ENAH

Summary

ENAH (ENAH actin regulator, HGNC:18271) is a protein-coding gene on chromosome 1q42.12, encoding Protein enabled homolog (Q8N8S7). Ena/VASP proteins are actin-associated proteins involved in a range of processes dependent on cytoskeleton remodeling and cell polarity such as axon guidance and lamellipodial and filopodial dynamics in migrating cells.

This gene encodes a member of the enabled/ vasodilator-stimulated phosphoprotein. Members of this gene family are involved in actin-based motility. This protein is involved in regulating the assembly of actin filaments and modulates cell adhesion and motility. Alternate splice variants of this gene have been correlated with tumor invasiveness in certain tissues and these variants may serve as prognostic markers. A pseudogene of this gene is found on chromosome 3.

Source: NCBI Gene 55740 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 83 total
• MANE Select transcript: NM_018212

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18271
Approved symbol	ENAH
Name	ENAH actin regulator
Location	1q42.12
Locus type	gene with protein product
Status	Approved
Aliases	FLJ10773, NDPP1, MENA
Ensembl gene	ENSG00000154380
Ensembl biotype	protein_coding
OMIM	609061
Entrez	55740

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 22 protein_coding, 2 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000284563, ENST00000358675, ENST00000366843, ENST00000366844, ENST00000391874, ENST00000483952, ENST00000497899, ENST00000498108, ENST00000635051, ENST00000696609, ENST00000893223, ENST00000893224, ENST00000893225, ENST00000893226, ENST00000893227, ENST00000893228, ENST00000893229, ENST00000893230, ENST00000931074, ENST00000931075, ENST00000931076, ENST00000931077, ENST00000931078, ENST00000931079, ENST00000931080, ENST00000931081

RefSeq mRNA: 9 — MANE Select: NM_018212 NM_001008493, NM_001377481, NM_001377482, NM_001377483, NM_001420159, NM_001420160, NM_001420161, NM_001420162, NM_018212

CCDS: CCDS31040, CCDS31041

Canonical transcript exons

ENST00000366843 — 14 exons

Exon	Start	End
ENSE00001129400	225514596	225514900
ENSE00001811595	225486829	225497812
ENSE00001888697	225652686	225653123
ENSE00003463753	225519198	225519565
ENSE00003479547	225567249	225567414
ENSE00003485859	225530554	225530638
ENSE00003496493	225500992	225501070
ENSE00003534455	225512871	225513016
ENSE00003567376	225554906	225555083
ENSE00003597630	225507951	225508017
ENSE00003627426	225511811	225511859
ENSE00003670110	225498347	225498404
ENSE00003681553	225512657	225512714
ENSE00003967846	225517196	225517306

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 99.08.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 51.0827 / max 598.3145, expressed in 1526 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
17714	45.0864	1523
17715	2.0798	923
17709	1.2435	670
17710	1.1255	577
17708	0.7548	411
17711	0.5419	273
17703	0.1931	78
17704	0.0575	28

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
saphenous vein	UBERON:0007318	99.08	gold quality
blood vessel layer	UBERON:0004797	98.53	gold quality
colonic epithelium	UBERON:0000397	98.49	gold quality
secondary oocyte	CL:0000655	98.36	gold quality
vena cava	UBERON:0004087	98.21	gold quality
urethra	UBERON:0000057	98.16	gold quality
seminal vesicle	UBERON:0000998	98.08	gold quality
cardia of stomach	UBERON:0001162	98.08	gold quality
ventricular zone	UBERON:0003053	98.07	gold quality
calcaneal tendon	UBERON:0003701	97.92	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	97.88	gold quality
sural nerve	UBERON:0015488	97.70	gold quality
choroid plexus epithelium	UBERON:0003911	97.67	gold quality
oocyte	CL:0000023	97.50	gold quality
bronchial epithelial cell	CL:0002328	97.39	gold quality
ganglionic eminence	UBERON:0004023	97.35	gold quality
adrenal tissue	UBERON:0018303	97.28	gold quality
embryo	UBERON:0000922	97.19	gold quality
pylorus	UBERON:0001166	97.18	gold quality
cauda epididymis	UBERON:0004360	97.03	gold quality
popliteal artery	UBERON:0002250	96.92	gold quality
tibial artery	UBERON:0007610	96.91	gold quality
mucosa of paranasal sinus	UBERON:0005030	96.90	gold quality
corpus epididymis	UBERON:0004359	96.83	gold quality
tibia	UBERON:0000979	96.80	gold quality
artery	UBERON:0001637	96.64	gold quality
corpus callosum	UBERON:0002336	96.50	gold quality
nipple	UBERON:0002030	96.43	gold quality
aorta	UBERON:0000947	96.42	gold quality
smooth muscle tissue	UBERON:0001135	96.23	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	13.64
E-CURD-112	yes	13.19
E-MTAB-8271	yes	7.17
E-MTAB-6678	yes	4.03

