BCAR1

Summary

BCAR1 (BCAR1 scaffold protein, Cas family member, HGNC:971) is a protein-coding gene on chromosome 16q23.1, encoding Breast cancer anti-estrogen resistance protein 1 (P56945). Docking protein which plays a central coordinating role for tyrosine kinase-based signaling related to cell adhesion. It is a selective cancer dependency (DepMap: 10.7% of cell lines).

The protein encoded by this gene is a member of the Crk-associated substrate (CAS) family of scaffold proteins, characterized by the presence of multiple protein-protein interaction domains and many serine and tyrosine phosphorylation sites. The encoded protein contains a Src-homology 3 (SH3) domain, a proline-rich domain, a substrate domain which contains 15 repeat of the YxxP consensus phosphorylation motif for Src family kinases, a serine-rich domain, and a bipartite Src-binding domain, which can bind both SH2 and SH3 domains. This adaptor protein functions in multiple cellular pathways, including in cell motility, apoptosis and cell cycle control. Dysregulation of this gene can have a wide range of effects, affecting different pathways, including cardiac development, vascular smooth muscle cells, liver and kidney function, endothelial migration, and cancer.

Source: NCBI Gene 9564 — RefSeq curated summary.

At a glance

• GWAS associations: 23
• Clinical variants (ClinVar): 266 total — 1 pathogenic, 1 likely-pathogenic
• Cancer dependency (DepMap): dependent in 10.7% of screened cell lines
• MANE Select transcript: NM_014567

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:971
Approved symbol	BCAR1
Name	BCAR1 scaffold protein, Cas family member
Location	16q23.1
Locus type	gene with protein product
Status	Approved
Aliases	P130Cas, Crkas, CAS, CASS1
Ensembl gene	ENSG00000050820
Ensembl biotype	protein_coding
OMIM	602941
Entrez	9564

Gene structure

Transcript identifiers

Ensembl transcripts: 31 — 26 protein_coding, 2 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000162330, ENST00000393420, ENST00000393422, ENST00000418647, ENST00000420641, ENST00000535626, ENST00000538440, ENST00000542031, ENST00000546196, ENST00000561970, ENST00000562556, ENST00000563038, ENST00000563323, ENST00000563700, ENST00000564028, ENST00000564170, ENST00000566465, ENST00000566982, ENST00000567215, ENST00000568864, ENST00000569006, ENST00000569340, ENST00000853596, ENST00000853597, ENST00000853598, ENST00000928348, ENST00000928349, ENST00000942292, ENST00000942293, ENST00000942294, ENST00000942295

RefSeq mRNA: 9 — MANE Select: NM_014567 NM_001170714, NM_001170715, NM_001170716, NM_001170717, NM_001170718, NM_001170719, NM_001170720, NM_001170721, NM_014567

CCDS: CCDS10915, CCDS54037, CCDS54038, CCDS54039, CCDS54040, CCDS54041, CCDS54042, CCDS54043

Canonical transcript exons

ENST00000162330 — 7 exons

Exon	Start	End
ENSE00001423684	75251471	75251624
ENSE00001515203	75228181	75230023
ENSE00003470509	75234889	75235986
ENSE00003534663	75237183	75237344
ENSE00003673045	75242470	75243090
ENSE00003678932	75236882	75236998
ENSE00003682348	75233846	75233935

Expression profiles

Bgee: expression breadth ubiquitous, 141 present calls, max score 96.54.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 35.9443 / max 236.2928, expressed in 1634 samples.

FANTOM5 promoters (15 alternative TSS)

Promoter ID	TPM avg	Samples expressed
158150	16.5201	1600
158156	12.5082	1575
158157	3.5404	1454
158152	0.9100	542
158155	0.5121	309
158151	0.4982	275
158146	0.3157	170
158159	0.3071	147
158145	0.2059	90
158154	0.1700	68

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	96.54	gold quality
metanephros cortex	UBERON:0010533	96.33	gold quality
cerebellum	UBERON:0002037	95.82	gold quality
cerebellar hemisphere	UBERON:0002245	95.79	gold quality
cerebellar cortex	UBERON:0002129	95.77	gold quality
ascending aorta	UBERON:0001496	95.57	gold quality
thoracic aorta	UBERON:0001515	95.48	gold quality
gastrocnemius	UBERON:0001388	95.35	gold quality
apex of heart	UBERON:0002098	95.29	gold quality
mucosa of transverse colon	UBERON:0004991	95.15	gold quality
body of stomach	UBERON:0001161	94.94	gold quality
descending thoracic aorta	UBERON:0002345	94.83	gold quality
adult mammalian kidney	UBERON:0000082	94.72	gold quality
cortex of kidney	UBERON:0001225	94.65	gold quality
placenta	UBERON:0001987	94.53	gold quality
muscle of leg	UBERON:0001383	94.46	gold quality
pituitary gland	UBERON:0000007	94.43	gold quality
heart left ventricle	UBERON:0002084	94.40	gold quality
skeletal muscle organ	UBERON:0014892	94.40	gold quality
right coronary artery	UBERON:0001625	94.33	gold quality
hindlimb stylopod muscle	UBERON:0004252	94.28	gold quality
fundus of stomach	UBERON:0001160	93.99	gold quality
adenohypophysis	UBERON:0002196	93.98	gold quality
stomach	UBERON:0000945	93.87	gold quality
popliteal artery	UBERON:0002250	93.79	gold quality
tibial artery	UBERON:0007610	93.78	gold quality
stromal cell of endometrium	CL:0002255	93.48	gold quality
right atrium auricular region	UBERON:0006631	93.34	gold quality
left testis	UBERON:0004533	93.21	gold quality
right testis	UBERON:0004534	93.14	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-9067	yes	6.35
E-ANND-3	yes	4.81

