Abstract 4687: Novel functions of the AMPK pathway to maintain spindle orientation during mitosis

Abstract

Abstract AMP activated protein kinase (AMPK) functions as an energy sensor that regulates cell signaling. It is phosphorylated by the tumor suppressor, LKB1 at times of energy stress in both the cell polarity and motility pathways. Here we show that phosphorylated AMPKα (Thr-172) localizes to the spindle poles at gamma tubulin sites during mitosis in an LKB1-independent manner and serves as an essential regulator of mitotic spindle orientation. Phosphorylated AMPK levels peak during mitosis and siRNA-based disruption AMPK-α1& α2 function, results in spindles that are mis-oriented relative to the normal spindle axis. This phenotype is accompanied by an aberrant, double-ring actin cage that encompasses the microtubule spindle, as well as reduced astral microtubules. Similar results were obtained by live cell imaging using compound C (AMPK pharmacological inhibitor) treated cells. Molecular studies show that AMPK regulates spindle orientation through a PI3k-AKT pathway at the spindle poles that signals to myosin regulatory light chain (MRLC). We postulate that AMPK is regulating astral microtubule docking onto actin through this pathway and when compromised spindles become misaligned. Taken together, this study reveals a novel PI3K-AKT-p-AMPK-MRLC mitotic signaling axis that regulates spindle orientation during mitosis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4687. doi:10.1158/1538-7445.AM2011-4687