BCAR1 (breast cancer anti-estrogen resistance 1)

2011-12-01   Allison Berrier  

Department of Oral, Craniofacial Biology, LSUHSC-NO School of Dentistry, 1100 Florida Avenue, Clinical Bldg, Room 8301, New Orleans, LA 70119, USA

Identity

HGNC
LOCATION
16q23.1
LOCUSID
ALIAS
CAS,CAS1,CASS1,CRKAS,P130Cas
FUSION GENES

DNA/RNA

Atlas Image
Figure 1.

Proteins

Note

BCAR1 isoforms
Isoform 1: 916 aa, calc MW= 97,7 kDa. Isoform 2: 888 aa, (alternate 5 sequence compared to variant 1) calc MW= 95,1 kDa. Isoform 3: 888 aa, (alternate 5 sequence compared to variant 1) calc MW= 95,3 kDa. Isoform 4: 888 aa, (alternate 5 sequence and alternate splice site in the substrate domain compared to variant 1 resulting in a different N-terminus and additional segment in the middle region compared to isoform 1) calc MW= 95,3 kDa. Isoform 5: 870 aa, (lacks an exon in the 5 region, alternate AUG start codon, has a different N-terminus compared to isoform 1) calc MW= 93,16 kDa. Isoform 6: 870 aa, (different N-terminus compared to isoform 1) calc MW= 93,2 kDa. Isoform 7, 868 aa (shorter, alternate 5 sequence, different N-terminus compared to isoform 1) calc MW= 93 kDa. Isoform 8, 722 aa, (alternate internal sequence compared to isoform 1, different N-terminus compared to isoform 1) calc MW= 77,6 kDa. Isoform 9: 660 aa, (shorter alternate 5 sequence, different N-terminus compared to isoform 1) calc MW= 70,7 kDa.

BCAR proteins migrate during SDS-PAGE electrophoresis at a significantly higher molecular weight than predicted from sequence analysis perhaps due to the extensive phosphorylation of BCAR proteins. Calculated MW 93,2 kDa, SDS-PAGE observed MW 130 kDa. Potential sites of human BCAR1 phosphorylation (PhosphoSitePlus): tyrosine residues aa 12, 128, 165, 192, 222, 224, 234, 249, 267, 287, 306, 327, 362, 372, 387, 410, 653, 664, 666; serine residues aa 134, 139, 292, 437, 639; and threonine residues aa 269, 326, 385. Inducers of BCAR1 phosphorylation include cell matrix adhesion, extracellular matrix rigidity, growth factors, hormones and progression through the cell cycle. Phosphorylation of BCAR1 regulates BCAR1 dependent activities through altering protein interactions, protein localization and signaling cascades (Tikhmyanova et al., 2010).

Atlas Image
Figure 2. Schematic diagram containing BCAR1 protein domains.

Description

BCAR1 domains as described in Tikhmyanova et al., 2010 are shown in the schematic diagram in figure 2. The amino terminal 1-65 aa contain the Src homology 3 domain (SH3) domain that binds proline-rich PxxP ligands. The adjacent region 66-447 aa contains the substrate domain (SD) comprised of 15 YxxP motifs that when phosphorylated by tyrosine kinases provides canonical binding sites for proteins containing SH2 domains such as Crk, mechanical forces and stretching of SD may induce conformational changes that allows phosphorylation by kinases and this stretching may promote protein-protein interactions in this domain (Sawada et al., 2006). The serine rich domain within 448-610 aa (serine rich protein interaction domain) contains a four-helix bundle that functions as a scaffold for BCAR1 binding proteins such as Grb2 and 14-3-3 (Nasertorabi et al., 2004; Briknarová et al., 2005). The C-terminal domain of 746-870 aa has a potential FAT (focal adhesion targeting) domain and a helix-loop-helix domain with homology to the transcription factor Id. This region contains the YDYVHL motif that is phosphorylated during cell adhesion.