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
EGR1	Activation
NAB2	Activation

Upstream regulators (CollecTRI, top): EGR1, NAB2

miRNA regulators (miRDB)

22 targeting BCAR1, 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-3148	99.97	75.06	6478
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-105-5P	99.54	69.24	2060
HSA-MIR-7853-5P	99.54	69.30	2055
HSA-MIR-4685-5P	99.25	65.99	1563
HSA-MIR-6837-5P	99.25	65.47	1632
HSA-MIR-5584-3P	99.23	68.79	1351
HSA-MIR-939-3P	98.97	65.07	2347
HSA-MIR-6827-5P	98.46	64.88	1256
HSA-MIR-509-3P	98.12	67.25	612
HSA-MIR-891A-3P	98.05	67.99	970

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 10.7% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Tyrosine phosphorylation of p130CAS regulates localization and downstream signaling with profound affects on cell movement. (PMID:11779709)
• Binding of the adapter protein p130Cas to the C-terminal of Pyk2 in cultured human umbilical vein endothelial cells is phosphorylation-independent and is not affected by acute exposure to thrombin. (PMID:11820787)
• The association of Cas with Wiskott-Aldrich syndrome protein is associated with cell migration in stromal cell-derived factor-1alpha-stimulated Jurkat cells (PMID:12135674)
• phosphorylation of p130(Cas) can prevent cells from anoikis and contribute to tumor cell anchorage independence and metastasis (PMID:12397603)
• R-Ras promotes focal adhesion formation by signaling to FAK and p130(Cas) through a novel mechanism that differs from but synergizes with the alpha2beta1 integrin. (PMID:12529399)
• Requirement of the p130CAS-Crk coupling for metastasis suppressor KAI1/CD82-mediated inhibition of cell migration in a metastatic prostate cancer cell line. (PMID:12738793)
• endogenous Sin influences T-lymphocyte signaling by sequestering signaling substrates and regulating their availability (PMID:15121874)
• BCAR1 has a role in progression of primary breast cancer (PMID:15448007)
• crystal structure of p130cas SH3 domain (PMID:15784259)
• Our studies suggested that pRb2/p130-complexes bind to the ER-alpha promoter and could be involved in the transcriptional regulation of the ER-alpha gene by altering chromatin structure and DNA methylation pattern. (PMID:15923424)
• p130Cas and paxillin function as effectors of GD3-mediated signaling, leading to such malignant properties as rapid cell growth and invasion in melanoma cells (PMID:16040804)
• LOX regulates cell motility/migration through changes in actin filament polymerization, which involve the regulation of the p130(Cas)/Crk/DOCK180 (PMID:16440329)
• Fibronectin rigidity response involves force-dependent Fyn phosphorylation of p130Cas with rigidity-dependent displacement. (PMID:16597701)
• PTP1B mediates of RhoA-dependent phosphorylation of p130Cas. (PMID:16644720)
• The interaction between Ack1 and p130(Cas) occurred through their respective SH3 domains, while the substrate domain of p130(Cas) was the major site of Ack1-dependent phosphorylation. (PMID:17038317)
• Cas acts as a primary force sensor, transducing force into mechanical extension and thereby priming phosphorylation and activation of downstream signaling. (PMID:17129785)
• p130CAS is an important component in the netrin signaling pathway acting between tyrosine kinases and small GTPase Rac1 and is essential for commissural axon guidance in vivo. (PMID:17251438)
• the spatial and temporal regulation of BCAR3/p130(Cas) interactions within the cell is important for controlling breast cancer cell motility (PMID:17616674)
• Activation of the FAK-src molecular scaffolds and p130Cas-JNK signaling cascades by alpha1-integrins during colon cancer cell invasion. (PMID:17982677)
• Focal adhesion kinase as well as p130Cas and paxillin should be a crucial molecule undergoing stronger tyrosine phosphorylation in GD3-expressing melanoma cells. (PMID:18078823)
• focal adhesion kinase positively regulates Caco-2 spreading on collagen IV via p130(Cas) phosphorylation (PMID:18095869)
• The interaction of MT1-MMP with p130Cas at the cell periphery suggests the existence of a close interplay between pericellular proteolysis and signaling pathways involved in endothelial cell migration. (PMID:18164686)
• p130Cas-mediated control of TGF-beta/Smad signaling may provide an additional clue to the mechanism underlying resistance to TGF-beta-induced growth inhibition. (PMID:18321991)
• uPAR cooperates with integrin complexes containing beta(3) integrin to drive formation of the p130Cas-CrkII signaling complex and activation of Rac, resulting in a Rac-driven elongated-mesenchymal morphology, cell motility, and invasion. (PMID:18725541)
• In hepatocellular carcinoma (HCC), there is a negative correlation between the positive expression of p130Cas and the normal expression of E-cadherin/beta-catenin. p130Cas plays important roles in the invasion, metastasis and prognosis of HCC. (PMID:18842495)
• The lysyl oxidase pro-peptide attenuates fibronectin-mediated activation of focal adhesion kinase and p130Cas in breast cancer cells. (PMID:19029090)
• Data suggest that endothelin-1 stimulates the GTPase Rap1 by a mechanism involving Pyk2 activation and recruitment of the p130Cas/BCAR3 complex in human glomerular mesangial cells. (PMID:19086031)
• Evidence for the role of CAS in the regulation of vascular smooth muscle contractility, cell migration, hypertrophy, and growth is presented (PMID:19329671)
• targeting the product of the BCAR1 gene by a peptide which mimics the phosphorylated substrate domain may provide a new molecular avenue for treatment of antiestrogen resistant breast cancers. (PMID:19330798)
• BCAR1 is essential for the rapid estrogen effect on osteoclast differentiation, through estrogen receptor alpha and possibly Traf6. (PMID:19331827)
• Propofol inhibits pressure-stimulated macrophage phagocytosis via the GABAA receptor and dysregulation of p130cas phosphorylation. (PMID:19357231)
• The crucial interactions required for anti-estrogen resistance occur within the substrate domain of BCAR1 (PMID:19412734)
• p130Cas is required for mammary tumor growth and transforming growth factor-beta-mediated metastasis through regulation of Smad2/3 activity (PMID:19822523)
• 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)
• CAS plays a role in regulating the extension of cell protrusions and promotes the migration of cancer cells. (PMID:20688056)
• Analyses indicate that p130Cas expression in ErbB2 positive human breast cancers significantly correlates with higher risk to develop distant metastasis, thus underlying the value of the p130Cas/ErbB2 synergism in regulating breast cancer invasion. (PMID:20961652)
• BCAR-1 is a physiological substrate of Syk. (PMID:21047529)
• Knockdown of NRP1 or P130Cas or expression of either NRP1DeltaC or a non-tyrosine-phosphorylatable substrate domain mutant protein (p130(Cas15F)) was sufficient to inhibit growth factor-mediated migration of glioma and endothelial cells. (PMID:21245381)
• p130Cas, Src and talin function in both oral carcinoma invasion and resistance to cisplatin. (PMID:21291860)
• These results indicate a role for NRP1 and NRP1 glycosylation in mediating PDGF-induced VSMC migration, possibly by acting as a co-receptor for PDGFRalpha and via selective mobilization of a novel p130Cas tyrosine phosphorylation pathway. (PMID:21306301)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	bcar1	ENSDARG00000056525
mus_musculus	Bcar1	ENSMUSG00000031955
rattus_norvegicus	Bcar1	ENSRNOG00000019253
drosophila_melanogaster	p130CAS	FBGN0035101

