BCAR3

Summary

BCAR3 (BCAR3 adaptor protein, NSP family member, HGNC:973) is a protein-coding gene on chromosome 1p22.1, encoding Breast cancer anti-estrogen resistance protein 3 (O75815). Acts as an adapter protein downstream of several growth factor receptors to promote cell proliferation, migration, and redistribution of actin fibers.

Breast tumors are initially dependent on estrogens for growth and progression and can be inhibited by anti-estrogens such as tamoxifen. However, breast cancers progress to become anti-estrogen resistant. Breast cancer anti-estrogen resistance gene 3 was identified in the search for genes involved in the development of estrogen resistance. The gene encodes a component of intracellular signal transduction that causes estrogen-independent proliferation in human breast cancer cells. The protein contains a putative src homology 2 (SH2) domain, a hall mark of cellular tyrosine kinase signaling molecules, and is partly homologous to the cell division cycle protein CDC48. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 8412 — RefSeq curated summary.

At a glance

• GWAS associations: 14
• Clinical variants (ClinVar): 163 total
• MANE Select transcript: NM_003567

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:973
Approved symbol	BCAR3
Name	BCAR3 adaptor protein, NSP family member
Location	1p22.1
Locus type	gene with protein product
Status	Approved
Aliases	NSP2, SH2D3B, AND-34, MIG7
Ensembl gene	ENSG00000137936
Ensembl biotype	protein_coding
OMIM	604704
Entrez	8412

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 18 protein_coding, 6 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000260502, ENST00000370243, ENST00000370244, ENST00000370247, ENST00000433544, ENST00000466632, ENST00000469315, ENST00000479503, ENST00000490377, ENST00000538653, ENST00000539242, ENST00000649852, ENST00000851870, ENST00000851871, ENST00000851872, ENST00000934132, ENST00000934133, ENST00000934134, ENST00000934135, ENST00000934136, ENST00000959686, ENST00000959687, ENST00000959688, ENST00000959689, ENST00000959690

RefSeq mRNA: 30 — MANE Select: NM_003567 NM_001261408, NM_001261409, NM_001261410, NM_001308251, NM_001412043, NM_001412044, NM_001412045, NM_001412046, NM_001412048, NM_001412049, NM_001412050, NM_001412051, NM_001412052, NM_001412054, NM_001412055, NM_001412056, NM_001412057, NM_001412058, NM_001412059, NM_001412060, NM_001412061, NM_001412062, NM_001412064, NM_001412066, NM_001412072, NM_001412073, NM_001412074, NM_001412076, NM_001412077, NM_003567

CCDS: CCDS58010, CCDS745, CCDS76181

Canonical transcript exons

ENST00000260502 — 12 exons

Exon	Start	End
ENSE00000777070	93571670	93571841
ENSE00000777071	93576014	93576129
ENSE00000777074	93588977	93589419
ENSE00001067618	93567740	93567851
ENSE00001206266	93681598	93681837
ENSE00001452146	93674614	93674941
ENSE00001805711	93592265	93592393
ENSE00003517009	93582301	93582953
ENSE00003524113	93567279	93567491
ENSE00003540352	93642304	93642343
ENSE00003690649	93584018	93584121
ENSE00003843022	93561741	93562419

Expression profiles

Bgee: expression breadth ubiquitous, 279 present calls, max score 91.82.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.1660 / max 534.9008, expressed in 1689 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
13323	17.3797	1621
13324	0.9708	629
13335	0.9204	600
13333	0.5046	87
13331	0.4636	68
13317	0.2581	156
13314	0.2464	103
13321	0.1137	30
13318	0.1034	55
13313	0.0622	37

