Fig. 2. Sustained JNK activation loop.

MAP3K such as TAK1, ASK1 and MLK2/3 can be initially activated by cytokine receptors, saturated fatty acids, ER stress and mitochondrial ROS release. MAP3K the activate MAP2K kinases, such as MKK4/7, which activate JNK1/2. P-JNK then phosphorylates Sab on the outer mitochondrial membrane which leads to the release and activation of Shp1, a phosphatase which then inactivates phospho-Src on the inner membrane platform, DOK-4. Inactivation of Src then impairs electron transport and leads to increased mitochondrial O₂⁻ production and H₂O₂ is released from mitochondria. ROS mediates activation of MAP3K (ASK1 and MLK/2/3) which continue to activate JNK. This activation leads to sustained JNK activation which promotes metabolic dysregulation and cell death through the various targets in Fig. 1.