Research Paper Volume 1, Issue 2 pp 254—265

Figure 4. Working model for the p66Shc-centered regulatory network. Under conditions of lower stress, Trx keeps p66Shc reduced and dimeric. This p66Shc form interacts with dimeric Prx1, which also helps to keep p66Shc in its dimeric, apoptosis-inactive state and additionally degrades p66Shc-generated ROS. p66Shc in turn keeps Prx1 in its dimeric, peroxidase-active state. Excessive cellular stress, however, leads to disassembly of the p66Shc/Prx1 complex, formation of the decameric chaperone form of Prx1, and phosphorylation of p66Shc. The increased ROS-generating activity of phosphorylated p66Shc is compensated by complex formation with Pin1, which also leads to p66Shc translocation to the mitochondrial IMS. Here, tetrameric p66Shc is formed which finally induces apoptosis by initiating mitochondrial rupture through a still not fully understood mechanism, possibly involving its ROS-forming activity.