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
parotid gland	UBERON:0001831	91.82	gold quality
right lung	UBERON:0002167	89.64	gold quality
omental fat pad	UBERON:0010414	88.75	gold quality
peritoneum	UBERON:0002358	88.72	gold quality
rectum	UBERON:0001052	88.45	gold quality
placenta	UBERON:0001987	88.41	gold quality
adipose tissue of abdominal region	UBERON:0007808	88.29	gold quality
mucosa of transverse colon	UBERON:0004991	88.15	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	87.83	gold quality
gastrocnemius	UBERON:0001388	87.77	gold quality
sural nerve	UBERON:0015488	87.66	gold quality
germinal epithelium of ovary	UBERON:0001304	87.64	gold quality
subcutaneous adipose tissue	UBERON:0002190	87.53	gold quality
biceps brachii	UBERON:0001507	87.50	gold quality
muscle of leg	UBERON:0001383	87.41	gold quality
tibial nerve	UBERON:0001323	87.35	gold quality
renal glomerulus	UBERON:0000074	86.93	gold quality
right coronary artery	UBERON:0001625	86.85	gold quality
upper lobe of left lung	UBERON:0008952	86.77	gold quality
upper lobe of lung	UBERON:0008948	86.57	gold quality
metanephric glomerulus	UBERON:0004736	86.14	gold quality
transverse colon	UBERON:0001157	86.11	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.09	gold quality
adipose tissue	UBERON:0001013	86.05	gold quality
hindlimb stylopod muscle	UBERON:0004252	86.05	gold quality
apex of heart	UBERON:0002098	85.92	gold quality
muscle organ	UBERON:0001630	85.90	gold quality
skin of leg	UBERON:0001511	85.80	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	85.70	gold quality
ventricular zone	UBERON:0003053	85.66	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.61

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

52 targeting BCAR3, 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-186-5P	99.99	70.83	3707
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-9718	99.94	68.91	918
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-664B-3P	99.84	71.65	3590
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-548A-3P	99.76	70.58	3524
HSA-MIR-199A-3P	99.75	70.48	929
HSA-MIR-199B-3P	99.75	70.48	929
HSA-MIR-3129-5P	99.75	70.46	914
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-4802-3P	99.72	70.13	1273
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-186-3P	99.51	66.24	1685
HSA-MIR-154-3P	99.50	70.05	831
HSA-MIR-487A-3P	99.50	69.95	840
HSA-MIR-12132	99.47	68.90	1341

Literature-anchored findings (GeneRIF, showing 27)

