Navigating AKT-ivity across cellular compartments.

Phosphoinositide (PIP)-mediated AKT signaling is essential for cellular homeostasis because it orchestrates crucial processes such as metabolism, survival, proliferation, and motility. Dysregulation of this pathway drives various pathologies, particularly cancer. Although cytosolic activation of AKT has been extensively studied, its emerging roles in the nucleus have gained attention over the past decade. The complexities of AKT compartmentalization and associated functional mechanisms remain largely unexplored. At the plasma membrane, AKT activation occurs at specialized microdomains and cell-cell junctions where it influences polarity, adhesion, and migration. In endosomes, PIPs coordinate intracellular trafficking and cytoskeletal organization with AKT signaling. Protein scaffolds refine AKT signal specificity by assembling complexes. In the nucleus, AKT interacts with the p53-PIP signalosome and specific kinases to regulate oncogenesis and chemoresistance. This review explores PIP-driven spatial regulation of AKT across cellular compartments, emphasizing its role in cellular responses and oncogenesis. Understanding AKT compartmentalization mechanisms provides valuable insights into cancer biology and novel therapeutic strategies.