Paralogs (3): CASS4 (ENSG00000087589), EFS (ENSG00000100842), NEDD9 (ENSG00000111859)

Protein

Protein identifiers

Breast cancer anti-estrogen resistance protein 1 — P56945 (reviewed: P56945)

Alternative names: CRK-associated substrate, Cas scaffolding protein family member 1, p130cas

All UniProt accessions (10): P56945, F5H855, H3BN62, H3BQJ7, H3BSB2, H3BSY4, H3BTB0, H3BTL5, H3BU42, H3BVF0

UniProt curated annotations — full annotation on UniProt →

Function. Docking protein which plays a central coordinating role for tyrosine kinase-based signaling related to cell adhesion. Implicated in induction of cell migration and cell branching. Involved in the BCAR3-mediated inhibition of TGFB signaling.

Subunit / interactions. Forms complexes in vivo with PTK2/FAK1, adapter protein CRKL and LYN kinase. Heterodimerizes with NEDD9. Component of a complex comprised of SH2D3C, BCAR1/CAS, and CRK. Within the complex, interacts with SH2D3C (via C-terminus), and CRK. 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. Interacts with BCAR3 (via Ras-GEF domain); the interaction regulates adhesion-dependent serine phosphorylation. Interacts with SMAD2 and SMAD3. Interacts with NPHP1. Interacts with PTK2B/PYK2. Interacts (via C-terminus) with SH2D3C/CHAT isoform 2 (via C-terminus). Interacts with activated CSPG4. Interacts with BMX, INPPL1/SHIP2 and PEAK1. Part of a collagen-stimulated complex involved in cell migration made of CDC42, CRK, TNK2 and BCAR1/p130cas. Interacts with TNK2 via SH3 domains. Interacts (when tyrosine-phosphorylated) with tensin TNS1; the interaction is increased by phosphorylation of TNS1.

Subcellular location. Cell junction. Focal adhesion. Cytoplasm. Cell projection. Axon.

Tissue specificity. Expressed in B-cells (at protein level). Widely expressed with an abundant expression in the testis. Low level of expression seen in the liver, thymus, and peripheral blood leukocytes.

Post-translational modifications. PTK2/FAK1 activation mediates phosphorylation at the YDYVHL motif; phosphorylation is most likely catalyzed by SRC family members. SRC-family kinases are recruited to the phosphorylated sites and can phosphorylate other tyrosine residues. Tyrosine phosphorylation is triggered by integrin-mediated adhesion of cells to the extracellular matrix. Dephosphorylated by PTPN14 at Tyr-128. Phosphorylated by SRC kinase in a EDN1- and PTK2B-mediated manner; phosphorylation strengthens its interaction with BCAR3 as part of the PTK2B/BCAR1/BCAR3/RAP1 signaling pathway.

Domain organisation. Contains a central domain (substrate domain) containing multiple potential SH2-binding sites and a C-terminal domain containing a divergent helix-loop-helix (HLH) motif. The SH2-binding sites putatively bind CRK, NCK and ABL1 SH2 domains. The HLH motif is absolutely required for the induction of pseudohyphal growth in yeast and mediates heterodimerization with NEDD9. A serine-rich region promotes activation of the serum response element (SRE). The SH3 domain is necessary for the localization of the protein to focal adhesions and interacts with one proline-rich region of PTK2/FAK11.

