Nucleophosmin/B23, a nuclear PI(3,4,5)P₃ receptor, mediates the antiapoptotic actions of NGF by inhibiting CAD

Phosphatidylinositol 3,4,5-triphosphate [PI(3,4,5)P₃] is an essential second messenger implicated in various cellular processes. Cytoplasmic PI(3,4,5)P₃ has been well characterized, but little is known about the physiological role of nuclear PI(3,4,5)P₃. Here, we describe a nuclear PI(3,4,5)P₃ receptor, nucleophosmin (NPM)/B23, that mediates the antiapoptotic effects of NGF by inhibiting DNA fragmentation activity of caspase-activated DNase (CAD). Employing PI(3,4,5)P₃ column and NGF-treated PC12 nuclear extracts, we identified B23 as a nuclear PI(3,4,5)P₃ binding protein. Purification from nuclear extract demonstrates that B23 contributes to DNA fragmentation inhibitory activity. Depletion of B23 from nuclear extracts or knockdown B23 in PC12 cells abolishes NGF-provoked protective effect, whereas overexpression of B23 in PC12 cells prevents apoptosis. Further, hydrolyzing PI(3,4,5)P₃ with PTEN or SHIP abrogates its antiapoptotic activity. Moreover, B23 mutants that can not associate with PI(3,4,5)P₃ fail to prevent DNA fragmentation. Thus, the nuclear B23-PI(3,4,5)P₃ complex regulates the antiapoptotic activity of NGF in the nucleus.