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTNNB1, TP53

miRNA regulators (miRDB)

309 targeting ENAH, 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-3163	100.00	77.23	8605
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-4803	99.98	71.99	3117

Literature-anchored findings (GeneRIF, showing 40)

• mena phosphorylation is regulated by Abi-1 and c-Abl (PMID:12672821)
• overexpression of ENAH is associated with breast cancer (PMID:16533770)
• Oservations identify Tes as an atypical binding partner of EVH1 domain of Mena and a regulator specific to a single Ena/VASP family member. (PMID:18158903)
• the hMena(+11a) isoform is associated with an epithelial phenotype and identifies EGFR-dependent cell lines that are sensitive to the EGFR inhibitor erlotinib (PMID:18676769)
• two isoforms of Mena, ++ and +++, are upregulated in the invasive tumor cells and one isoform, 11a, is downregulated (PMID:18985426)
• the Mena invasion isoform potentiates EGF-induced carcinoma cell invasion and metastasis (PMID:19081071)
• Increased hMena expression is associated with colorectal carcinomas. (PMID:19082477)
• hMena possesses properties which help to regulate the formation of lamellipodia through the modulation of the activity of Rac1. (PMID:19277120)
• Mena was not expressed in the normal cervical squamous epithelium but its expression was increased in parallel with the increasing grade of CIN, with up-regulation upon transition to CIN3 and further to invasive carcinoma. (PMID:19434313)
• ENAH polymorphisms are associated with increased susceptibility, development of proteinuria and gross hematuria, and pathological progression of childhood IgAN. (PMID:19641378)
• hMena and HER2 signalling has a role in breast cancer (PMID:21209853)
• Mammalian enabled (Mena) is a critical regulator of cardiac function. (PMID:21335464)
• ENA/VASP-family proteins are functionally redundant in homologous recombination, and MENA, VASP and EVL may be involved in the DSB repair pathway in humans (PMID:21398369)
• Data show that VASP and Mena interact with RSK1. (PMID:21423205)
• results indicate that by mediating intensive F-actin accumulation at the sites of cell infiltration, WAVE2, N-WASP, and Mena are crucial for PI3K-dependent cell invasion induced by PDGF (PMID:21769917)
• Mena protein seems to play a role in malignant transformation and its intensity is correlated with the type and grade of tumor and also with vascular invasion. Its positivity in endothelial cells may suggest its potential role in tumor angiogenesis. (PMID:22472896)
• Overexpression of Wnt1 and Wnt3a ligands increased MENA mRNA levels. (PMID:22615875)
• High Menacalc levels identify a subgroup of breast cancer patients with poor disease-specific survival, suggesting that Menacalc may serve as a biomarker for metastasis. (PMID:22971274)
• This study demonistrated that dysregulation of ENAH eeox in brain of patient with schizophrenia. (PMID:23062752)
• These data suggest that polarized and growth-arrested cellular architecture correlates with absence of alternative hMENA isoform expression. (PMID:23129656)
• we consider that it is necessary to analyze the expression of Mena splice variants in a higher number of cases, in different epithelial lesions, and also in experimental studies to define its exact role in carcinogenesis (PMID:23956979)
• this study suggests a novel mechanism in which Lpd mediates EGFR endocytosis via Mena downstream of endophilin. (PMID:24076656)