Similarity. Belongs to the CAS family.

Isoforms (8)

UniProt ID	Names	Canonical?
P56945-1	1	yes
P56945-2	2
P56945-3	3
P56945-4	4
P56945-5	5
P56945-6	6
P56945-7	7
P56945-8	8

RefSeq proteins (9): NP_001164185, NP_001164186, NP_001164187, NP_001164188, NP_001164189, NP_001164190, NP_001164191, NP_001164192, NP_055382* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001452	SH3_domain	Domain
IPR014928	Serine_rich_dom	Domain
IPR021901	CAS_C	Domain
IPR035745	BCAR1_SH3	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR037362	CAS_fam	Family
IPR038319	Serine_rich_sf	Homologous_superfamily
IPR046976	BCAR1_C	Domain

Pfam: PF00018, PF08824, PF12026

UniProt features (67 total): modified residue 14, sequence conflict 12, splice variant 8, compositionally biased region 6, region of interest 6, helix 6, strand 5, sequence variant 4, mutagenesis site 3, chain 1, domain 1, short sequence motif 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
1WYX	X-RAY DIFFRACTION	1.14
3T6G	X-RAY DIFFRACTION	2.5
5O2M	SOLUTION NMR
5O2P	SOLUTION NMR
5O2Q	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P56945-F1	62.07	0.29

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 (14): 1, 128, 134, 139, 234, 249, 269, 292, 362, 372, 410, 428, 437, 639

Mutagenesis-validated functional residues (3):

Position	Phenotype
787	weakens interaction with sh2d3c.
794	weakens interaction with sh2d3c.
797	weakens interaction with sh2d3c.

Function

Pathways and Gene Ontology

Reactome pathways

14 pathways

ID	Pathway
R-HSA-186763	Downstream signal transduction
R-HSA-372708	p130Cas linkage to MAPK signaling for integrins
R-HSA-4420097	VEGFA-VEGFR2 Pathway
R-HSA-8849471	PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases
R-HSA-109582	Hemostasis
R-HSA-162582	Signal Transduction
R-HSA-186797	Signaling by PDGF
R-HSA-194138	Signaling by VEGF
R-HSA-354192	Integrin signaling
R-HSA-76002	Platelet activation, signaling and aggregation
R-HSA-76009	Platelet Aggregation (Plug Formation)
R-HSA-8848021	Signaling by PTK6
R-HSA-9006927	Signaling by Non-Receptor Tyrosine Kinases
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases

MSigDB gene sets: 195 (showing top): GOBP_PLATELET_DERIVED_GROWTH_FACTOR_RECEPTOR_SIGNALING_PATHWAY, BIOCARTA_PTEN_PATHWAY, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_CELL_CHEMOTAXIS, REACTOME_PLATELET_AGGREGATION_PLUG_FORMATION, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, PID_NETRIN_PATHWAY, PID_PRL_SIGNALING_EVENTS_PATHWAY, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_GROWTH, GOBP_VASCULAR_ENDOTHELIAL_GROWTH_FACTOR_RECEPTOR_SIGNALING_PATHWAY, GOCC_RUFFLE, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND

GO Biological Process (23): regulation of cell growth (GO:0001558), actin filament organization (GO:0007015), cell adhesion (GO:0007155), cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), epidermal growth factor receptor signaling pathway (GO:0007173), G protein-coupled receptor signaling pathway (GO:0007186), integrin-mediated signaling pathway (GO:0007229), insulin receptor signaling pathway (GO:0008286), positive regulation of endothelial cell migration (GO:0010595), cell migration (GO:0016477), positive regulation of cell migration (GO:0030335), cellular response to hepatocyte growth factor stimulus (GO:0035729), regulation of apoptotic process (GO:0042981), platelet-derived growth factor receptor signaling pathway (GO:0048008), vascular endothelial growth factor receptor signaling pathway (GO:0048010), neurotrophin TRK receptor signaling pathway (GO:0048011), hepatocyte growth factor receptor signaling pathway (GO:0048012), antigen receptor-mediated signaling pathway (GO:0050851), T cell receptor signaling pathway (GO:0050852), B cell receptor signaling pathway (GO:0050853), cell division (GO:0051301), cell chemotaxis (GO:0060326), endothelin receptor signaling pathway (GO:0086100)

GO Molecular Function (3): SH3 domain binding (GO:0017124), protein kinase binding (GO:0019901), protein binding (GO:0005515)

