PLEKHA2 is a pleckstrin homology domain-containing adapter protein that functions as a phosphoinositide-binding effector in cellular signaling. Primary function: PLEKHA2 binds specifically to phosphatidylinositol 3,4-bisphosphate [PtdIns(3,4)P2] 1 and recruits other proteins to the plasma membrane through its PH domain 2, participating in phosphoinositide-driven signaling cascades. Mechanism: As a member of the PH domain-containing protein family, PLEKHA2 is recruited to the plasma membrane in response to phosphatidylinositol 3-kinase (PI3K) signaling 3, where it accumulates in membrane regions involved in cell-matrix adhesion and cytoskeletal reorganization 1. Disease relevance: PLEKHA2 expression is dysregulated in multiple pathological conditions, including hepatitis B virus infection where mRNA levels are significantly decreased 4, postmenopausal osteoporosis where it shows differential DNA methylation patterns 5, and T-cell prolymphocytic leukemia where it is located within breakpoint regions 6. Additionally, lithium treatment—used therapeutically in bipolar disorder—influences PLEKHA2 expression in peripheral cells 7. Clinical significance: Dysregulation of PLEKHA2 and related phosphoinositide signaling may contribute to disease pathogenesis, suggesting potential therapeutic targeting through the PI3K-phosphoinositide pathway.