BCAR1 (breast cancer anti-estrogen resistance 1)

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BCAR1 (breast cancer anti-estrogen resistance 1)

Written	2011-12	Allison Berrier
		Department of Oral, Craniofacial Biology, LSUHSC-NO School of Dentistry, 1100 Florida Avenue, Clinical Bldg, Room 8301, New Orleans, LA 70119, USA

(Note : for Links provided by Atlas : click)

Identity

Alias (NCBI)	CAS
	CAS1
	CASS1
	CRKAS
	FLJ12176
	FLJ45059
	P130Cas
HGNC (Hugo)	BCAR1
HGNC Alias symb	P130Cas
	Crkas
	CAS
	CASS1
HGNC Alias name	Crk-associated substrate
	Cas scaffolding protein family member 1
HGNC Previous name	breast cancer anti-estrogen resistance 1
	BCAR1, Cas family scaffolding protein
	BCAR1, Cas family scaffold protein
LocusID (NCBI)	9564
Atlas_Id	761
Location	16q23.1 [Link to chromosome band 16q23]
Location_base_pair	Starts at 75228181 and ends at 75251624 bp from pter ( according to GRCh38/hg38-Dec_2013) [Mapping BCAR1.png]

Fusion genes
(updated 2017)

Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)

	BCAR1 (16q23.1)::BCAR1 (16q23.1)	LDHB (12p12.1)::BCAR1 (16q23.1)	RBM6 (3p21.31)::BCAR1 (16q23.1)

DNA/RNA



	Figure 1.

Protein

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).



	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. Barrett's 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).


	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.

Note

Entity	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	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	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	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	Nasal polyps
Oncogenesis	Nasal polyps can express high levels of BCAR1 (Zhang et al., 2003).


Entity	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	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	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	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).


Entity	Anaplastic large-cell lymphomas
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	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	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).

	Nomenclature
HGNC (Hugo)	BCAR1 971
	Cards
Atlas	BCAR1ID761ch16q23
Atlas Explorer : (Salamanque)	BCAR1
Entrez_Gene (NCBI)	BCAR1 BCAR1 scaffold protein, Cas family member
Aliases	CAS; CAS1; CASS1; CRKAS;
	P130Cas
GeneCards (Weizmann)	BCAR1
Ensembl hg19 (Hinxton)	ENSG00000050820 [Gene_View]
Ensembl hg38 (Hinxton)	ENSG00000050820 [Gene_View] ENSG00000050820 [Sequence] chr16:75228181-75251624 [Contig_View] BCAR1 [Vega]
ICGC DataPortal	ENSG00000050820
TCGA cBioPortal	BCAR1
AceView (NCBI)	BCAR1
Genatlas (Paris)	BCAR1
SOURCE (Princeton)	BCAR1
Genetics Home Reference (NIH)	BCAR1
	Genomic and cartography
GoldenPath hg38 (UCSC)	BCAR1 - chr16:75228181-75251624 - 16q23.1 [Description] (hg38-Dec_2013)
GoldenPath hg19 (UCSC)	BCAR1 - 16q23.1 [Description] (hg19-Feb_2009)
GoldenPath	BCAR1 - 16q23.1 [CytoView hg19] BCAR1 - 16q23.1 [CytoView hg38]
ImmunoBase	ENSG00000050820
Genome Data Viewer NCBI	BCAR1 [Mapview hg19]
OMIM	602941
	Gene and transcription
Genbank (Entrez)	AB040024 AF218451 AJ242987 AK026121 AK027608
RefSeq transcript (Entrez)	NM_001170714 NM_001170715 NM_001170716 NM_001170717 NM_001170718 NM_001170719 NM_001170720 NM_001170721 NM_014567
Consensus coding sequences : CCDS (NCBI)	BCAR1
Gene Expression	BCAR1 [ NCBI-GEO ] BCAR1 [ EBI - ARRAY_EXPRESS ] BCAR1 [ SEEK ] BCAR1 [ MEM ]
Gene Expression Viewer (FireBrowse)	BCAR1 [ Firebrowse - Broad ]
Genevisible	Expression of BCAR1 in : [tissues] [cell-lines] [cancer] [perturbations]
BioGPS (Tissue expression)	9564
GTEX Portal (Tissue expression)	BCAR1
Human Protein Atlas	ENSG00000050820-BCAR1 [pathology] [cell] [tissue]
	Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Conserved Domain (NCBI)	BCAR1
Human Protein Atlas [tissue]	ENSG00000050820-BCAR1 [tissue]
HPRD	04248
	Protein Interaction databases
BioGRID	BCAR1
STRING (EMBL)	BCAR1
ZODIAC	BCAR1
	Ontologies - Pathways
	Litterature
PubMed	265 Pubmed reference(s) in Entrez
GeneRIFs	Gene References Into Functions (Entrez)
EVEX	BCAR1

REVIEW articles	automatic search in PubMed
Last year publications	automatic search in PubMed