GO Cellular Component (11): ruffle (GO:0001726), cytoplasm (GO:0005737), cytosol (GO:0005829), focal adhesion (GO:0005925), actin cytoskeleton (GO:0015629), membrane (GO:0016020), lamellipodium (GO:0030027), axon (GO:0030424), plasma membrane (GO:0005886), cell projection (GO:0042995), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
Signal Transduction	3
Signaling by Receptor Tyrosine Kinases	2
Signaling by PDGF	1
Integrin signaling	1
Signaling by VEGF	1
Signaling by PTK6	1
Platelet Aggregation (Plug Formation)	1
Hemostasis	1
Platelet activation, signaling and aggregation	1
Signaling by Non-Receptor Tyrosine Kinases	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell surface receptor protein tyrosine kinase signaling pathway	5
cellular anatomical structure	4
antigen receptor-mediated signaling pathway	2
cell leading edge	2
plasma membrane bounded cell projection	2
cell growth	1
regulation of growth	1
regulation of cellular component organization	1
actin cytoskeleton organization	1
supramolecular fiber organization	1
cellular process	1
enzyme-linked receptor protein signaling pathway	1
ERBB signaling pathway	1
G protein-coupled receptor activity	1
signal transduction	1
cell surface receptor signaling pathway	1
cellular response to insulin stimulus	1
regulation of endothelial cell migration	1
positive regulation of cell migration	1
endothelial cell migration	1
cell motility	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
response to hepatocyte growth factor	1
cellular response to growth factor stimulus	1
apoptotic process	1
regulation of programmed cell death	1
neurotrophin signaling pathway	1
immune response-activating cell surface receptor signaling pathway	1
protein domain specific binding	1
kinase binding	1
binding	1
intracellular anatomical structure	1
cytoplasm	1
cell-substrate junction	1
cytoskeleton	1
neuron projection	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

3628 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BCAR1	PXN	P49023	998
BCAR1	CRK	P46108	998
BCAR1	SRC	P12931	998
BCAR1	VCL	P18206	997
BCAR1	PTK2	Q05397	997
BCAR1	TLN1	Q9Y490	996
BCAR1	DOCK1	Q14185	996
BCAR1	TLN2	Q9Y4G6	996
BCAR1	RAPGEF1	Q13905	982
BCAR1	CRKL	P46109	968
BCAR1	BCAR3	O75815	965
BCAR1	GRB2	P29354	956
BCAR1	PTK2B	Q14289	951
BCAR1	NCK1	P16333	948
BCAR1	ZYX	Q15942	939

IntAct

151 interactions, top by confidence:

A	B	Type	Score
MAPK14	MAPKAPK2	psi-mi:“MI:0914”(association)	0.940
PTPN1	SRC	psi-mi:“MI:0914”(association)	0.940
NPHP4	NPHP1	psi-mi:“MI:0914”(association)	0.930
BCAR1	CRK	psi-mi:“MI:0914”(association)	0.820
BCAR1	CRK	psi-mi:“MI:0915”(physical association)	0.820
CRK	BCAR1	psi-mi:“MI:0915”(physical association)	0.820
YWHAH	ABLIM1	psi-mi:“MI:0914”(association)	0.800
PTPN1	BCAR1	psi-mi:“MI:0203”(dephosphorylation reaction)	0.790
BCAR1	PTPN1	psi-mi:“MI:0915”(physical association)	0.790
BCAR1	PTPN1	psi-mi:“MI:0407”(direct interaction)	0.790
FYN	BCAR1	psi-mi:“MI:0915”(physical association)	0.780
FYN	BCAR1	psi-mi:“MI:0914”(association)	0.780
EGFR	CTNND1	psi-mi:“MI:0914”(association)	0.750
SH2D3C	BCAR1	psi-mi:“MI:0407”(direct interaction)	0.690
SH2D3C	BCAR1	psi-mi:“MI:0915”(physical association)	0.690
BCAR1	SRC	psi-mi:“MI:0915”(physical association)	0.690
SRC	BCAR1	psi-mi:“MI:0914”(association)	0.690
PTPN12	BCAR1	psi-mi:“MI:0407”(direct interaction)	0.690

BioGRID (690): BCAR1 (Affinity Capture-MS), BCAR1 (Affinity Capture-Western), BCAR1 (Affinity Capture-Western), ALK (Affinity Capture-Western), BCAR1 (Biochemical Activity), BCAR1 (Affinity Capture-MS), BCAR1 (Affinity Capture-MS), BCAR1 (Affinity Capture-MS), ERBB2 (Affinity Capture-Western), PTEN (Reconstituted Complex), RAPGEF1 (Two-hybrid), BCAR1 (Two-hybrid), BCAR1 (Affinity Capture-Western), BCAR1 (Co-localization), BCAR1 (Proximity Label-MS)

ESM2 similar proteins: A5PKL7, D3ZZN9, O15049, O43281, O94989, O95153, P56945, P60669, Q07912, Q13671, Q15772, Q16584, Q2M3G4, Q2M3V2, Q3LUD3, Q3LUD4, Q3UYR4, Q494U1, Q5BJT1, Q5FWH6, Q5SW24, Q5XJV6, Q61140, Q62407, Q63767, Q64355, Q66HA1, Q6PAJ3, Q6ZMQ8, Q6ZS72, Q6ZVH7, Q6ZW31, Q75VX8, Q7TNF8, Q80W87, Q80XI6, Q8BG26, Q8BLS7, Q8TER5, Q8VC98

Diamond homologs: A0A8I3PDQ1, A1CEK6, A1DFN5, A2QW93, A4FU49, A4RF61, A7A261, O13736, O35177, O35179, O35964, O42287, O43281, P29355, P34109, P38753, P43603, P56945, Q08012, Q0CJU8, Q0P5B1, Q0U6X7, Q14511, Q15811, Q16584, Q1E878, Q2GT05, Q4R729, Q4WHP5, Q557J6, Q5BBL4, Q5I1X5, Q61140, Q62419, Q62420, Q63767, Q64355, Q66HA1, Q6BNP6, Q6C2N2

SIGNOR signaling

40 interactions.