• High expression of Mena is associated with hepatocellular carcinoma. (PMID:24683008)
• determined the alpha-synuclein-binding domain of beta-III tubulin and demonstrated that a short fragment containing this domain can suppress alpha-synuclein accumulation in the primary cultured cells (PMID:25031323)
• the higher relative expression of hMena(11a) compared with hMena(INV) may predict malignant transformation in breast epithelial cells, and, furthermore, a reversal of expression of hMena(11a) and hMena(INV) may dictate the state of cancer progression (PMID:25109497)
• Invasive breast ductal-carcinoma cells that migrated thru a layer of human endothelial cells were enriched for the transcript encoding Mena(INV), an invasive isoform of Mena. (PMID:25429076)
• High ENAH expression is associated with trastuzumab-resistant breast cancer. (PMID:25449779)
• our results indicate that hMENA11a is an anti-apoptotic regulator involved in the HER3-mediated mechanisms of resistance to PI3K inhibition in breast cancer (PMID:25961924)
• we evaluate the prognostic value of Menacalc in a cohort of ANN patients. Our primary objective was to determine if there was an association between Menacalc and overall patient mortality. (PMID:26112005)
• these data provide the first description of endogenous Mena(INV) protein expression in mouse and human breast tumors. (PMID:26680363)
• PPARgamma might inhibit the proliferation and migration of GC cell lines through suppressing the expression of TERT and ENAH (PMID:26956036)
• SHIP2 recruits Mena to invadopodia and disruption of SHIP2-Mena interaction in cancer cells leads to attenuated capacity for ECM degradation and invasion in vitro, as well as reduced metastasis in vivo. (PMID:27597754)
• the difference between mRNAs encoding constitutive Mena sequences and those containing the 11a exon correlates with metastasis in colorectal cancer, suggesting that 11a exon exclusion contributes to invasive phenotypes and leads to poor clinical outcome (PMID:27748415)
• Mena(INV) promotes invadopodium maturation by inhibiting normal dephosphorylation of cortactin at tyrosine 421 by the phosphatase PTP1B. (PMID:27824079)
• Endothelin-1 is a regulator of Mena expression in the serous ovarian cancer.Mena expression is associated with a poor prognosis in serous ovarian cancer patients.Mena is recruited to mature invadopodia in endothelin-1 and beta-arrestin-1 signaling. (PMID:29439204)
• hMENA regulates beta1 integrin expression and hMENA(11a) reduces and hMENADeltav6 increases beta1 integrin activation and signaling (PMID:29907768)
• Enah is upregulated in gastric cancer tissues and cell lines and is correlated with clinicopathological parameters and survival of gastric cancer patients. (PMID:30250066)
• Findings show that Mena is a splicing target of PTBP1 which regulates exon11a skipping to promote lung cancer cells metastasis. (PMID:31075540)
• Scaffold stiffness influences breast cancer cell invasion via EGFR-linked Mena upregulation and matrix remodeling. (PMID:31323325)
• IRSp53 is a novel interactor of SHIP2: A role of the actin binding protein Mena in their cellular localization in breast cancer cells. (PMID:32535200)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	enah	ENSDARG00000032049
mus_musculus	Enah	ENSMUSG00000022995
rattus_norvegicus	Enah	ENSRNOG00000031934
drosophila_melanogaster	ena	FBGN0000578
drosophila_melanogaster	Spred	FBGN0020767
caenorhabditis_elegans		WBGENE00006770