• AND-34 activates phosphatidylinositol 3-kinase and induces anti-estrogen resistance in a SH2 and GDP exchange factor-like domain-dependent manner (PMID:15671247)
• BCAR3 and NSP1 are more highly expressed than SH2D3C (SHEP1) in breast cancer cells, and the expression patterns suggest differential roles for the three genes during breast cancer progression. (PMID:17270363)
• BCAR3 induces anti-estrogen resistance in breast tumor cell lines by altering cell-cell/cell-matrix interactions and cyclin D1 promoter activity. (PMID:17427198)
• the spatial and temporal regulation of BCAR3/p130(Cas) interactions within the cell is important for controlling breast cancer cell motility (PMID:17616674)
• BCAR3 protein, through its SH2 domain, is involved in the signaling pathways of EGF leading to cell cycle progression; BCAR3 itself is part of a mitogenic signaling pathway. (PMID:18722344)
• The expression of breast cancer anti-estrogen resistance 3 results in basal serine phosphorylation of Crk-Associated Substrate Protein that normally occurs during adhesion of breast cancer cells to fibronectin. (PMID:19454314)
• the c-Src/Cas/BCAR3 signaling axis is a prominent regulator of c-Src activity, which in turn controls cell behaviors that lead to aggressive and invasive breast tumor phenotypes (PMID:19940159)
• BCAR3-p130Cas complex formation is not required for BCAR3-mediated anti-estrogen resistance, Rac activation or discohesion of epithelial breast cancer cells (PMID:21262352)
• BCAR3 expression may regulate Src signaling in a BCAR3-p130(cas) complex-dependent fashion by altering the ability of the Src SH3 domain to bind the p130(cas) SBD (PMID:22711540)
• The high expressions of Mig-7 and MMP-2 in gastric carcinoma tissues may have a synergistic promoting effect on VM formation. VM is closely associated with the invasion, metastasis and poor prognosis of gastric carcinoma. (PMID:23388341)
• BCAR3 promotes cell motility by regulating actin cytoskeletal and adhesion remodeling in invasive breast cancer cells. (PMID:23762409)
• Taken together, these results demonstrated that BCAR3 plays an important role in the signaling pathways of insulin leading to cell cycle progression and cytoskeleton reorganization, but not GLUT4 translocation. (PMID:24216110)
• BCAR1 and BCAR3 scaffolding proteins have roles in cell signaling and antiestrogen resistance (PMID:24584939)
• BCAR3 acts as a putative suppressor of breast cancer progression by inhibiting the prometastatic TGFbeta/Smad signaling pathway in invasive breast tumors. (PMID:25499443)
• BCAR3 is an essential interactor and mediator of HEF1-induced migration. (PMID:25817040)
• Inhibiting MIG-7 by RNA interference in grafted EOC cells retarded tumor growth, angiogenesis and improved host survival, and suppressing MIG-7 expression with a small molecule inhibitor D-39 identified from the mitigated EOC growth and invasion and specifically abrogated the expression of vascular endothelial growth factor. (PMID:27050277)
• MIG7 expression in hepatocellular carcinoma tissue is high and correlated positively with vasculogenic mimicry formation, invasion and metastasis. (PMID:28616909)
• MIG-7 mRNA expression may serve as an additional molecular marker of vasculogenic mimicry in ovarian malignancies. (PMID:29192416)
• Study provides evidence that MIG7 expression in hepatocellular carcinoma (HCC) tissue is correlated positively with vasculogenic mimicry (VM) formation and MIG7 expression in different HCC cell lines is coincident with their VM formation, invasion and metastasis. (PMID:29251318)
• MIG-7 serves as an independent unfavorable prognostic indicator in osteosarcoma patients and MIG-7 is an important mediator of osteosarcoma Vascular Mimicry formation. (PMID:29750896)
• high expression level of BCAR3 predicted better prognosis of multiple myeloma patients. (PMID:30563570)
• Silencing of Mig-7 gene inhibits vasculogenic mimicry formation and invasion of U251 cells possibly by suppressing MEK/ERK signaling, suggesting the important role of Mig-7 gene in vasculogenic mimicry formation and invasion of human glioma cells (PMID:31140421)
• miR-126-5p negatively regulated BCAR3 expression in eutopic endometriosis, enhanced the migration and invasion of endometrial cells, and promoted the occurrence of endometriosis. (PMID:31233772)
• this study indicates that the expression of Mig-7 in gliomas is positively correlated with vasculogenic mimicry formation and is related to the glioma pathological grade (PMID:31688418)
• A Cas-BCAR3 co-regulatory circuit controls lamellipodia dynamics. (PMID:34169835)
• Comprehensive immunohistochemical analysis of RET, BCAR1, and BCAR3 expression in patients with Luminal A and B breast cancer subtypes. (PMID:35031902)
• CircBCAR3 sponges miR-27a-3p and mediates ferroptosis in human B-prolymphocytic leukaemia cells via SLC7A11. (PMID:38063095)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	bcar3	ENSDARG00000016981
mus_musculus	Bcar3	ENSMUSG00000028121
rattus_norvegicus	Bcar3	ENSRNOG00000013737
drosophila_melanogaster	CG9098	FBGN0031762

Paralogs (2): SH2D3C (ENSG00000095370), SH2D3A (ENSG00000125731)

Protein

Protein identifiers

Breast cancer anti-estrogen resistance protein 3 — O75815 (reviewed: O75815)

Alternative names: Novel SH2-containing protein 2, SH2 domain-containing protein 3B

All UniProt accessions (2): A0A384MTS3, O75815

UniProt curated annotations — full annotation on UniProt →

Function. Acts as an adapter protein downstream of several growth factor receptors to promote cell proliferation, migration, and redistribution of actin fibers. Specifically involved in INS/insulin signaling pathway by mediating MAPK1/ERK2-MAPK3/ERK1 activation and DNA synthesis. Promotes insulin-mediated membrane ruffling. In response to vasoconstrictor peptide EDN1, involved in the activation of RAP1 downstream of PTK2B via interaction with phosphorylated BCAR1. Inhibits cell migration and invasion via regulation of TGFB-mediated matrix digestion, actin filament rearrangement, and inhibition of invadopodia activity. May inhibit TGFB-SMAD signaling, via facilitating BCAR1 and SMAD2 and/or SMAD3 interaction. Regulates EGF-induced DNA synthesis. Required for the maintenance of ocular lens morphology and structural integrity, potentially via regulation of focal adhesion complex signaling. Acts upstream of PTPRA to regulate the localization of BCAR1 and PTPRA to focal adhesions, via regulation of SRC-mediated phosphorylation of PTPRA. Positively regulates integrin-induced tyrosine phosphorylation of BCAR1. Acts as a guanine nucleotide exchange factor (GEF) for small GTPases RALA, RAP1A and RRAS. However, in a contrasting study, lacks GEF activity towards RAP1.