A	Effect	B	Mechanism
SRC	“up-regulates activity”	BCAR1	phosphorylation
PTPN12	down-regulates	BCAR1	dephosphorylation
BCAR1	down-regulates	SMAD3	binding
PTK6	“up-regulates activity”	BCAR1	phosphorylation
PTK6	up-regulates	BCAR1	phosphorylation
PTPN14	down-regulates	BCAR1	dephosphorylation
NAB2	“up-regulates quantity by expression”	BCAR1	“transcriptional regulation”
EGR1	“up-regulates quantity by expression”	BCAR1	“transcriptional regulation”
BCAR1	“up-regulates quantity by expression”	NAB2	“transcriptional regulation”
BCAR1	“up-regulates quantity by expression”	EGR1	“transcriptional regulation”
PXN	“up-regulates activity”	BCAR1
BCAR1	“up-regulates activity”	PIK3R1	binding
PTPRF	“down-regulates quantity by destabilization”	BCAR1	dephosphorylation
FYN	“up-regulates activity”	BCAR1	phosphorylation
ABL1	“up-regulates activity”	BCAR1	phosphorylation
PTK2B	“up-regulates activity”	BCAR1	phosphorylation
FGFR1	up-regulates	BCAR1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 80 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
Activation of BAD and translocation to mitochondria	5	66.8×	5e-07
DCC mediated attractive signaling	5	62.6×	7e-07
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	5	58.9×	8e-07
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	5	58.9×	8e-07
Activation of BH3-only proteins	5	43.5×	2e-06
Signaling by RAS mutants	5	37.1×	5e-06
Signaling by high-kinase activity BRAF mutants	6	33.4×	9e-07
EPHB-mediated forward signaling	7	32.6×	1e-07

GO biological processes:

GO term	Partners	Fold	FDR
cellular response to platelet-derived growth factor stimulus	6	52.5×	7e-07
ephrin receptor signaling pathway	7	32.5×	7e-07
vascular endothelial growth factor receptor signaling pathway	5	32.5×	6e-05
establishment of cell polarity	5	25.9×	2e-04
positive regulation of substrate adhesion-dependent cell spreading	5	25.3×	2e-04
substantia nigra development	5	24.8×	2e-04
epidermal growth factor receptor signaling pathway	7	23.4×	4e-06
integrin-mediated signaling pathway	6	13.0×	4e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	219
Likely benign	13
Benign	12

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
3063404	GRCh37/hg19 16q22.3-23.1(chr16:74079694-75352818)x1	Pathogenic
981833	NM_014567.5(BCAR1):c.12+2T>C	Likely pathogenic

SpliceAI

1284 predictions. Top by Δscore:

Variant	Effect	Δscore
16:75230019:TTCAG:T	acceptor_gain	1.0000
16:75230021:CAG:C	acceptor_gain	1.0000
16:75230022:AG:A	acceptor_gain	1.0000
16:75230023:GCT:G	acceptor_loss	1.0000
16:75230024:C:CC	acceptor_gain	1.0000
16:75230024:CT:C	acceptor_loss	1.0000
16:75230025:T:C	acceptor_loss	1.0000
16:75230030:C:CT	acceptor_gain	1.0000
16:75230031:A:T	acceptor_gain	1.0000
16:75233840:CCTCA:C	donor_loss	1.0000
16:75233841:CTCA:C	donor_loss	1.0000
16:75233842:TCAC:T	donor_loss	1.0000
16:75233843:CACC:C	donor_loss	1.0000
16:75233844:A:C	donor_loss	1.0000
16:75233845:CCTG:C	donor_gain	1.0000
16:75235982:TAGAC:T	acceptor_gain	1.0000
16:75235983:AGAC:A	acceptor_gain	1.0000
16:75235984:GAC:G	acceptor_gain	1.0000
16:75235985:AC:A	acceptor_gain	1.0000
16:75235985:ACC:A	acceptor_loss	1.0000
16:75235986:CC:C	acceptor_gain	1.0000
16:75235987:C:CA	acceptor_loss	1.0000
16:75235987:C:CC	acceptor_gain	1.0000
16:75236880:A:AC	donor_gain	1.0000
16:75236881:C:CT	donor_gain	1.0000
16:75236881:CTG:C	donor_gain	1.0000
16:75236996:CAC:C	acceptor_gain	1.0000
16:75237180:TAC:T	donor_loss	1.0000
16:75237181:A:AC	donor_gain	1.0000
16:75237181:ACCT:A	donor_gain	1.0000

AlphaMissense

5581 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:75229631:C:A	K831N	1.000
16:75229631:C:G	K831N	1.000
16:75229656:A:G	L823P	1.000
16:75229728:A:G	L799P	1.000
16:75229734:T:A	D797V	1.000
16:75229738:C:G	G796R	1.000
16:75229738:C:T	G796R	1.000
16:75229742:G:C	F794L	1.000
16:75229742:G:T	F794L	1.000
16:75229744:A:G	F794L	1.000
16:75229756:G:C	H790D	1.000
16:75229758:G:T	A789D	1.000
16:75229767:A:T	I786N	1.000
16:75229770:A:T	V785D	1.000
16:75242928:G:C	R59G	1.000
16:75242928:G:T	R59S	1.000
16:75242945:C:T	G53D	1.000
16:75242946:C:G	G53R	1.000
16:75242965:G:C	C46W	1.000
16:75242967:A:G	C46R	1.000
16:75242974:C:A	W43C	1.000
16:75242974:C:G	W43C	1.000
16:75242976:A:G	W43R	1.000
16:75242976:A:T	W43R	1.000
16:75243031:G:C	F24L	1.000
16:75243031:G:T	F24L	1.000
16:75243032:A:G	F24S	1.000
16:75243033:A:G	F24L	1.000
16:75243038:A:G	L22P	1.000
16:75229545:A:G	F860S	0.999

