Abstract
Abstract BAG3, a BAG co-chaperone family member, co-localizes with actin microfilaments and influences processes that involve actin function, including adhesion and migration. Because actin function regulates cell division, we hypothesized that the BAG3 WW-domain regulates cellular division through its cytoskeletal association. We show that BAG3 co-localizes with leading lamellipodia exclusively during G2 and mitosis phases. Co-immunoprecipitation of BAG3 and pulldown of GST-tagged BAG3 WW-domain confirmed that BAG3 WW-domain association with actin increased during G2 and mitosis relative to asynchronous cells. Deletion of the BAG3 WW-domain caused an abnormal cellular morphology, degenerate F-actin organization, longer doubling time (p<0.05, n=4), and three-fold increase in polynucleated cells relative to empty vector and full length-BAG3 (FL-BAG3; p<0.001, n=3). We confirmed polyploidy development and absence of cytokinesis in αWW-BAG3 cells by live-cell imaging, and observed mitotic delay relative to control and FL-BAG3 cells. To identify a potential regulation mechanism for BAG3-actin binding, we identified WBP2 as a novel BAG3 WW domain interacting protein in a yeast two-hybrid assay. BAG3 and WBP2 co-immunoprecipitated only in G1 and S phases, indicating cell cycle-specific BAG3-WBP2 binding. WBP2 silencing caused indiscriminate BAG3 co-immunoprecipitation with actin across all cell cycle phases, suggesting that association with WBP2 prevents BAG3-actin binding. We are the first to identify a function for WBP2, which our data show regulates BAG3 WW-domain association with actin in a cell cycle-specific manner. Because actin dysfunction has been proposed to contribute to chromosomal instability and tumor formation, the WW-domain of BAG3 is a potential target to reduce abnormal cell division. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2032. doi:1538-7445.AM2012-2032
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