Signaling AKTivation and UPRegulation dynamics control opposing cell fate choices

MATÍAS BLAUSTEIN; DANIELA PÉREZ-MUNIZAGA; MANUEL ALEJANDRO SÁNCHEZ; CAROLINA URRUTIA; ALICIA GRANDE; GUILLERMO RISSO; ANABELLA SREBROW; SEBASTIAN BERNALES; JENNIFER ALFARO; ALEJANDRO COLMAN LERNER

Toronto

Congreso; International Conference on Systems Biology; 2012

International Society of Systems Biology

To understand the mechanisms that underlie cell fate decisions in cancer progression, it is important to investigate the architecture, the function and the spatiotemporal dynamics of integrated signaling systems. Feedback loops embedded in these systems have been shown to generate many of the system?s level behaviors that explain overall function and accordingly the interest in their study in relation to cancer has recently increased. Of particular interest for this topic are the PI3K/Akt/mTOR and the Unfolded Protein Response (UPR) pathways, which are often deregulated in tumors and activated in response to hypoxia, a situation to which solid tumor cells are exposed. Akt is typically activated by a large variety of growth factors, while the UPR is typically activated by unfolded proteins inside the endoplasmic reticulum (ER) lumen. Even though both pathways maintain homeostasis by regulating cell survival and cell death, for a long time they have been studied independently from each other. Here, we show that a chemical inhibitor reported to modulate Akt activity and to exhibit antiproliferative properties, strongly and persistently activated the three branches of the UPR. PERK/eIF2α activation occurred within minutes while IRE1 and ATF6 required at least two hours. Phosphorylation of eIF2α was Akt- and PERK-dependent but PI3K independent. Interestingly, we show that Akt phosphorylates PERK in vitro, suggesting that Akt is a novel PERK kinase. Consistent with this notion, phospho-Akt proteins co-localized with PERK by immunofluorescence. Finally, we show that during a physiologically relevant condition activation of eIF2α requires Akt. The crosstalk between Akt and PERK/eiF2α pathways emerges as a master control mechanism of cell decision-making in terms of survival of death.