Uncovering New Signaling Pathways in Cancer

A Marriage Between p53 and PI 3-Kinase Signaling Reveals a Third Messenger Signaling pathway in Cancer

Webinar with Dr. Richard Anderson | December 10, 2025

Phosphoinositide lipids (PIPs) are second messengers that modulate most biological processes and have fundamental roles in multiple human diseases. These PIPs are phosphorylated on the inositol head group generating seven distinct PIP second messengers that are spatially organized to regulate membrane trafficking, cell migration and invasion, cell stress pathways, cell proliferation and cell death.  In the canonical PIP pathways, the PIPs are organized as lipids immersed in membrane compartments with the PIP myo-inositol head at the cytoplasmic interface.

Remarkably the PIPs also become covalently linked at a repertoire of regulatory proteins in cells. These PIP linked proteins are both nuclear and cytoplasmic. The founding member is p53. Now we know that p53 becomes initially linked to a PI likely through the glycerol backbone.  The p53-PI is then acted on by PIP kinases and phosphatases ultimately generating a p53-phosphoinositol-3,4,5-trisphosphate (p53-PIP3) signalosome that activates a nuclear Akt pathway that appears key for p53’s roles in cancer. We have named this PIP linked pathway a third messenger pathway.  This new pathway involves many regulatory proteins that will require novel approaches to detect the PIP linkage on proteins, and their clear diagnostic and therapeutic possibilities were discussed.       

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