Linking Phosphoinositides to Proteins: A Novel Signaling PIPeline

Phosphoinositide (PIP_n) signaling plays pivotal roles in myriad biological processes and is altered in many diseases including cancer. Canonical PIP_n signaling involves membrane-associated PIP_n lipid second messengers that modulate protein recruitment and activity at membrane focal points. In the nucleus, PIP_n signaling operates separately from membranous compartments defining the paradigm of non-canonical PIP_n signaling. However, the mechanisms by which this non-membranous nuclear PIP_n pool is established and mediates stress signaling is poorly understood. The recent discovery of a p53-signalosome by Chen et al. (Nature Cell Biology 2022) represents a new PIP_n signaling axis that operates independently from membrane structures where PIP_ns are dynamically linked to nuclear p53 and modified by PIP_n kinases and phosphatases, allowing the activation of a nuclear PI 3-kinase/Akt pathway that is entirely distinct from the canonical membrane-localized pathway. Here, we will discuss emerging insights about the non-canonical PIP_n pathway, which links PIP_ns to a growing number of cellular targets and highlight the similarities/differences with its canonical counterpart. We will also discuss potential therapeutic targets in this non-canonical PIP_n pathway, which is likely to be deregulated in many diseases.