BCAR1 interacting proteins (BioGRID)
CRKII, p60-Src, PTPN12, PTK2 (FAK), RapGEF1 (C3G), NPHP1, PTPN1 (PTP1B), FES, SHIP2 (INPPL1), ARHGAP32 (p250GAP), Pyk2 (PTK2B), Fyn, CRKL, YWHAZ, SrcIN1 (SNIP), p85-alpha (PI3KR1), c-ABL (bcr/abl), Lyn, Grb2, Dock1, paxillin, TRIP6, SH-PTP2, ID2A, UHRF2, NEDD9, NCK1, VCL, SAP1, Zyxin, BCAR3 (AND-34), CD2AP, LCK, SFN, SH2D3C, JNK/SAPK1, SH3KBP1, tensin 1 (TNS1), HCK, EFS, E2F2, VPS11, HspA5, TUBA1A, GADD34, p140Cap, BCAR1 (p130CAS), PTP-PEST, CIZ, Aurora-A, 14-3-3, CHAT-H, AIP4, APC/C and CDH1.

Expression

BCAR1 is ubiquitously expressed and is reportedly detectable in all phases of the cell cycle. In lymphoid development, BCAR is expressed at higher levels in differentiated cells compared to precursors. Barretts esophagus cancer cell line compared to normal tissue 2,51 increase in BCAR1 expression (Oncomine). Colorectal cancer Ramaswamy multi-cancer there is a 4,2 fold increase in BCAR1 expression compared to other cancers (Oncomine). Gastric cancer cell line Gyorffy cell line 2 there is a 5,0 fold reduction in BCAR 1 expression (Oncomine). In lymphomas, BCAR1 expression is reduced 2,5 fold (Oncomine).

Localisation

Cytoplasm, ruffles, cell junctions (Donaldson et al., 2000), nucleus (Kim et al., 2004) and focal adhesions (Nakamoto et al., 1997; Volberg et al., 1995; Winograd-Katz et al., 2009).

Function

BCAR1 regulates numerous cellular processes such as invasion, migration, transformation, survival and drug resistance (Di Stefano et al., 2011; Brábek et al., 2004; Brábek et al., 2005) (summarized in figure 3). BCAR1 lacks intrinsic enzymatic activity, yet it is a substrate for several kinases including the Src tyrosine kinase. The original name for BCAR1 was p130CAS abbreviated from Crk-associated substrate because it was first identified as a tyrosine phosphorylated protein in cells transformed by v-src and v-crk oncogenes. BCAR1 regulates cellular behavior by controlling signaling cascades and the dynamic localization of multi-protein complexes. The BCAR1 phosphorylation state is regulated during the cell cycle. During the exit of G2, BCAR1 serine and threonine phosphorylation levels increase and these events disrupt the interactions of BCAR1 with Src and FAK and thus dissociates this complex and contributes to the disassembly of focal adhesions allowing cells to loosen matrix adhesions and thus permitting cell rounding in mitosis. The subsequent reformation of matrix adhesions promotes progression through the cell cycle from mitosis to G1 (Pugacheva et al., 2006).
Atlas Image
Figure 3. Extracellular cues that control CAR1 phosphorylation and cellular processes that are regulated by BCAR1.

Homology

There is a family containing four proteins related to BCAR1 (breast cancer resistance) that possess names related to the prior nomenclature for BCAR1 homologs in the rat and mouse. The non-human homologs of BCAR1 were named CAS for Crk-associated substrate. This family of proteins includes the protein EFS (embryonal Fyn-associated substrate) (CAS3, CASS3, EFS1, EFS2, HEFS, SIN) identified because of interactions with the Src-family kinases Fyn and Yes and maps to chromosome 14q11.2-q12. A third family member is HEF1 (human enhancer of filamentation 1 known as CASL, CAS-L, NEDD9, CAS2 and CASS2) that maps to chromosome 6p25-p24 and was isolated as a human gene that promotes filamentous growth in yeast. This screen was performed to identify regulators of the cell cycle and polarity. It was also identified as a protein that is tyrosine phosphorylated after clustering integrin β1 in T-lymphocytes. NEDD9 (neural precursor cell expressed, developmentally down-regulated 9) is a gene restricted in expression to early embryonic, but not adult mouse brain. The fourth family member is CASS4 ((HEF-EFS-P130CAS-like)/CAS4) that maps to chromosome 20q13.2-q13.31 and is the newest member of the family that was identified by genomic and transcript homology and demonstrated to function similarly to other BCAR family members. These 4 proteins are conserved from jawed vertebrates through mammals. One BCAR member is found in lower vertebrates and insects. However, no BCAR family member is detectable in C. elegans, S. cerevisiae and other lower eukaryotes.

