Mutations in the gene encoding Shc (p66Shc), which is induced by oxidative stress, are known to lengthen lifespan in rodents (i.e., the wildtype gene shortens lifespan, making it a gerontogene). p66Shc is known to play a role in the mitochondrial branch of the apoptotic pathway, but the mechanism by which it acts to convert oxidative stress into cell death remains to be elucidated.
A step in that direction is provided by Pinton et al., who demonstrate that protein kinase C ß (PKC ß) plays an important role in activating Shc’s apoptotic functions. Note the bold sentence at the end of the abstract (emphasis mine):
The 66-kilodalton isoform of the growth factor adapter Shc (p66Shc) translates oxidative damage into cell death by acting as reactive oxygen species (ROS) producer within mitochondria. However, the signaling link between cellular stress and mitochondrial proapoptotic activity of p66Shc was not known. We demonstrate that protein kinase C ß, activated by oxidative conditions in the cell, induces phosphorylation of p66Shc and triggers mitochondrial accumulation of the protein after it is recognized by the prolyl isomerase Pin1. Once imported, p66Shcc causes alterations of mitochondrial Ca2+ responses and three-dimensional structure, thus inducing apoptosis. These data identify a signaling route that activates an apoptotic inducer shortening the life span and could be a potential target of pharmacological approaches to inhibit aging.
Knowing about a kinase acting upstream of p66Shc is exciting largely because rational design of kinase inhibitors is becoming something of a cottage industry: Structurally speaking, kinases are by far the most well-characterized protein superfamily, and their active sites have enough similarities that established strategies can be used to design small-molecule inhibitors, yet enough differences that these molecules have a good chance of being specific to a kinase of interest. The crystal structure of PKC was solved more than ten years ago, and there already exist a number of family-specific inhibitors that might be useful starting points for drug design.