Deciphering PI4K2A: a key modulator in cellular signaling, autophagy, and disease pathogenesis

Phosphatidylinositol 4-kinase type 2 alpha (PI4K2A) is a key enzyme in phosphoinositide signaling and a central coordinator of membrane trafficking, autophagy and cellular signaling. Increasing evidence supports a role for PI4K2A in normal physiology and its dysregulation in pathological conditions, particularly neurological disorders and cancer. This review synthesizes the literature around the biological themes that define PI4K2A biology: its structure and membrane anchoring, its functions in membrane trafficking, autophagy and signaling, and its contributions to disease. We consolidate mechanistic evidence established in cell-based studies and then refer back to it when discussing disease associations, so that the mechanistic basis of each disease link is explicit. We also highlight the disagreements that remain unresolved—most importantly the apparently opposing pro-tumorigenic and anti-tumorigenic activities of PI4K2A, and the conflicting data on insulin secretion—and we set out the specific questions that define the current state of the field. Finally, we address potential therapeutic strategies targeting PI4K2A, aiming to offer novel insights into disease intervention. We propose that the value of PI4K2A as a therapeutic target depends on identifying the cellular contexts in which its inhibition is beneficial, which is now the central problem for the field.