Paralogs (5): VASP (ENSG00000125753), SPRED1 (ENSG00000166068), SPRED3 (ENSG00000188766), EVL (ENSG00000196405), SPRED2 (ENSG00000198369)

Protein

Protein identifiers

Protein enabled homolog — Q8N8S7 (reviewed: Q8N8S7)

All UniProt accessions (6): Q8N8S7, A0A075B6E5, A0A0U1RQP7, A0A0U1RRM6, A0A4D6J698, A0A8Q3WLE0

UniProt curated annotations — full annotation on UniProt →

Function. Ena/VASP proteins are actin-associated proteins involved in a range of processes dependent on cytoskeleton remodeling and cell polarity such as axon guidance and lamellipodial and filopodial dynamics in migrating cells. ENAH induces the formation of F-actin rich outgrowths in fibroblasts. Acts synergistically with BAIAP2-alpha and downstream of NTN1 to promote filipodia formation.

Subunit / interactions. Homotetramer. Interacts with APBB1IP, APBB1, PFN1 and ROBO4. Isoforms, containing the polyproline-rich regions with PPLP motifs, bind the WW domain of APBB1IP. Isoforms, containing the PPSY motif, bind, in vitro, to the WW2 and WW3 domains of NEDD4 and to the WW1 domain of YAP1. Binds the SH3 domain of BAIAP2-alpha but only after the autoinhibitory region of BAIAP2-alpha has been blocked by interaction with CDC42. Interacts, via the EVH1/WH1 domain, with the Pro-rich domains from VCL, ZYX and Listeria monocytogenes actA and with TES (via LIM domains). The TES LIM domain and the Pro-rich domains from VCL or ZYX compete for the same binding site. Interaction with ZYX is important for targeting ENAH to focal adhesions and enhances production of actin-rich structures at the apical surface of cells. Interacts, through the Pro-rich region, with the C-terminal SH3 domain of DNMPB. Binds GPHN. Interacts with FAT1 (via EVH1 domains). Heterotrimer with TES and ACTL7A. Interacts with PRPF40A.

Subcellular location. Cytoplasm. Cytoskeleton. Cell projection. Lamellipodium. Filopodium. Synapse. Cell junction. Focal adhesion.

Tissue specificity. Expressed in myoepithelia of parotid, breast, bronchial glands and sweat glands. Expressed in colon-rectum muscolaris mucosae epithelium, pancreas acinar ductal epithelium, endometrium epithelium, prostate fibromuscolar stroma and placenta vascular media. Overexpressed in a majority of breast cancer cell lines and primary breast tumor lesions.

Post-translational modifications. NTN1-induced PKA phosphorylation on Ser-265 directly parallels the formation of filopodial protrusions.

Domain organisation. The EVH2 domain is comprised of 3 regions. Block A is a thymosin-like domain required for G-actin binding. The KLKR motif within this block is essential for the G-actin binding and for actin polymerization. Block B is required for F-actin binding and subcellular location, and Block C for tetramerization.

Miscellaneous. Required to transform actin polymerization into active movement for the propulsive force of Listeria monocytogenes. Expression restricted to invasive cancer cells.

Similarity. Belongs to the Ena/VASP family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8N8S7-1	1	yes
Q8N8S7-2	2
Q8N8S7-3	3, Deltav6

RefSeq proteins (9): NP_001008493, NP_001364410, NP_001364411, NP_001364412, NP_001407088, NP_001407089, NP_001407090, NP_001407091, NP_060682* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000697	WH1/EVH1_dom	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR014885	VASP_tetra	Domain
IPR038023	VASP_sf	Homologous_superfamily

Pfam: PF00568, PF08776

UniProt features (59 total): modified residue 10, repeat 9, compositionally biased region 9, strand 9, region of interest 8, splice variant 3, turn 3, coiled-coil region 2, helix 2, chain 1, domain 1, short sequence motif 1, sequence conflict 1

Structure

Experimental structures (PDB)

27 structures.

PDB	Method	Resolution (Å)
7A5M	X-RAY DIFFRACTION	0.78
6RD2	X-RAY DIFFRACTION	1
5NCG	X-RAY DIFFRACTION	1.02
6RCF	X-RAY DIFFRACTION	1.1
5NBF	X-RAY DIFFRACTION	1.15
5N9C	X-RAY DIFFRACTION	1.16
5NEG	X-RAY DIFFRACTION	1.29
2HO2	X-RAY DIFFRACTION	1.33
6RCJ	X-RAY DIFFRACTION	1.35
7AKI	X-RAY DIFFRACTION	1.36
5NCF	X-RAY DIFFRACTION	1.4
6XVT	X-RAY DIFFRACTION	1.4
9C66	X-RAY DIFFRACTION	1.4
5NDU	X-RAY DIFFRACTION	1.42
5ND0	X-RAY DIFFRACTION	1.45
5NAJ	X-RAY DIFFRACTION	1.46
6XXR	X-RAY DIFFRACTION	1.48
5N91	X-RAY DIFFRACTION	1.49
5NC2	X-RAY DIFFRACTION	1.58
5NBX	X-RAY DIFFRACTION	1.65
5NCP	X-RAY DIFFRACTION	1.65
4MY6	X-RAY DIFFRACTION	1.7
5N9P	X-RAY DIFFRACTION	1.8
7LXE	X-RAY DIFFRACTION	1.88
2IYB	X-RAY DIFFRACTION	2.35
2XQN	X-RAY DIFFRACTION	2.62
5NC7	X-RAY DIFFRACTION	2.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N8S7-F1	72.69	0.46

