Functions of the adapter protein Cas: signal convergence and the determination of cellular responses

The substrate domain of BCAR1 is essential for anti-estrogen-resistant proliferation of human breast cancer cells

“…Within this domain, 15 YXXP motifs, which represent substrates for phosphorylation by tyrosine kinases and which may subsequently recruit different SH2-domain containing proteins, are conserved between rodents and humans [12]. Proteins binding to these motifs in the substrate domain of BCAR1 have been identified for different types of biological functions, including migration and regulation of the actin cytoskeleton [20,36]. Despite extensive sequence differences within this substrate domain, 11 of these motifs have been retained in HEF1, although the spacing and sequence context may have changed (http:// www.ensembl.org/Homo_sapiens/Gene/Compara_Paralog/).…”

“…How BCAR1 achieved tamoxifen-resistant tumor cell proliferation was not clear from our previous work, but was anticipated to involve SRC-BCAR1 complexes [7,20,23,24]. SRC was shown to bind to the Src-binding site and to phosphorylate several YXXP motifs of BCAR1 [30][31][32][33].…”

“…BCAR1/p130Cas (hereafter referred to as BCAR1), exhibits a modular structure containing a Sarc homology 3 (SH3) domain, a Proline-rich region, a substrate region containing multiple YXXP phosporylation motifs, a Serine-rich domain, a Src Binding domain and a conserved Cterminus [19,20]. These domains are mostly conserved among the family members NEDD9 (HEF1/Cas-L), EFS (Sin) and HEPL [21].…”

“…These domains are mostly conserved among the family members NEDD9 (HEF1/Cas-L), EFS (Sin) and HEPL [21]. As a consequence of the multiple protein interaction sites, BCAR1 serves as a docking molecule and has been implicated in many cellular processes, including cell transformation, integrin signaling, estrogen signaling, cell death, cytoskeletal rearrangements, migration, proliferation, force sensing, and bacterial infection [7,12,19,20,[22][23][24][25]. The closely related family member NEDD9/HEF1/CAS-L (hereafter referred to as HEF1) is unable to substitute for BCAR1 in vivo, since p130Cas knock-out mice die in utero due to developmental cardiovascular defects and growth retardation [26].…”

Expression levels of the focal adhesion-associated proteins paxillin and p130CAS in canine and feline mammary tumors

“…The tyrosine kinases p125 FAK , RAFTK and Csk, a negative regulator of p60 src , are but a few proteins which interact with paxillin at focal adhesions [25]. p130 CAS is another focal adhesionassociated protein which has been suggested to play an important role in cell migration [2]. p130 CAS was first identified as a phosphotyrosine-containing protein in cells transformed by the oncogenes v-src and v-crk [12].…”