Uncovering the nuclear PIPn-p53 signalosome in cancer cell migration

In this review, the authors present recent findings that uncover a previously unappreciated nuclear signaling hub: the PIPn-p53 signalosome. This complex not only modulates AKT activation within the nucleus but also integrates two major oncogenic pathways-p53 dysregulation and PI3K-AKT amplification-into a unified mechanism driving cancer cell migration and invasion.

Key points of the review include:

1. Nuclear PIPn signaling expands beyond classical models: Phosphoinositides, long thought to be confined to plasma and endomembranes for cytoplasmic signaling, are now shown to form active signaling complexes in the nucleus, reshaping our understanding of lipid-mediated regulation.
2. Wild-type and mutant p53 serve as nuclear scaffolds: Both forms of p53 anchor nuclear PIPns and facilitate the assembly of lipid-protein complexes (signalosomes), directly influencing gene expression, chromatin remodeling, and cytoskeletal dynamics.
3. De novo AKT activation in the nucleus: Unlike canonical membrane-bound activation, nuclear AKT is activated by PtdIns(3,4,5)P₃ generated by the PIPn-p53 complex. This activation promotes cancer cell survival and migration-particularly under stress.
4. Therapeutic implications: Disruption of the nuclear PIPn-p53 signalosome, especially in mutant p53-driven cancers, could impair metastasis. Targeting nuclear-specific PIPn enzymes or restoring p53 function may synergize with PI3K/AKT inhibitors to suppress cancer dissemination.

This review highlights the nuclear PIPn-p53 signalosome as a central regulator of cancer cell motility and a promising target for metastasis therapy. The work entitled "The Nuclear Phosphoinositide-p53 Signalosome in the Regulation of Cell Motility" was published in Protein & Cell (Advance access May 26, 2025).