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 (10): 125, 265, 506, 508, 502, 508, 512, 465, 471, 475

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-202433	Generation of second messenger molecules
R-HSA-376176	Signaling by ROBO receptors

MSigDB gene sets: 0 (showing top):

GO Biological Process (4): axon guidance (GO:0007411), actin polymerization or depolymerization (GO:0008154), actin polymerization-dependent cell motility (GO:0070358), postsynaptic cytoskeleton organization (GO:0099188)

GO Molecular Function (6): actin binding (GO:0003779), profilin binding (GO:0005522), SH3 domain binding (GO:0017124), WW domain binding (GO:0050699), protein binding (GO:0005515), protein domain specific binding (GO:0019904)

GO Cellular Component (12): cytosol (GO:0005829), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), focal adhesion (GO:0005925), lamellipodium (GO:0030027), filopodium (GO:0030175), postsynapse (GO:0098794), GABA-ergic synapse (GO:0098982), cytoplasm (GO:0005737), cell projection (GO:0042995), synapse (GO:0045202), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
TCR signaling	1
Axon guidance	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
protein binding	2
protein domain specific binding	2
synapse	2
cell junction	2
axonogenesis	1
neuron projection guidance	1
actin filament organization	1
cell motility	1
cytoskeleton organization	1
postsynapse organization	1
cytoskeletal protein binding	1
binding	1
cytoplasm	1
intracellular membraneless organelle	1
membrane	1
cell periphery	1
cell-substrate junction	1
cell leading edge	1
plasma membrane bounded cell projection	1
actin-based cell projection	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1496 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ENAH	ESRP1	Q6NXG1	906
ENAH	ESRP2	Q9H6T0	904
ENAH	CTNND1	O60716	752
ENAH	WASL	O00401	735
ENAH	ABI1	Q8IZP0	707
ENAH	BAIAP2	Q9UQB8	693
ENAH	PFN1	P07737	677
ENAH	APBB1	O00213	667
ENAH	WASF1	Q92558	659
ENAH	WIPF2	Q8TF74	654
ENAH	PFN4	Q8NHR9	654
ENAH	PFN3	P60673	652
ENAH	GPHN	Q9NQX3	628
ENAH	FGFR2	P18443	623
ENAH	RAPH1	Q70E73	586

IntAct

82 interactions, top by confidence:

A	B	Type	Score
VASP	CEP43	psi-mi:“MI:0914”(association)	0.740
ZYX	ENAH	psi-mi:“MI:0915”(physical association)	0.670
DLGAP4	LIN7A	psi-mi:“MI:0914”(association)	0.590
TES	ENAH	psi-mi:“MI:0407”(direct interaction)	0.540
TES	ENAH	psi-mi:“MI:0915”(physical association)	0.540
SYNGAP1	IGF2BP3	psi-mi:“MI:0914”(association)	0.530
SYNGAP1	SEC16A	psi-mi:“MI:0914”(association)	0.530
VASP	GTPBP1	psi-mi:“MI:0914”(association)	0.530
BAG2	HGS	psi-mi:“MI:0914”(association)	0.530
TACC3	HSPA8	psi-mi:“MI:0914”(association)	0.530
NECTIN4	EIF2B2	psi-mi:“MI:0914”(association)	0.530
ZYX	TBC1D10B	psi-mi:“MI:0914”(association)	0.530
NHSL3	NCK2	psi-mi:“MI:0914”(association)	0.530
EVL	VASP	psi-mi:“MI:0914”(association)	0.530
DYRK1B	BMAL1	psi-mi:“MI:0914”(association)	0.530
ENAH	TERF2IP	psi-mi:“MI:0915”(physical association)	0.510
DCAF7	CLASP2	psi-mi:“MI:0914”(association)	0.510
FAT1	ENAH	psi-mi:“MI:0407”(direct interaction)	0.440
ENAH	FAT1	psi-mi:“MI:0407”(direct interaction)	0.440
ACTL7A	ENAH	psi-mi:“MI:0915”(physical association)	0.400
ENAH	RPS6KA1	psi-mi:“MI:0915”(physical association)	0.400
ENAH	BAIAP2	psi-mi:“MI:0915”(physical association)	0.400
ENAH	MYO10	psi-mi:“MI:0915”(physical association)	0.400
HMGB1	ENAH	psi-mi:“MI:0915”(physical association)	0.370
MAPK1	ENAH	psi-mi:“MI:0915”(physical association)	0.370
ENAH	SPTA1	psi-mi:“MI:0915”(physical association)	0.370
TACC3	DHRS2	psi-mi:“MI:0914”(association)	0.350
PRPF4		psi-mi:“MI:0914”(association)	0.350