dbSNP variants (sampled 300 via entrez): RS1000000831 (16:75257991 G>A), RS1000001749 (16:75231099 T>C), RS1000052574 (16:75255295 G>A), RS1000105045 (16:75259902 A>G,T), RS1000130696 (16:75236245 G>A,T), RS1000161103 (16:75253406 G>T), RS1000290003 (16:75249247 G>C), RS1000295765 (16:75263069 G>A,C), RS1000321911 (16:75255465 C>T), RS1000520571 (16:75263865 G>A,C), RS1000561055 (16:75228637 G>A,T), RS1000654474 (16:75245304 A>G), RS1000674779 (16:75268542 G>C), RS1000688375 (16:75231231 T>TGCGCC), RS1000694381 (16:75241502 G>C)

Disease associations

OMIM: gene MIM:602941 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): hereditary breast ovarian cancer syndrome (MONDO:0003582)

Orphanet (1): Hereditary breast and/or ovarian cancer syndrome (Orphanet:145)

HPO phenotypes

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

GWAS associations

23 associations (top):

Study	Trait	p-value
GCST002018_1	Crohn’s disease (time to surgery)	9.000000e-06
GCST002553_10	Pancreatic cancer	1.000000e-10
GCST003219_12	Advanced age-related macular degeneration	5.000000e-12
GCST004860_122	Alcoholic chronic pancreatitis	4.000000e-09
GCST004860_124	Alcoholic chronic pancreatitis	8.000000e-07
GCST004860_129	Alcoholic chronic pancreatitis	8.000000e-07
GCST004860_136	Alcoholic chronic pancreatitis	2.000000e-06
GCST004860_137	Alcoholic chronic pancreatitis	7.000000e-06
GCST004860_154	Alcoholic chronic pancreatitis	1.000000e-07
GCST004860_62	Alcoholic chronic pancreatitis	5.000000e-06
GCST005047_107	Type 2 diabetes	7.000000e-08
GCST005047_54	Type 2 diabetes	4.000000e-08
GCST005414_1	Type 2 diabetes	1.000000e-07
GCST005434_15	Pancreatic cancer	1.000000e-11
GCST005536_37	Type 1 diabetes	3.000000e-19
GCST007612_2	Chronic obstructive pulmonary disease or coronary artery disease (pleiotropy)	4.000000e-08
GCST008363_5	Offspring birth weight	1.000000e-09
GCST009379_170	Type 2 diabetes	4.000000e-32
GCST009379_171	Type 2 diabetes	3.000000e-06
GCST010867_15	Coronary artery disease	1.000000e-12
GCST011020_9	Intracranial aneurysm	5.000000e-11
GCST011021_14	Intracranial aneurysm	6.000000e-15
GCST011365_148	Myocardial infarction	4.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:1001492	atrophic macular degeneration
EFO:0004344	birth weight
EFO:0005939	parental genotype effect measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D061325	Hereditary Breast and Ovarian Cancer Syndrome	C04.588.180.483; C04.588.322.455.431; C04.700.517; C12.050.351.500.056.630.705.431; C12.050.351.937.418.685.431; C12.100.250.056.630.705.431; C12.900.418.685.431; C16.320.700.517; C17.800.090.500.483; C19.344.410.431; C19.391.630.705.431

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, increases abundance	3
Fulvestrant	affects response to substance, affects cotreatment, decreases methylation, decreases expression, decreases reaction (+1 more)	3
Arsenic	affects methylation, increases abundance, increases expression	3
Particulate Matter	affects cotreatment, increases abundance, increases expression, decreases expression	3
Benzo(a)pyrene	affects methylation, increases expression	2
Cadmium	increases abundance, increases expression, decreases expression	2
Cisplatin	increases response to substance	2
Aflatoxin B1	decreases methylation	2
aristolochic acid I	increases expression	1
FR900359	decreases phosphorylation	1
methylmercuric chloride	increases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
bisphenol A	affects expression	1
sodium arsenate	increases expression, increases abundance	1
2,4,5,2’,4’,5’-hexachlorobiphenyl	affects expression	1
tetrahydropalmatine	decreases expression	1
arsenite	increases expression	1
afimoxifene	decreases response to substance	1
sulindac sulfide	decreases phosphorylation	1
benzo(e)pyrene	decreases methylation	1
oxophenylarsine	affects cotreatment, decreases reaction, increases phosphorylation	1
aflatoxin B2	decreases methylation	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1
oxotremorine M	affects cotreatment, decreases reaction, increases phosphorylation	1
beta-methylcholine	affects expression	1
caffeic acid phenethyl ester	decreases phosphorylation	1
ML 7	decreases phosphorylation	1
chromium hexavalent ion	increases activity, affects reaction	1
cyproconazole	decreases expression	1
K 7174	increases expression	1