Mutations

Somatic

Catalogue of somatic mutations in cancer: there are currently 10 known somatic mutations in BCAR1. Proceeding from the N-terminus to the C-Terminus of BCAR1, aa 118 proline (identified in the central nervous system), 185 alanine (identified in the central nervous system), 407 threonine (identified in breast tissue), 430 serine (upper aerodigestive tract), 583 serine (identified in prostate tissue), 592 histidine (identified in liver), 708 lysine (identified in the central nervous system), 759 threonine (identified in central nervous system), 780 valine (identified in central nervous system), 795 isoleucine (identified in upper aerodigestive tract). Mutations at aa 118 and 185 are in the substrate domain, 407 and 430 are amino-terminal to the 4 helical bundle, 583 and 592 are in the 4-helix bundle, whereas 759, 780 and 795 localize to the C-terminal domain.

Implicated in

Entity name
Various cancers
Note
Overexpression of BCAR1 is linked to poor prognosis and increased cancer metastasis in many cancers. BCAR1 can be upregulated by gene amplification, transcriptional upregulation and changes in protein stability. Hyperphosphorylation of BCAR1 drives cell migration, invasion, cell survival and drug resistance.
Entity name
Breast cancer
Prognosis
In breast cancers that express high levels of BCAR1, the cancer is more likely to relapse and the tumors frequently have an intrinsic reduced response to tamoxifen (van der Flier et al., 2000; Dorssers et al., 2004).
Oncogenesis
Elevated BCAR levels in breast cancers correlates with increased expression of HER2/neu and enhanced cell proliferation (Cabodi et al., 2006; Cabodi et al., 2010). BCAR1 overexpression in breast cancer cells is linked to resistance to the cytotoxic agent Adriamycin (Ta et al., 2008). BCAR1 overexpression is sufficient to induce hyperplasia in the mammary pad during development and pregnancy.
Entity name
Prostate cancer
Oncogenesis
In prostate cancer, BCAR1 expression is higher compared to control tissue and expression of BCAR1 in prostate cancer correlates with elevated EGFR expression levels (Fromont et al., 2007; Fromont et al., 2011; Cabodi et al., 2010).
Entity name
Hepatocellular carcinoma
Prognosis
In hepatocellular carcinoma, tumor invasion and poor prognosis correlate with overexpression of BCAR1 and reductions in E-cadherin and β-catenin levels (Guo et al., 2008).
Entity name
Nasal polyps
Oncogenesis
Nasal polyps can express high levels of BCAR1 (Zhang et al., 2003).
Entity name
Colorectal cancer
Oncogenesis
Celecoxib cytotoxicity in colorectal cancer is linked to cleavage of BCAR1 and apoptosis. Overexpression of BCAR1 in colorectal cancer cell lines is linked to resistance to celecoxib (Casanova et al., 2006; Weyant et al., 2000).
Entity name
Non-small-cell lung cancer (NSCLC)
Oncogenesis
BCAR1 is not detected in normal lung tissue, however in non-small-cell lung cancer and tuberculosis and other pulmonary disorders elevated levels of BCAR1 are observed in both the diseased tissue and elevated levels are noted in serum (Deng et al., 2011). In patients with NSCLC the serum levels of BCAR1 proportionally increase with the progression of tumor stage. Interestingly, in patients with elevated serum BCAR1 levels, the serum levels of BCAR1 diminish after removal of the pulmonary lesion or tumor.
Entity name
Ovarian cancer
Prognosis
In ovarian cancer, an increase in BCAR1 expression correlates with poor 5 year survival rates and reductions in BCAR1 expression result in reduced tumor growth following docetaxel chemotherapy (Nick et al., 2011).
Entity name
