Based on mouse model studies, the JUN transcription factor undergoes biphasic activation in Alzheimer's disease. JUN is phosphorylated directly by p25-bound CDK5 at serine residues S63 and S73. CDK5:p25-mediated increase in the level of reactive oxygen species (ROS) triggers activation of JNK kinases (MAPK8, MAPK9, MAPK10), which phosphorylate JUN at S63 and S73 at a later time point (Sun et al. 2009).
Aberrant activation of CDK5 by p25 binding also triggers activation of MKK6 (MAP2K6), a p38 MAP kinase. Levels of phosphorylated MAP2K6 are increased in Alzheimer's disease. Activation of p38 MAP kinase(s) results in increased JUN expression (Chang et al. 2010).