e-03
Signaling by Interleukins	8	5.3×	8e-03

GO biological processes:

GO term	Partners	Fold	FDR
amyloid fibril formation	5	24.1×	1e-03
establishment of mitotic spindle orientation	5	19.3×	2e-03
JNK cascade	6	13.1×	2e-03
positive regulation of ERK1 and ERK2 cascade	9	6.1×	4e-03
cell migration	10	4.9×	8e-03
negative regulation of apoptotic process	13	3.6×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	75
Likely benign	22
Benign	10

Top pathogenic / likely-pathogenic (0)

SpliceAI

1968 predictions. Top by Δscore:

Variant	Effect	Δscore
6:158767076:CGT:C	acceptor_gain	1.0000
6:158767079:C:CC	acceptor_gain	1.0000
6:158767512:CCTT:C	acceptor_gain	1.0000
6:158767515:T:C	acceptor_gain	1.0000
6:158767515:T:TC	acceptor_gain	1.0000
6:158769322:TCA:T	donor_loss	1.0000
6:158769323:CA:C	donor_loss	1.0000
6:158769324:A:AC	donor_gain	1.0000
6:158769324:AC:A	donor_gain	1.0000
6:158769324:ACC:A	donor_gain	1.0000
6:158769324:ACCC:A	donor_loss	1.0000
6:158769325:C:CC	donor_gain	1.0000
6:158769325:CC:C	donor_gain	1.0000
6:158769325:CCC:C	donor_gain	1.0000
6:158769325:CCCT:C	donor_gain	1.0000
6:158769415:CAGC:C	acceptor_gain	1.0000
6:158769416:AGC:A	acceptor_gain	1.0000
6:158769417:GC:G	acceptor_gain	1.0000
6:158769417:GCCT:G	acceptor_loss	1.0000
6:158769418:CC:C	acceptor_gain	1.0000
6:158769419:C:CA	acceptor_loss	1.0000
6:158769419:C:CC	acceptor_gain	1.0000
6:158769420:T:C	acceptor_loss	1.0000
6:158769771:AGG:A	donor_gain	1.0000
6:158769783:CCAG:C	donor_gain	1.0000
6:158769804:T:C	donor_gain	1.0000
6:158769833:T:TA	donor_gain	1.0000
6:158769940:GAGCT:G	acceptor_gain	1.0000
6:158769941:AGCT:A	acceptor_gain	1.0000
6:158769943:CT:C	acceptor_gain	1.0000

AlphaMissense

3904 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:158766940:G:T	R579S	1.000
6:158771289:A:G	M305T	1.000
6:158771361:A:G	L281P	1.000
6:158776453:G:C	F250L	1.000
6:158776453:G:T	F250L	1.000
6:158776455:A:G	F250L	1.000
6:158776477:C:A	W242C	1.000
6:158776477:C:G	W242C	1.000
6:158776479:A:G	W242R	1.000
6:158776479:A:T	W242R	1.000
6:158776483:A:C	F240L	1.000
6:158776483:A:T	F240L	1.000
6:158776484:A:G	F240S	1.000
6:158776485:A:G	F240L	1.000
6:158783544:A:G	L225P	1.000
6:158783547:C:T	G224E	1.000
6:158783548:C:G	G224R	1.000
6:158783548:C:T	G224R	1.000
6:158783562:C:T	G219E	1.000
6:158783565:A:G	L218P	1.000
6:158783571:A:G	L216P	1.000
6:158784693:A:G	W168R	1.000
6:158784693:A:T	W168R	1.000
6:158789298:A:G	L29P	1.000
6:158789307:C:T	G26E	1.000
6:158789308:C:G	G26R	1.000
6:158789308:C:T	G26R	1.000
6:158789331:A:G	F18S	1.000
6:158789337:A:G	L16P	1.000
6:158766926:G:C	F583L	0.999

dbSNP variants (sampled 300 via entrez): RS1000040015 (6:158803328 G>A,T), RS1000257173 (6:158803727 A>C,G), RS1000261213 (6:158767688 C>A,T), RS1000305386 (6:158794929 C>T), RS1000348545 (6:158792304 T>C), RS1000413938 (6:158801034 C>T), RS1000419762 (6:158798083 G>A), RS1000444177 (6:158765922 AACAAAC>A), RS1000509894 (6:158787059 G>A,T), RS1000600713 (6:158793696 G>A,C), RS1000645897 (6:158797808 T>C), RS1000677212 (6:158794779 A>G), RS1000688132 (6:158799694 C>T), RS1000738290 (6:158799360 G>A), RS1000820330 (6:158781467 T>C)

Disease associations

OMIM: gene MIM:123900 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal recessive non-syndromic intellectual disability	Supportive	Autosomal recessive