Oral cancer
Oncogenesis
In oral cancers elevated levels of UPAR are indicative of more invasive tumors and enhanced lymph node metastasis. The levels of UPAR in oral cancer correlate with the levels of BCAR1 (Shi et al., 2011).
Oncogenesis
In anaplastic large-cell lymphomas, the anaplastic lymphoma kinase (ALK) is frequently translocated and a fusion protein with nucleophosmin (NPM)-ALK is generated that contains kinase activity. NPM-ALK transforms fibroblasts, however in BCAR1-/- fibroblasts NPM-ALK fails to induce transformation. Hence, BCAR1 is critical for ALK transformation activity (Ambrogio et al., 2005).
Entity name
Chemotherapeutic resistance
Note
Overexpression of BCAR1 is linked to drug resistance in multiple tumor types such as breast cancer, lung cancers, glioblastoma and melanoma (Ta et al., 2008). BCAR1 and NEDD9 interact with BCAR3 to mediate anti-estrogen resistance and to control Rap1 GTPase activation (Cai et al., 2003). In a screen of an estrogen dependent cell line, BCAR1 was identified as a gene required for tamoxifen resistance (Brinkman et al., 2000; van der Flier et al., 2000).
Entity name
Role of BCAR1 in other pathological conditions or diseases
Note
BCAR1 dysfunction is linked to inflammatory disorders, ischemic stroke (Ziemka-Nalecz et al., 2007; Zalewska et al., 2005) and developmental defects. Knockout of BCAR1 is lethal at embryonic stages days 11,5 to 12,5 as a result of cardiovascular dysfunction (Honda et al., 1998). BCAR1 is critical for the pathology of many infectious diseases. The bacterial species Yersinia encodes and secretes a phosphatase YOP that inactivates/dephosphorylates BCAR1 and YOP activity minimizes phagocytosis by macrophages and neutrophils facilitating Yersinia evasion of components of the cellular immune response which disrupts clearance of the bacteria by the host (Deleuil et al., 2003; Hamid et al., 1999). In contrast, in epithelial cells, Yersinia uptake is associated with phosphorylation of BCAR1, thus the bacterium triggers BCAR1 phosphorylation to promote the uptake of the organism in non-phagocytic cells (Weidow et al., 2000). S. typhimurium is an obligate intracellular bacterial pathogen that requires eukaryotic cellular uptake for infection. These bacteria utilize host eukaryotic BCAR1 for efficient bacterial uptake and their infectious cycle (Shi et al., 2006). In addition to bacteria, many viruses also utilize the host protein machinery and BCAR1 for their viral propagation. For instance, internalization of adenovirus is initiated by virus binding to host integrin receptors and virus internalization requires BCAR1 phosphorylation (Li et al., 1998; Li et al., 2000).

Article Bibliography

Pubmed IDLast YearTitleAuthors

Other Information

Locus ID:

NCBI: 9564
MIM: 602941
HGNC: 971
Ensembl: ENSG00000050820

Variants:

dbSNP: 9564
ClinVar: 9564
TCGA: ENSG00000050820
COSMIC: BCAR1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000050820ENST00000162330P56945
ENSG00000050820ENST00000393420P56945
ENSG00000050820ENST00000393422P56945
ENSG00000050820ENST00000418647P56945
ENSG00000050820ENST00000420641P56945
ENSG00000050820ENST00000535626P56945
ENSG00000050820ENST00000538440P56945
ENSG00000050820ENST00000542031P56945
ENSG00000050820ENST00000546196F5H855
ENSG00000050820ENST00000561970H3BU42
ENSG00000050820ENST00000562556F5H855
ENSG00000050820ENST00000563323H3BTB0
ENSG00000050820ENST00000564028H3BQJ7
ENSG00000050820ENST00000566465H3BSY4
ENSG00000050820ENST00000567215H3BTL5
ENSG00000050820ENST00000568864H3BSB2
ENSG00000050820ENST00000569006H3BVF0
ENSG00000050820ENST00000569340H3BN62

