Modulation of the Akt Pathway Reveals a Novel Link with PERK/eIF2α, which Is Relevant during Hypoxia
Figure 6
A physiological link between Akt and PERK/eIF2α.
(A) WT or Akt DKO MEF cells were subjected to normoxia (C) or hypoxia (0.1%±0.1 O2) (H) for the indicated times. Protein extracts were analyzed by WB using the indicated antibodies. The fold change in peIF2α/eIF2α ratio induced by hypoxia was quantified for two independent experiments. On average, this fold change was reduced to 0, 40 or 60% of the original effect in MEF Akt DKO cells compared to WT cells (1 h, 2 h and 4 h, respectively). (B) A model summarizing our results. Akt-IV (or other stimuli, such as hypoxia) targets an unknown kinase, possibly PDK1, triggering apoptotic cell blebbing and activating Akt in a PI3K-independent manner (1). Subsequently, UPR is activated (2). Akt presence and activity are necessary for eIF2α phosphorylation due to the existence of a connection between Akt and PERK/eIF2α signaling pathways. IRE1 (4) and ATF6 (5) are activated are later times. At the end, activation of IRE1 and PERK and dephosphorylation of Akt and GSK3β are associated with cell death (6).