Subunit / interactions. Part of a complex comprised of PTPRA, BCAR1, BCAR3 (via SH2 domain) and SRC; the formation of the complex is dependent on integrin mediated-tyrosine phosphorylation of PTPRA. Within the complex, interacts (via SH2 domain) with PTPRA (when phosphorylated on ‘Tyr-798’). Interacts (via Ras-GEF domain) with BCAR1. Interacts (via Ras-GEF domain) with NEDD9. Interacts with PTK2/FAK1. Interacts with PTPN1. Interacts (via SH2 domain) with EGFR (when tyrosine-phosphorylated).

Subcellular location. Cytoplasm. Cell junction. Focal adhesion.

Tissue specificity. Ubiquitously expressed. Found in several cancer cell lines, but not in nonmalignant breast tissue.

Post-translational modifications. Phosphorylated on tyrosine residues.

Domain organisation. The SH2 domain mediates interaction with tyrosine-phosphorylated proteins. However, not involved in the binding to phosphorylated BCAR1. Required for cell cycle progression in response to INS/insulin. Required for regulation of EFR-induced DNA synthesis. The Ras-GEF domain appears to adopt a closed conformation rendering it incapable of carrying out canonical exchange factor function, this closed conformation is probably required for interaction with BCAR1.

Miscellaneous. Overexpression confers anti-estrogen resistance via RRAS-independent activation of the PI3K pathway, and activation of the cyclin D1 promoter in breast cancer cell lines. Plays a role in insulin-mediated ERK activation and DNA synthesis in breast cancer cells.

Isoforms (3)

UniProt ID	Names	Canonical?
O75815-1	1	yes
O75815-2	2
O75815-3	3

RefSeq proteins (30): NP_001248337, NP_001248338, NP_001248339, NP_001295180, NP_001398972, NP_001398973, NP_001398974, NP_001398975, NP_001398977, NP_001398978, NP_001398979, NP_001398980, NP_001398981, NP_001398983, NP_001398984, NP_001398985, NP_001398986, NP_001398987, NP_001398988, NP_001398989, NP_001398990, NP_001398991, NP_001398993, NP_001398995, NP_001399001, NP_001399002, NP_001399003, NP_001399005, NP_001399006, NP_003558* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000980	SH2	Domain
IPR001895	RASGEF_cat_dom	Domain
IPR023578	Ras_GEF_dom_sf	Homologous_superfamily
IPR036860	SH2_dom_sf	Homologous_superfamily
IPR036964	RASGEF_cat_dom_sf	Homologous_superfamily
IPR044102	SH2_SHEP1/BCAR3/NSP1	Domain
IPR051853	SH2-Ras-GEF_adapter	Family

Pfam: PF00017, PF00617

UniProt features (55 total): helix 22, modified residue 12, splice variant 3, mutagenesis site 3, domain 2, sequence variant 2, sequence conflict 2, region of interest 2, compositionally biased region 2, initiator methionine 1, chain 1, strand 1, turn 1, site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
3T6A	X-RAY DIFFRACTION	2.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75815-F1	66.36	0.36

Functional residue map

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

Catalytic / active sites (1): 748 (required for interaction with nedd9)

Post-translational modifications (12): 32, 78, 83, 182, 290, 334, 358, 363, 375, 442, 471, 2

Mutagenesis-validated functional residues (3):