Expression (GTEx)

0
10
20
30
40
50
60
70

Pathways

PathwaySourceExternal ID
Focal adhesionKEGGko04510
Leukocyte transendothelial migrationKEGGko04670
Regulation of actin cytoskeletonKEGGko04810
Focal adhesionKEGGhsa04510
Leukocyte transendothelial migrationKEGGhsa04670
Regulation of actin cytoskeletonKEGGhsa04810
Chemokine signaling pathwayKEGGko04062
Chemokine signaling pathwayKEGGhsa04062
Bacterial invasion of epithelial cellsKEGGko05100
Bacterial invasion of epithelial cellsKEGGhsa05100
Rap1 signaling pathwayKEGGhsa04015
Rap1 signaling pathwayKEGGko04015
HemostasisREACTOMER-HSA-109582
Platelet activation, signaling and aggregationREACTOMER-HSA-76002
Platelet Aggregation (Plug Formation)REACTOMER-HSA-76009
Integrin alphaIIb beta3 signalingREACTOMER-HSA-354192
p130Cas linkage to MAPK signaling for integrinsREACTOMER-HSA-372708
Signal TransductionREACTOMER-HSA-162582
Signaling by PDGFREACTOMER-HSA-186797
Downstream signal transductionREACTOMER-HSA-186763
Signaling by VEGFREACTOMER-HSA-194138
VEGFA-VEGFR2 PathwayREACTOMER-HSA-4420097
Signaling by PTK6REACTOMER-HSA-8848021
PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinasesREACTOMER-HSA-8849471

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA448871celecoxibChemicalPathwayassociated22336956

References

Pubmed IDYearTitleCitations
363751192023BTG1 inactivation drives lymphomagenesis and promotes lymphoma dissemination through activation of BCAR1.3
364002482023The interaction of CFLAR with p130Cas promotes cell migration.3
363751192023BTG1 inactivation drives lymphomagenesis and promotes lymphoma dissemination through activation of BCAR1.3
364002482023The interaction of CFLAR with p130Cas promotes cell migration.3
349229452022Docking Protein p130Cas Regulates Acinar to Ductal Metaplasia During Pancreatic Adenocarcinoma Development and Pancreatitis.3
350319022022Comprehensive immunohistochemical analysis of RET, BCAR1, and BCAR3 expression in patients with Luminal A and B breast cancer subtypes.1
349229452022Docking Protein p130Cas Regulates Acinar to Ductal Metaplasia During Pancreatic Adenocarcinoma Development and Pancreatitis.3
350319022022Comprehensive immunohistochemical analysis of RET, BCAR1, and BCAR3 expression in patients with Luminal A and B breast cancer subtypes.1
331446942021Mutant TP53 interacts with BCAR1 to contribute to cancer cell invasion.5
341698352021A Cas-BCAR3 co-regulatory circuit controls lamellipodia dynamics.4
341925482021Targeting p130Cas- and microtubule-dependent MYC regulation sensitizes pancreatic cancer to ERK MAPK inhibition.10
343266872021BCAR1 plays critical roles in the formation and immunoevasion of invasive circulating tumor cells in lung adenocarcinoma.6
348302442021p130Cas Is Correlated with EREG Expression and a Prognostic Factor Depending on Colorectal Cancer Stage and Localization Reducing FOLFIRI Efficacy.0
331446942021Mutant TP53 interacts with BCAR1 to contribute to cancer cell invasion.5
341698352021A Cas-BCAR3 co-regulatory circuit controls lamellipodia dynamics.4

Citation

Allison Berrier

BCAR1 (breast cancer anti-estrogen resistance 1)

Atlas Genet Cytogenet Oncol Haematol. 2011-12-01

Online version: http://atlasgeneticsoncology.org/gene/761/teaching-explorer/gene-explorer/case-report-explorer/