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BCAR1 SCAFFOLD PROTEIN, CAS FAMILY MEMBER; BCAR1

BCAR1 SCAFFOLD PROTEIN, CAS FAMILY MEMBER; BCAR1

Alternative titles; symbolsBREAST CANCER ANTIESTROGEN RESISTANCE 1CRK-ASSOCIATED SUBSTRATE; CRKASp130CASCASCAS SCAFFOLD PROTEIN FAMILY, MEMBER 1; CASS1HGNC Appro...

Alternative titles; symbols

  • BREAST CANCER ANTIESTROGEN RESISTANCE 1
  • CRK-ASSOCIATED SUBSTRATE; CRKAS
  • p130CAS
  • CAS
  • CAS SCAFFOLD PROTEIN FAMILY, MEMBER 1; CASS1

HGNC Approved Gene Symbol: BCAR1

Cytogenetic location: 16q23.1 Genomic coordinates (GRCh38): 16:75,228,180-75,268,006 (from NCBI)

▼ Description
BCAR1, or CAS, is an Src (190090) family kinase substrate involved in various cellular events, including migration, survival, transformation, and invasion (Sawada et al., 2006).

▼ Cloning and Expression
Rat Cas is an adaptor molecule with a unique structure that contains an Src homology-3 (SH3) domain followed by multiple YXXP motifs and a proline-rich region (Sakai et al., 1994). Cas was originally cloned as a highly tyrosine-phosphorylated protein in chicken embryo cells transformed by v-Src (Reynolds et al., 1989; Kanner et al., 1991).

In breast cancer, the antiestrogen tamoxifen has been prescribed for both primary treatment and treatment of advanced metastatic disease. Although the drug induces remission in most patients with estrogen receptor (see 133430)-positive disease, all patients eventually develop resistance. Dorssers et al. (1993) showed that an estrogen-dependent breast cancer cell line became antiestrogen resistant after random insertion of a replication-defective retrovirus genome. Insertion at a locus designated BCAR1 resulted in the drug-resistant phenotype. By exon trapping and screening a cosmid library, Brinkman et al. (2000) isolated a cDNA encoding BCAR1. The predicted 870-amino acid BCAR1 protein has a calculated mass of 93 kD. BCAR1 contains an SH3 domain in its N-terminal part, multiple potential tyrosine phosphorylation sites in its central part, and a proline-rich stretch in its C-terminal part. BCAR1 shares 91% amino acid identity with rat and mouse p130Cas. SDS-PAGE and Western blot analyses demonstrated that BCAR1 encodes a 116-kD protein; the mouse and rodent p130Cas proteins exhibit the same size. Northern blot analysis detected a 3.2-kb BCAR1 transcript in all tissues tested, with highest expression in testis and low expression in liver, thymus, and peripheral blood leukocytes.

▼ Gene Function
Brinkman et al. (2000) showed that the C-terminal proline-rich stretch of BCAR1 interacted with the SH3-binding site of the Src protein. Transgenic cell lines showing high expression of BCAR1 demonstrated proliferation in the presence of tamoxifen and impaired expression of TFF1 (113710).

By Western blot analysis of BCAR1 protein in cytosol extracts from 937 primary breast carcinomas, van der Flier et al. (2000) showed that high BCAR1 levels were associated with age and menopausal status as well as levels of estrogen and progesterone receptors. In univariate and multivariate survival analyses, high BCAR1 levels were associated with poor relapse-free survival and poor overall survival. The response to tamoxifen therapy in patients with recurrent disease was reduced if the primary tumor expressed high levels of BCAR1 protein.

Sawada et al. (2006) stated that tyrosine phosphorylation of CAS in a cytoskeletal complex is involved in force-dependent activation of the small GTPase RAP1 (179520). They showed that mechanical extension of recombinant CAS substrate domain in vitro led to enhanced phosphorylation by Src family kinases. An antibody that recognized the extended CAS substrate domain in vitro revealed CAS extension in the peripheral regions of intact spreading cells, where higher traction forces were expected and where phosphorylated CAS localized. Sawada et al. (2006) proposed that CAS acts as a primary force sensor, transducing force into mechanical extension and thereby priming downstream signaling.

▼ Gene Structure
Brinkman et al. (2000) determined that the BCAR1 gene contains 7 exons spanning 25 kb of genomic DNA. The 5-prime flanking region contains multiple CpG islands, characteristic of a housekeeping gene and ubiquitous expression.

▼ Mapping
By in situ hybridization and PCR analysis of hybrid cell lines, Brinkman et al. (2000) mapped the BCAR1 gene to chromosome 16q23.1.

▼ Animal Model
To determine the role of Cas in vivo, Honda et al. (1998) generated mice lacking Cas. Cas-deficient embryos died in utero and showed marked systemic congestion and growth retardation. Histologically, the heart was poorly developed and blood vessels were prominently dilated. Electron microscopic analysis of the heart revealed disorganization of myofibrils and disruption of Z discs. In addition, actin stress fiber formation was severely impaired in Cas-deficient primary fibroblasts. Moreover, expression of activated Src in Cas-deficient primary fibroblasts did not induce a fully transformed phenotype, possibly owing to insufficient accumulation of actin cytoskeleton in podosomes. These findings defined Cas function in cardiovascular development, actin filament assembly, and Src-induced transformation. The experiments demonstrated that Cas is essential for embryogenesis, particularly in cardiovascular development. Impaired heart development had been reported in mice lacking several proteins, such as transcriptional enhancer factor-1 (189967; Chen et al., 1994), gp130 (Yoshida et al., 1996), or Gata4 (600576; Kuo et al., 1997). Unlike the case of Cas-deficient mice, mice lacking these genes showed normal myofibril organization and intact Z discs. The finding that Cas-deficient embryos died at 11.5 to 12.5 dpc, a period beginning when the heart begins productive beating, suggested that the disruption of contractile structures results in cardiac pump failure and venous dilatation, which leads to low blood pressure, systemic hypoxia, and embryonic death.

Honda et al. (1998) found that fibroblasts established from Cas-deficient embryos were flat, thin, and round-shaped in comparison with wildtype cells. Transient reexpression of Cas in Cas-deficient cells displayed restoration of actin stress fiber formation, demonstrating that the impaired actin assembly was due to Cas-deficiency. Similar cytoskeletal changes were noted in focal adhesion kinase (FAK; 600758)-deficient cells, where focal adhesion formation was present but long actin fibers were absent. These coincident findings suggested that Cas and Fak may coordinately function at a critical step for actin filaments to assemble and grow from focal adhesions. Thus, Cas is an example of an adaptor molecule that maintains cytoskeletal organization and is pivotal in embryonic development and in oncogene-mediated transformation.

Brugge (1998) commented on the contribution of Honda et al. (1998) in the understanding of the specific role of an individual Src substrate in integrin-mediated cytoskeletal rearrangements and Src-mediated transformation. Oncogenic transformation by v-Src is associated with dramatic alterations in cell morphology, actin organization, and anchorage dependence. These changes correlate with tyrosine phosphorylation of multiple proteins that associate with cytoskeletal structures known as focal adhesions (FA)--membrane-associated sites where clustered integrin receptors couple extracellular matrix (ECM) proteins to intracellular cytoskeletal proteins and actin stress fibers.

Tags: 16q23.1