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8BT	Abcam HCT 116 BCAR1 KO	Cancer cell line	Male
CVCL_B9DX	Abcam A-549 BCAR1 KO	Cancer cell line	Male
CVCL_D2DZ	Abcam MCF-7 BCAR1 KO	Cancer cell line	Female
CVCL_E4WT	ZR-75-1 BCAR1 clone 4A12	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02562170	PHASE4	COMPLETED	Protexa® Versus TiLoopBra® in Immediate Breast Reconstruction- A Pilot Study
NCT00673335	PHASE3	COMPLETED	Letrozole in Preventing Breast Cancer in Postmenopausal Women With a BRCA1 or BRCA2 Mutation
NCT00685256	PHASE3	COMPLETED	Standard Genetic Counseling With or Without a Decision Guide in Improving Communication Between Mothers Undergoing BRCA1/2 Testing and Their Minor-Age Children
NCT03162276	PHASE3	UNKNOWN	Trial of Inquiry Based Stress Reduction (IBSR) Program for BRCA1/2 Mutation Carriers
NCT00253539	PHASE2	COMPLETED	Arzoxifene or Tamoxifen in Preventing Breast Cancer in Premenopausal Women at High Risk for Breast Cancer
NCT00305695	PHASE2	COMPLETED	Zoledronate or Observation in Maintaining Bone Mineral Density in Patients Who Are Undergoing Surgery to Remove Both Ovaries
NCT00321633	PHASE2	COMPLETED	Carboplatin or Docetaxel in Treating Women With Metastatic Genetic Breast Cancer
NCT01333748	PHASE2	COMPLETED	Search Allelic Imbalance of Expression of BRCA Genes in Hereditary Risk of Breast and/or Ovarian Cancer
NCT01367639	PHASE2	COMPLETED	Trial of Inquiry Based Stress Reduction (IBSR) Program for BRCA1/2 Mutation Carriers
NCT00535119	PHASE1	COMPLETED	Veliparib, Carboplatin, and Paclitaxel in Treating Patients With Advanced Solid Cancer
NCT00892736	PHASE1	COMPLETED	Veliparib in Treating Patients With Malignant Solid Tumors That Do Not Respond to Previous Therapy
NCT03832985	EARLY_PHASE1	COMPLETED	Pediatric Reporting of Adult-Onset Genomic Results
NCT00005095	Not specified	RECRUITING	Specimen and Data Study for Ovarian Cancer Early Detection and Prevention
NCT00609505	Not specified	COMPLETED	Telemedicine vs. Face-to-Face Cancer Genetic Counseling
NCT01273909	Not specified	UNKNOWN	Outcomes After Perforator Flap Reconstruction for Breast Reconstruction and/or Lymphedema Treatment
NCT01445275	Not specified	WITHDRAWN	Cost of Cancer Risk Management in Women at Elevated Genetic Risk for Ovarian Cancer Who Participated on GOG-0199
NCT01608074	Not specified	ACTIVE_NOT_RECRUITING	Radical Fimbriectomy for Young BRCA Mutation Carriers
NCT02087592	Not specified	COMPLETED	Feasibility of Lifestyle Intervention in BRCA1/2 Mutation Carriers
NCT02302742	Not specified	RECRUITING	Triple Negative Breast Cancer and Germline Hereditary Breast and Ovarian Cancer Mutation Carrier Registry
NCT02324062	Not specified	COMPLETED	Cancer Genetics Hereditary Cancer Panel Testing
NCT02516540	Not specified	UNKNOWN	Efficacy of Lifestyle Intervention in BRCA1/2 Mutation Carriers
NCT02653105	Not specified	ACTIVE_NOT_RECRUITING	Women at Risk of Breast Cancer and OLFM4
NCT02705924	Not specified	TERMINATED	Impact of a Psychoeducational Intervention on Expectations and Coping in Young Women Exposed to a High HBOC Risk
NCT02760849	Not specified	ACTIVE_NOT_RECRUITING	Surgery in Preventing Ovarian Cancer in Patients With Genetic Mutations
NCT02786147	Not specified	COMPLETED	Identification and Referral of Women at Risk for Hereditary Breast/Ovarian Cancer
NCT02956681	Not specified	COMPLETED	Statewide Communication to Reach Diverse Low Income Women
NCT03015376	Not specified	UNKNOWN	Inherited Susceptible Genes Among Epithelial Ovarian Cancer
NCT03050268	Not specified	RECRUITING	Familial Investigations of Childhood Cancer Predisposition
NCT03075540	Not specified	COMPLETED	Enhancing At-risk Latina Women’s Use of Genetic Counseling for Hereditary Breast and Ovarian Cancer
NCT03124212	Not specified	RECRUITING	Cascade Genetic Testing for Hereditary Breast/Ovarian Cancer and Lynch Syndrome in Switzerland
NCT03246841	Not specified	ACTIVE_NOT_RECRUITING	Investigation of Tumour Spectrum of Germline Mutations in Breast and Ovarian Cancer Genes.
NCT03294343	Not specified	UNKNOWN	Risk-Reducing Surgeries for Hereditary Ovarian Cancer
NCT03421327	Not specified	COMPLETED	Genetic Risk: Whether, When, and How to Tell Adolescents
NCT03510689	Not specified	COMPLETED	Genetics and Heart Health After Cancer Therapy
NCT03511690	Not specified	COMPLETED	Testing an Intelligent Tutoring System to Enhance Genetic Risk Assessment
NCT03784859	Not specified	COMPLETED	Tissue Expansion in Breast Reconstruction Without Drains
NCT03979612	Not specified	UNKNOWN	Evaluation of the Adhesion to the GENEPY Network
NCT04197856	Not specified	ACTIVE_NOT_RECRUITING	Direct Information to At-risk Relatives
NCT04407611	Not specified	COMPLETED	Scalable Communication Modalities for Returning Genetic Research Results
NCT04508764	Not specified	TERMINATED	Implementation of the Families Accelerating Cascade Testing Toolkit (FACTT) for Hereditary Breast and Ovarian Cancer and Lynch Syndrome