Following activation at the plasma membrane, Akt is subsequently deactivated in the cytoplasm. Although activation and deactivation of Akt must sometimes be separated in order to elicit and control cellular responses, the exact details of the spatiotemporal organization of Akt signaling are incompletely understood. Here we show that microtubule dynamics specifically modulate the deactivation phase of Akt signaling. Localization of Akt to microtubules sustains its activity, while disruption of microtubules attenuates Akt signaling independent of its initial activation. Conversely, stabilization of microtubules elevates Akt signaling both in vitro and in muscle tissues in vivo. Localization of Akt to microtubules is mediated by the microtubule binding protein dynactin p150, which is shown to be a direct target of Akt. Finally, microtubule disruption-induced Akt deactivation contributes to delayed cell cycle progression and accelerated cell death. Taken together, we revealed that, after initiation, the overall intensity and duration of oncogenic Akt signaling are determined by microtubule dynamics, a mechanism that could be exploited for therapeutic purposes.
Keywords: Akt; Cell death; Microtubules; Protein phosphorylation; Signal transduction.
Copyright © 2014 Elsevier Inc. All rights reserved.