ROS/Heat Shock: MAPK Signalling (Ask1 -> MKK346 -> p38)

• mitogen activated protein kinases (MAPK) signalling families can involve detecting ROS/heat shock in cells by sequentially phosphorylating a series of kinases to modify things in the cell to adapt to a new set of conditions

  • stress/damage/cytokines/maybe GF directly activate this MAPK family

  
• reactive oxygen species (ROS) result from either

  • NADPH oxidase -> mitochondrial enzyme in ETC that catalyzes oxygen to super oxide free radical which is bad for the cell since they're highly reactive and will terminally alter the structure/function
  • there are detox enzymes but if defective then excess ROS
  • ETC in mitochondria during ATP production

  ROS can lead to

  • ROS directly activates a sensor to activate signalling cascade to prevent protein/DNA/lipid damage AND/OR
  • protein/DNA/lipid damage

  
• ROS are sensed by p38/MAPK

  • certain ROS can covalently attach to Ask1/MAP3K through hydroxylation which phosphorylates MKK346/MAP2K which phosphorylates p38/MAPK which phosphorylates other targets in cell to help growth arrest or induce apoptosis

  
• sensing of ROS by p38

  • no ROS -> thioredoxin (Trx1) forms a complex with Ask1 which blocks its residues for phosphorylation to keep OFF
  • ROS -> ROS oxidizes cysteine residues on Trx1 and changes conformation -> Trx1 dissociates from Ask1 -> Ask1 gets hydroxylated by ROS as a result and activated by phosphorylation by a kinase -> Ask1 ON!

  
• sensing of heat shock by p38

  • no heat shock -> GSTM1 forms a complex with Ask1 which blocks its residues for phosphorylation to keep OFF
  • heat shock -> GSTM1 denatures due to intrinsic melting point and dissociates from Ask1 -> Ask1 gets allosterically phosphorylated and turned ON to turn on MAPK pathway (Ask1 -> MKK346 -> p38)