Position	Phenotype
177	abolishes localization to focal adhesions. reduces interaction with ptpra.
744	weakens interaction with bcar1.
748	abolishes interaction with bcar1 and src.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 290 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, DORN_ADENOVIRUS_INFECTION_12HR_UP, GOBP_REGULATION_OF_GTPASE_ACTIVITY, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, RACCACAR_AML_Q6, TGACCTY_ERR1_Q2, GGGTGGRR_PAX4_03, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_CELLULAR_RESPONSE_TO_INSULIN_STIMULUS, GOBP_POSITIVE_REGULATION_OF_CATALYTIC_ACTIVITY, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_REGULATION_OF_HYDROLASE_ACTIVITY, GOBP_POSITIVE_REGULATION_OF_MOLECULAR_FUNCTION, GOBP_CELLULAR_RESPONSE_TO_HORMONE_STIMULUS, GOBP_RESPONSE_TO_INSULIN

GO Biological Process (10): lens morphogenesis in camera-type eye (GO:0002089), signal transduction (GO:0007165), epidermal growth factor receptor signaling pathway (GO:0007173), small GTPase-mediated signal transduction (GO:0007264), positive regulation of cell population proliferation (GO:0008284), insulin receptor signaling pathway (GO:0008286), response to xenobiotic stimulus (GO:0009410), positive regulation of MAPK cascade (GO:0043410), positive regulation of GTPase activity (GO:0043547), endothelin receptor signaling pathway (GO:0086100)

GO Molecular Function (4): phosphotyrosine residue binding (GO:0001784), guanyl-nucleotide exchange factor activity (GO:0005085), kinase binding (GO:0019900), protein binding (GO:0005515)

GO Cellular Component (4): cytoplasm (GO:0005737), focal adhesion (GO:0005925), membrane (GO:0016020), anchoring junction (GO:0070161)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
lens development in camera-type eye	1
anatomical structure morphogenesis	1
camera-type eye morphogenesis	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
ERBB signaling pathway	1
intracellular signaling cassette	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
cell surface receptor protein tyrosine kinase signaling pathway	1
cellular response to insulin stimulus	1
response to chemical	1
MAPK cascade	1
regulation of MAPK cascade	1
positive regulation of intracellular signal transduction	1
GTPase activity	1
regulation of GTPase activity	1
positive regulation of hydrolase activity	1
G protein-coupled receptor signaling pathway	1
protein phosphorylated amino acid binding	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
enzyme binding	1
binding	1
intracellular anatomical structure	1
cell-substrate junction	1
cell junction	1

Protein interactions and networks

STRING

1265 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BCAR3	BCAR1	P56945	965
BCAR3	NEDD9	Q14511	779
BCAR3	CRK	P46108	640
BCAR3	VCP	P55072	637
BCAR3	SRC	P12931	599
BCAR3	SH2D3C	Q8N5H7	589
BCAR3	ESR1	P03372	574
BCAR3	MC1R	Q01726	455
BCAR3	FNBP1L	Q5T0N5	442
BCAR3	SLC35F2	Q8IXU6	423
BCAR3	PTPRM	P28827	418
BCAR3	TULP4	Q9NRJ4	418
BCAR3	BCL2	P10415	417
BCAR3	RAPGEF1	Q13905	404
BCAR3	SOX8	P57073	398

IntAct

111 interactions, top by confidence:

