Cytosolic regulation of Endoplasmic Reticulum stress pathways by Akt during hypoxia and cell blebbing

MATÍAS BLAUSTEIN

Buenos Aires

Seminario; Seminario del Departamento de Química Biológica; 2012

Departamento de Química Biológica, FCEyN-UBA

In mammalian cells, Akt signaling regulates many processes including cell growth, proliferation, survival and metabolism. The unfolded protein response (UPR) is an intracellular signaling pathway that is activated by the accumulation of unfolded proteins in the endoplasmic reticulum (ER) and it has also been shown to maintain homeostasis by regulating cell survival and cell death. While the UPR directly activates the Akt pathway, it is unclear whether conversely Akt can modulate the UPR. We used a series of chemical compounds that modulate the PI3K/AKT pathway to study this interconnection. Akt-IV, a potent antiviral and antiproliferative molecule, strongly induced the activation of the three branches of the UPR. PERK/eIF2a was the first UPR branch to be activated and this activation was dependent on the presence and activity of Akt. . Akt-IV also induced a UPR-dependent cell death and caused a rapid relocalization of Akt into apoptotic cell blebs, where it co-localized with eIF2a, providing further insight into the mechanism of action of Akt-IV. These results suggest that Akt is a novel cytosolic regulator of the UPR pathway. Interestingly, we show that Akt is a novel PERK kinase and mediates PERK activation induced by hypoxia, which confirms a physiologically relevant interaction between these two proteins. The crosstalk between Akt and PERK pathways emerges as a master control mechanism of cell decision making in terms of survival of death.