BioGRID (188): ENAH (Affinity Capture-Western), ENAH (Affinity Capture-Western), ENAH (Affinity Capture-Western), ENAH (Reconstituted Complex), ENAH (Reconstituted Complex), ENAH (Reconstituted Complex), ENAH (Affinity Capture-MS), ENAH (Affinity Capture-MS), ENAH (Affinity Capture-MS), ENAH (Affinity Capture-MS), ENAH (Co-fractionation), EVL (Co-fractionation), ENAH (Affinity Capture-MS), ENAH (Proximity Label-MS), ENAH (Affinity Capture-MS)

ESM2 similar proteins: A1A5Q0, A2VDK6, A7Z063, B2RYF7, B5DF93, E1BTG2, O00401, O08816, P49140, P50551, Q02225, Q0IIJ3, Q13191, Q13435, Q28DN4, Q3TC46, Q3UHZ5, Q3UJB0, Q3UQU0, Q5BJU7, Q5NVG8, Q5PQQ2, Q5R8Q4, Q5T8P6, Q5U3K5, Q5ZKA6, Q62415, Q68EF0, Q6NZN0, Q6P0D5, Q6P5Q4, Q6PFT9, Q7Z5R6, Q86TB9, Q8BH43, Q8CH02, Q8IWZ8, Q8N8S7, Q8R5A3, Q8R5H6

Diamond homologs: O08719, P50551, P50552, P70429, P70460, Q03173, Q2TA49, Q3C2P8, Q5R896, Q5RDN2, Q5TJ65, Q5Y171, Q64GL0, Q6NYK3, Q7Z698, Q8N8S7, Q8T4F7, Q924S7, Q9UI08, Q2MJR0, Q6P6N5, Q9Z2X5, A2VDU1, O43597, O43610, Q08E39, Q2PFN5, Q3UUD2, Q5R959, Q66JG9, Q7Z699, Q866R9, Q924S8, Q9C004, Q9PTL2, Q9QXV8, Q9WTP2

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
PKA	“up-regulates activity”	ENAH	phosphorylation
PRKG1	“down-regulates activity”	ENAH	phosphorylation
ENAH	up-regulates	Axonal_growth_cone_formation
ENAH	up-regulates	Neurite_outgrowth
BAIAP2	“up-regulates activity”	ENAH	binding
RAPH1	“up-regulates activity”	ENAH	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 95 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.

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of actin filament polymerization	5	18.4×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	59
Likely benign	5
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

3387 predictions. Top by Δscore:

Variant	Effect	Δscore
1:225507945:TGATA:T	donor_loss	1.0000
1:225507946:GATAC:G	donor_loss	1.0000
1:225507947:ATAC:A	donor_loss	1.0000
1:225507948:TACC:T	donor_loss	1.0000
1:225507949:A:C	donor_loss	1.0000
1:225507950:C:CG	donor_loss	1.0000
1:225508015:GTTC:G	acceptor_loss	1.0000
1:225508017:TCTT:T	acceptor_loss	1.0000
1:225508018:C:CC	acceptor_gain	1.0000
1:225508019:T:A	acceptor_loss	1.0000
1:225508019:T:C	acceptor_gain	1.0000
1:225508020:T:C	acceptor_gain	1.0000
1:225508020:T:TC	acceptor_gain	1.0000
1:225512655:A:AC	donor_gain	1.0000
1:225512656:C:CC	donor_gain	1.0000
1:225512656:CA:C	donor_gain	1.0000
1:225513018:T:C	acceptor_gain	1.0000
1:225519561:GTTGT:G	acceptor_gain	1.0000
1:225519562:TTGT:T	acceptor_gain	1.0000
1:225519563:TGT:T	acceptor_gain	1.0000
1:225519564:GT:G	acceptor_gain	1.0000
1:225519565:TCTG:T	acceptor_loss	1.0000
1:225519566:C:CC	acceptor_gain	1.0000
1:225530549:TTTAC:T	donor_loss	1.0000
1:225530550:TTA:T	donor_loss	1.0000
1:225530551:TA:T	donor_loss	1.0000
1:225530553:C:T	donor_loss	1.0000
1:225530553:CCTT:C	donor_gain	1.0000
1:225530556:T:A	donor_gain	1.0000
1:225530634:TGGCC:T	acceptor_gain	1.0000

