Figure 7

Cells’ defense mechanism is triggered in response to rising levels of oxidative stress (due to endogenous/exogenous factors) in which Nrf2 regulation has a key role. A probable mechanism is that enhanced ROS generation disturbs redox balance and sends signals to the Nrf2 co-ordinated defense system via pathways involving Akt (left panel). Activated Akt inactivates GSK3β by phosphorylating its Ser9 residue. This results in inactivation of Fyn kinase which relieves ubiquitination-mediated Nrf2 suppression and thereby reinforces cell defense mechanism. PHLPP2 is a phosphatase that exclusively dephosphorylates Akt at its Ser473 residue. An event of toxic/oxidative insult may trigger signaling pathways leading to PHLPP2 induction that selectively downmodulates Akt Ser473 phosphorylation (right panel). This lifts the repression imposed by Akt on GSK3β activity, which phosphorylates and hence activates Fyn kinase resulting in Nrf2 degradation. Weakened cellular defense response further aggravates the stress levels that may lead to bio-molecular degeneration and ultimately cell death