Apoptosis and survival NGF signaling pathway
NGF signaling NGF (nerve growth factor) activates a variety of cascades in neuron cells. Oneof them, PI3K (phosphoinositide-3-kinase)/ AKT (serine/threonine-proteinkinases) pathway, is particularly important for mediating neuronal survival under a widevariety of circumstances . NGF binds to the tyrosine kinasereceptor TrkA, which induces the recruitment of the complex of adapter moleculesShc/Grb2 , . This complex activates PI3Kregulatory subunits via another Grb2 -associated protein Gab1  or via SOS (guanine nucleotide exchange factor)/ H-RAS (p21protein). In both cases, this event activates PI3K catalytic subunit. ThusPI3K is recruited to the vicinity of the plasma membrane, where thecatalytic subunits of PI3K generate the phosphoinositide3,4,5-trisphosphate ( PtdIns(3,4,5)P3 ), which, in turn, leads to the membranetranslocation of AKT and activation of its signaling cascades. AKT inhibitsapoptosis by impinging on the cytoplasmic and nuclear machinery through phosphorylation.For instance, AKT phosphorylates the proapoptotic Bcl-2 family member BAD,and apoptosis-related cysteine protease Caspase-9, thereby inhibiting theirproapoptotic functions . PI3K and AKT are predominantly located in the cytoplasm, but they alsooccur in the nucleus, or translocate to the nucleus upon stimulation ,. Antiapoptotic actions of NGF was also shown to be mediated through nuclearPtdIns(3,4,5)P3 and nuclear AKT by PI3K enhancer PIKE . Nucleophosmin (nucleolar phosphoprotein B23) also mediates theantiapoptotic effects of NGF by inhibiting DNA fragmentation activity ofcaspase-activated DNase ( DFF40 ) . NGF stimulation of TrkA induces activation of phospholipase CPLC-gamma 1, which acts as a guanine nucleotide exchange factor for PIKE. PIKE is the brain-specific nuclear GTPase that interacts withnuclear PI3K to stimulate its lipid kinase activity. Activation of nuclearPI3K by PIKE is inhibited by the NGF-stimulated 4.1N (band 4.1-likeprotein 1) translocation to the nucleus and its interaction with PIKE . Thus, PIKE physiologically modulates activation of nuclear PI3Kby NGF. Nuclear PI3K activates nuclear AKT through nuclearPtdIns(3,4,5)P3. Activated AKT by unknown mechanism can inhibit Caspase-activatedDNase DFF40 DNA fragmentation activity .