AlphaMissense

3656 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:225497809:A:T	I581N	1.000
1:225498355:A:G	L577P	1.000
1:225498364:T:A	K574I	1.000
1:225498367:A:G	L573P	1.000
1:225512711:T:A	R456S	1.000
1:225512711:T:G	R456S	1.000
1:225512712:C:G	R456T	1.000
1:225512714:C:A	R455S	1.000
1:225512714:C:G	R455S	1.000
1:225512871:C:A	R455M	1.000
1:225512871:C:G	R455T	1.000
1:225512878:C:G	A453P	1.000
1:225512880:A:G	L452P	1.000
1:225512880:A:T	L452Q	1.000
1:225512883:A:G	L451P	1.000
1:225512891:C:A	M448I	1.000
1:225512891:C:G	M448I	1.000
1:225512891:C:T	M448I	1.000
1:225512892:A:C	M448R	1.000
1:225512892:A:G	M448T	1.000
1:225512892:A:T	M448K	1.000
1:225554932:A:G	L108S	1.000
1:225554935:G:T	A107D	1.000
1:225554936:C:G	A107P	1.000
1:225554944:A:C	M104R	1.000
1:225554944:A:T	M104K	1.000
1:225554947:G:T	A103D	1.000
1:225554948:C:G	A103P	1.000
1:225554954:C:G	A101P	1.000
1:225554955:G:C	F100L	1.000

dbSNP variants (sampled 300 via entrez): RS1000002575 (1:225654367 A>G), RS1000015503 (1:225581677 A>G), RS1000067187 (1:225536464 A>G,T), RS1000107718 (1:225597995 G>A), RS1000119965 (1:225654547 C>T), RS1000125039 (1:225528287 G>C), RS1000132335 (1:225525305 A>G), RS1000187084 (1:225594495 A>T), RS1000203622 (1:225650343 C>G,T), RS1000210319 (1:225508081 A>G,T), RS1000225632 (1:225652669 C>T), RS1000244131 (1:225543722 C>T), RS1000260093 (1:225630436 T>C), RS1000265764 (1:225643502 A>C), RS1000272959 (1:225512379 T>C)

Disease associations

OMIM: gene MIM:609061 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST001762_686	Obesity-related traits	2.000000e-06
GCST003447_2	Neuroticism	2.000000e-08
GCST005851_25	Delirium	4.000000e-06
GCST006427_22	Depression in smokers	4.000000e-06
GCST010796_5335	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-08
GCST90013407_89	Liver enzyme levels (gamma-glutamyl transferase)	4.000000e-21

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004810	interleukin-6 measurement
EFO:0007660	neuroticism measurement
EFO:0004327	electrocardiography
EFO:0004532	serum gamma-glutamyl transferase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression	6
trichostatin A	affects cotreatment, decreases expression	3
Estradiol	increases reaction, affects expression, affects binding	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tretinoin	decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
bisphenol F	increases expression	1
oxybenzone	decreases expression	1
bisphenol A	increases expression	1
arsenite	decreases reaction, affects binding	1
butyraldehyde	decreases expression	1
potassium chromate(VI)	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
pentanal	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
calfactant	increases expression, affects cotreatment	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
bromovanin	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
bis-N,N-dimethylamino-2-(N-methylpyrrolyl)methyl cyclopentadienyl titanium (IV)	decreases expression	1
bisphenol AF	increases expression	1
Resveratrol	decreases expression, affects cotreatment	1
Arsenic Trioxide	increases expression	1
Leflunomide	increases expression	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	decreases expression	1
Cisplatin	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

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