Mondo (1): autosomal recessive non-syndromic intellectual disability (MONDO:0019502)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST002397_4	Bladder cancer (smoking interaction)	1.000000e-06
GCST006075_7	Hair color	1.000000e-77
GCST006988_149	Blond vs. brown/black hair color	1.000000e-25
GCST006988_42	Blond vs. brown/black hair color	9.000000e-55
GCST006989_17	Brown vs. black hair color	4.000000e-13
GCST010002_339	Refractive error	5.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0003924	hair color

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1932896 (SINGLE PROTEIN)

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

ChEMBL bioactivities

10 potent at pChembl≥5 of 15 total, top 10 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.08	Kd	82.71	nM	CHEMBL5653589
7.08	ED50	82.71	nM	CHEMBL5653589
5.30	Kd	5000	nM	CHEMBL3104731
5.16	Kd	6900	nM	CHEMBL3104724
5.16	Kd	7000	nM	CHEMBL3104722
5.14	Kd	7290	nM	CHEMBL3752910
5.14	ED50	7290	nM	CHEMBL3752910
5.10	Kd	8000	nM	CHEMBL3104729
5.10	Kd	7900	nM	CHEMBL3104725
5.04	Kd	9100	nM	CHEMBL3104721

PubChem BioAssay actives

8 with measured affinity, of 22 total; 8 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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148355: Binding affinity to human EZR incubated for 45 mins by Kinobead based pull down assay	kd	0.0827	uM
7-[2-(4-hydroxy-3,5-dimethylphenyl)ethylamino]quinoline-5,8-dione	1062991: Binding affinity to recombinant ezrin (unknown origin) by surface plasmon resonance spectrometry	kd	5.0000	uM
7-[2-(4-hydroxyphenyl)ethylamino]quinoline-5,8-dione	1062991: Binding affinity to recombinant ezrin (unknown origin) by surface plasmon resonance spectrometry	kd	6.9000	uM
7-[2-(3-chloro-4-methoxyphenyl)ethylamino]quinoline-5,8-dione	1062991: Binding affinity to recombinant ezrin (unknown origin) by surface plasmon resonance spectrometry	kd	7.0000	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148355: Binding affinity to human EZR incubated for 45 mins by Kinobead based pull down assay	kd	7.2896	uM
7-[2-(3,4-dihydroxyphenyl)ethylamino]quinoline-5,8-dione	1062991: Binding affinity to recombinant ezrin (unknown origin) by surface plasmon resonance spectrometry	kd	7.9000	uM
7-[2-(3,5-dichloro-4-hydroxyphenyl)ethylamino]quinoline-5,8-dione	1062991: Binding affinity to recombinant ezrin (unknown origin) by surface plasmon resonance spectrometry	kd	8.0000	uM
7-[2-(3-bromophenyl)ethylamino]quinoline-5,8-dione	1062991: Binding affinity to recombinant ezrin (unknown origin) by surface plasmon resonance spectrometry	kd	9.1000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects methylation, decreases expression, increases expression	6
Valproic Acid	increases expression, affects expression, increases methylation, affects cotreatment	6
cyanoginosin LR	increases phosphorylation, increases expression, increases response to substance, decreases reaction	4
trichostatin A	affects cotreatment, increases expression	3
ochratoxin A	decreases expression, increases phosphorylation, increases expression	3
Tobacco Smoke Pollution	affects expression, increases expression	3
Particulate Matter	increases abundance, affects cotreatment, decreases expression	3
sodium arsenite	decreases expression, increases expression	2
cobaltous chloride	decreases expression	2
entinostat	affects cotreatment, increases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	2
Arsenic Trioxide	increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Acetaminophen	affects expression, increases expression	2
Air Pollutants	decreases expression, affects cotreatment, increases abundance, increases oxidation	2
Benzo(a)pyrene	affects methylation, increases expression	2
Estradiol	increases expression	2
Phenylmercuric Acetate	increases expression, affects cotreatment	2
Tretinoin	decreases expression	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
testosterone enanthate	affects expression	1
methylmercuric chloride	increases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
withaferin A	affects cotreatment, decreases expression	1
zinc chromate	decreases expression, increases abundance	1
4-hydroxy-2-nonenal	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
cupric oxide	decreases expression	1
methacrylaldehyde	increases abundance, affects cotreatment, increases oxidation	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1937278	Binding	Inhibition of ezrin phosphorylation in human DLD1 cells assessed as increase in alpha-ERM-Thr567 phosphorylation at 10 to 40 uM after 15 hrs by chemiluminescence method	Emodin inhibits migration and invasion of DLD-1 (PRL-3) cells via inhibition of PRL-3 phosphatase activity. — Bioorg Med Chem Lett

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1RR	Abcam HeLa EZR KO	Cancer cell line	Female
CVCL_D1W9	Abcam A-549 EZR KO	Cancer cell line	Male
CVCL_D2AM	Abcam HCT 116 EZR KO	Cancer cell line	Male
CVCL_SM69	HAP1 EZR (-) 1	Cancer cell line	Male
CVCL_XN60	HAP1 EZR (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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