Disease relevance of Bcar1

• Cas was originally cloned as a highly tyrosine-phosphorylated protein in cells transformed by v-Src (refs 2,3) or v-Crk (ref. 4) and has subsequently been implicated in a variety of biological processes including cell adhesion, cell migration, growth factor stimulation, cytokine receptor engagement and bacterial infection [1].
• Crk-associated substrate tyrosine phosphorylation sites are critical for invasion and metastasis of SRC-transformed cells [2].

High impact information on Bcar1

• 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 [1].
• In addition, actin stress fiber formation was severely impaired in Cas-deficient primary fibroblasts [1].
• p130Cas (Cas), the protein encoded by the Crkas gene (also known as Cas), is an adaptor molecule with a unique structure that contains a Src homology (SH)-3 domain followed by multiple YXXP motifs and a proline-rich region [1].
• Tyrosine phosphorylation of Cas, paxillin, and tensin were markedly decreased in VSMCs expressing KI-Src and in src-/- VSMCs [3].
• Thus, these results have revealed the Rho-dependent Rac activation signaling that is mediated by mDia1 through Cas phosphorylation and antagonized by the action of ROCK [4].

Biological context of Bcar1

• The screen identified two proteins that interact with FAK via their Src homology 3 (SH3) domains: a v-Crk-associated tyrosine kinase substrate (Cas), p130Cas, and a still uncharacterized protein, FIPSH3-2, which contains an SH3 domain closely related to that of p130Cas [5].
• These findings demonstrate that Cas acts as a key scaffold that links the proteins associated with tyrosine phosphorylation signaling pathways to the granule cell axon elongation [6].
• Crk-associated substrate (Cas) is a tyrosine-phosphorylated docking protein that is indispensable for the regulation of the actin cytoskeletal organization and cell migration in fibroblasts [6].
• Cas coimmunoprecipitates with Src family protein tyrosine kinases, Crk, and cell adhesion molecules and colocalizes with these proteins in granule cells [6].
• The axon extension of granule cells is inhibited by either RNA interference knockdown of Cas or overexpression of the Cas mutant lacking the YDxP motifs, which are tyrosine phosphorylated and thereby interact with Crk [6].

Anatomical context of Bcar1

• The present study examines the interaction between PYK2 and p130(Cas) (Crk-associated substrate), suggested to be part of the signaling pathway initiated by osteoclast adhesion [7].
• During cerebellar development, Cas is highly tyrosine phosphorylated and is concentrated in the neurites and growth cones of granule cells [6].
• In this study, we have attempted to identify kinases that mediate Cas phosphorylation in integrin signaling by examining various mutant cell lines that do not express either p125FAK, c-Scr, c-Fyn or c-Abl [8].
• These findings have defined Cas function in cardiovascular development, actin filament assembly and Src-induced transformation [1].
• Requirements for localization of p130cas to focal adhesions [9].

Associations of Bcar1 with chemical compounds

• CAS ('Crk-associated substrate') is an Src substrate found at sites of integrin-mediated cell adhesion and linked to cell motility and survival [10].
• To evaluate the requirement for CAS YXXP sites in stimulating cell migration, a series of phenylalanine substitution variants were expressed in CAS -/- mouse embryo fibroblasts [11].
• Furthermore, PP2A dephosphorylates serine residues on Cas in vitro [12].
• Serine/threonine phosphorylation of Cas has previously been shown to occur in a cell cycle regulated matter [12].
• The Cas/HEF1 association domain also shows sequence similarity with guanine nucleotide exchange factors for Ras family small GTPases [13].

Enzymatic interactions of Bcar1

• Src phosphorylates Cas on tyrosine 253 to promote migration of transformed cells [14].

Regulatory relationships of Bcar1

• In this study, we found that the Src homology (SH) 3 domain of Cas blocked v-Src-stimulated anchorage-independent cell growth, Matrigel invasion, and tumor growth in nude mice [15].
• However, it abolishes the association of TRIP6 with Crk and p130cas in cells and significantly reduces the function of TRIP6 to promote LPA-induced ERK activation [16].

Other interactions of Bcar1

• Fluoroaluminate stimulates phosphorylation of p130 Cas and Fak and increases attachment and spreading of preosteoblastic MC3T3-E1 cells [17].
• Interestingly, tyrosine phosphorylation of paxillin, but not p130cas, was induced by expression of Src-FAT, suggesting a potential role of paxillin in mediating stimulation of cell migration by the chimeric molecule [18].
• Through its specific association to p130cas and further dephosphorylation, PTP-PEST plays a critical role in cell-matrix interactions, which are essential during embryogenesis [19].
• Phosphorylation of immunoprecipitated p130 Cas increased upon stimulation with fluoroaluminate and with agonists of G-protein-coupled receptors, but not with growth factors [17].
• Analysis of tyrosine-phosphorylated proteins demonstrated that Crk-associated substrate (p130(Cas)), not the activated PDGFbetaR itself, is the major Nck SH2 domain-binding protein in PDGF-B-stimulated cells [20].
• Src utilizes Cas to inhibit gap junctional communication mediated by Cx43 [21].

Analytical, diagnostic and therapeutic context of Bcar1

• Using an immunofluorescence study, we examined the subcellular localization of Cas and determined the regions required for its localization to focal adhesions [9].
• Using site-directed mutagenesis combined with tryptic phosphopeptide mapping, we determined that the ten tyrosines in YXXP motifs 6-15 are the major sites of CAS SD phosphorylation by Src [11].
• Using specific antibodies, p130 was identified as Cas. By immunocytochemistry, Cas was localized to the peripheral regions of OCLs and its distribution overlapped that of F-actin [22].

References