A	B	Type	Score
EGFR	CTNND1	psi-mi:“MI:0914”(association)	0.750
NEDD9	BCAR3	psi-mi:“MI:0915”(physical association)	0.740
BCAR3	NEDD9	psi-mi:“MI:0915”(physical association)	0.740
BCAR3	FUS	psi-mi:“MI:0915”(physical association)	0.680
BCAR3	OSGIN1	psi-mi:“MI:0915”(physical association)	0.670
IRS1	BCAR3	psi-mi:“MI:0915”(physical association)	0.570
BCAR3	CCDC57	psi-mi:“MI:0915”(physical association)	0.560
BCAR3	UBASH3A	psi-mi:“MI:0915”(physical association)	0.560
BCAR3	GAS8	psi-mi:“MI:0915”(physical association)	0.560
BCAR3	AP1M1	psi-mi:“MI:0915”(physical association)	0.560
BCAR3	GAST	psi-mi:“MI:0914”(association)	0.530
CRK	ARHGAP42	psi-mi:“MI:0914”(association)	0.530
PCDHB16	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
EGFR	XPOT	psi-mi:“MI:0914”(association)	0.530
BCAR3	ERBB2	psi-mi:“MI:0407”(direct interaction)	0.440
ERBB2	BCAR3	psi-mi:“MI:0407”(direct interaction)	0.440
BCAR3	ERBB3	psi-mi:“MI:0407”(direct interaction)	0.440
BCAR3	GAB1	psi-mi:“MI:0407”(direct interaction)	0.440
BCAR3	KIT	psi-mi:“MI:0407”(direct interaction)	0.440
BCAR3	MET	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (82): BCAR3 (Two-hybrid), BCAR3 (Two-hybrid), IRS1 (Affinity Capture-Luminescence), AGR3 (Two-hybrid), ATAD2 (Two-hybrid), BAP1 (Two-hybrid), BEX1 (Two-hybrid), BEX2 (Two-hybrid), CASZ1 (Two-hybrid), CCL5 (Two-hybrid), CST6 (Two-hybrid), DKK3 (Two-hybrid), EPSTI1 (Two-hybrid), ERRFI1 (Two-hybrid), GLCE (Two-hybrid)

ESM2 similar proteins: A0A0G2JUG7, A0A8M9QN10, A1L390, A2RV61, D3ZAZ5, E9Q0S6, G3X9J0, O00750, O75815, P0CE43, P57095, P59729, Q12923, Q13009, Q3UVC0, Q4R8R1, Q58DL5, Q5JV73, Q5PQS0, Q60610, Q60760, Q61097, Q64512, Q6IFT4, Q6ING4, Q6INP9, Q6P112, Q6REY9, Q6VAB6, Q6ZUJ8, Q7TSI1, Q803Q4, Q80XS6, Q8IVT5, Q8IWE5, Q8IYT8, Q8N103, Q8N5H7, Q8R0S2, Q8R4H2

Diamond homologs: D3ZAZ5, O14796, O70142, O70143, O75791, O75815, O88900, P00519, P00520, P00521, P00522, P00530, P00541, P00542, P00543, P07332, P10447, P14238, P16591, P16879, P29350, P29351, P29353, P29355, P42684, P46109, P47941, P53356, P62993, P62994, P70451, P81718, P87379, P98077, P98083, Q07883, Q08012, Q0IIE2, Q13588, Q4JIM5

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 88 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
Constitutive Signaling by Aberrant PI3K in Cancer	7	13.1×	2e-04
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	8	11.4×	2e-04
Ribosome Quality Control (RQC) complex extracts and degrades nascent peptide	6	9.4×	2e-03
UCH proteinases	5	9.1×	6e-03
PIP3 activates AKT signaling	9	8.8×	2e-04
Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC)	5	8.7×	7e-03
Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC)	6	8.6×	4e-03
Regulation of expression of SLITs and ROBOs	8	8.1×	5e-04

GO biological processes:

GO term	Partners	Fold	FDR
epidermal growth factor receptor signaling pathway	6	17.9×	8e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	143
Likely benign	7
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

2291 predictions. Top by Δscore:

