Molecular Mechanism of BCAR3-p130Cas in Breast Cancer

Anti-estrogen drugs such as tamoxifen have become widely used to treat patients with estrogen-receptor positive tumors. Although effective in many cases, significant proportions of estrogen-receptor positive tumors are intrinsically unresponsive to anti-estrogens or have acquired resistance over time. Two proteins that have emerged as key players in this resistance are aptly named Breast Cancer Antiestrogen Resistance 3 (BCAR3) and BCAR1 (also known as p130Cas). Not only can BCAR3 and p130Cas confer anti-estrogen resistance individually, but the two have subsequently been found to directly interact with each other. We have solved the crystal structures of the p130Cas interaction domain of BCAR3, and the complex of the close BCAR3 homolog, NSP3, bound to the C-terminal domain of p130Cas. Unbound breast cancer antiestrogen resistance 3 (BCAR3/NSP2) adopts the Cdc25-homology fold characteristic of Ras GTPase exchange factors, but in a unique closed conformation incapable of enzymatic activity. The structure of the BCAR3 relative, NSP3, in complex with p130Cas further reveals that the closed conformation is instrumental for interaction with a focal adhesion-targeting (FAT)- like region in Cas proteins. This novel enzyme-to-adaptor conversion enables high affinity interactions between BCAR3 (or NSP3) and Cas family proteins to link their signaling networks.
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