Variant	Effect	Δscore
1:93562417:AACC:A	acceptor_loss	1.0000
1:93562419:CC:C	acceptor_loss	1.0000
1:93562421:T:C	acceptor_loss	1.0000
1:93567276:TA:T	donor_loss	1.0000
1:93567277:A:AC	donor_gain	1.0000
1:93567277:ACCTG:A	donor_gain	1.0000
1:93567278:C:CC	donor_gain	1.0000
1:93567278:C:G	donor_loss	1.0000
1:93567278:CCTG:C	donor_gain	1.0000
1:93567278:CCTGC:C	donor_gain	1.0000
1:93571665:TTTA:T	donor_loss	1.0000
1:93571666:TTACC:T	donor_loss	1.0000
1:93571667:TACCT:T	donor_loss	1.0000
1:93571668:ACC:A	donor_loss	1.0000
1:93582299:AC:A	donor_gain	1.0000
1:93582300:CC:C	donor_gain	1.0000
1:93588972:CCTA:C	donor_loss	1.0000
1:93588973:CTAC:C	donor_loss	1.0000
1:93588974:TAC:T	donor_loss	1.0000
1:93588976:C:CA	donor_loss	1.0000
1:93589140:T:TA	donor_gain	1.0000
1:93590247:A:AC	donor_gain	1.0000
1:93590248:C:CC	donor_gain	1.0000
1:93592260:GGTAC:G	donor_loss	1.0000
1:93592261:GTAC:G	donor_loss	1.0000
1:93592262:TA:T	donor_loss	1.0000
1:93592263:ACCT:A	donor_loss	1.0000
1:93592264:C:CT	donor_loss	1.0000
1:93592389:GAGAA:G	acceptor_gain	1.0000
1:93592390:AGAA:A	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000001650 (1:93796808 CAG>C), RS1000014221 (1:93748190 G>C,T), RS1000014862 (1:93705219 A>G), RS1000043970 (1:93741049 G>A,C), RS1000044965 (1:93690855 C>A,G), RS1000046329 (1:93840989 A>G,T), RS1000047086 (1:93783209 G>A), RS1000047494 (1:93818792 A>G), RS1000050266 (1:93635057 T>G), RS1000054255 (1:93645837 T>C,G), RS1000061558 (1:93804039 A>G), RS1000069901 (1:93793565 C>T), RS1000104857 (1:93828291 C>A), RS1000105556 (1:93733713 A>G), RS1000115094 (1:93639627 C>T)

Disease associations

OMIM: gene MIM:604704 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST005547_9	Major depressive disorder	5.000000e-07
GCST006136_1	Alzheimer’s disease progression score	9.000000e-06
GCST006624_2	Systolic blood pressure	2.000000e-11
GCST008058_21	Estimated glomerular filtration rate	3.000000e-09
GCST008059_154	Estimated glomerular filtration rate	4.000000e-11
GCST008062_90	Blood urea nitrogen levels	6.000000e-06
GCST008595_9	Cognitive ability, years of educational attainment or schizophrenia (pleiotropy)	9.000000e-09
GCST010678_4	Liver fibrosis (total hepatic collagen content)	4.000000e-06
GCST90020026_538	Hip index	5.000000e-18
GCST90020026_539	Hip index	2.000000e-10
GCST90020026_540	Hip index	3.000000e-09
GCST90020026_541	Hip index	7.000000e-11
GCST90020026_617	Hip index	1.000000e-09
GCST90020028_572	Hip circumference adjusted for BMI	4.000000e-11

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0006514	Alzheimer’s disease biomarker measurement
EFO:0006335	systolic blood pressure
EFO:0004337	intelligence
EFO:0004784	self reported educational attainment
EFO:0010576	liver fibrosis measurement
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cisplatin	affects reaction, decreases expression, affects cotreatment, increases expression	4
trichostatin A	affects cotreatment, increases expression	3
Cyclosporine	increases expression	3
bisphenol A	decreases expression, decreases methylation	2
afimoxifene	decreases expression, decreases reaction, decreases response to substance	2
chloropicrin	decreases expression	2
Acetaminophen	decreases expression, increases expression	2
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, decreases expression	2
Benzo(a)pyrene	affects methylation, decreases methylation	2
Estradiol	affects cotreatment, decreases expression	2
Formaldehyde	decreases expression	2
Silicon Dioxide	increases expression	2
Valproic Acid	increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	affects expression, decreases expression	2
Aflatoxin B1	increases expression, increases methylation	2
Cadmium Chloride	decreases expression, increases expression	2
Particulate Matter	decreases expression, increases abundance, affects cotreatment	2
aristolochic acid I	increases expression	1
GSK-J4	increases expression	1
chloroacetaldehyde	increases expression	1
methylmercuric chloride	decreases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
sodium arsenate	increases abundance, increases expression	1
beta-lapachone	increases expression, decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
aflatoxin B2	decreases methylation	1
cupric oxide	decreases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1L3	Abcam HeLa BCAR3 KO	Cancer cell line	Female
CVCL_E4WU	ZR-75-1 BCAR3 clone B3-10	Cancer cell line	Female

Clinical trials (associated diseases)

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