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Apoptosis and survival NGF signaling pathway


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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 [1]. NGF binds to the tyrosine kinasereceptor TrkA, which induces the recruitment of the complex of adapter moleculesShc/Grb2 [2], [3]. This complex activates PI3Kregulatory subunits via another Grb2 -associated protein Gab1 [4] 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 [5].

PI3K and AKT are predominantly located in the cytoplasm, but they alsooccur in the nucleus, or translocate to the nucleus upon stimulation [6],[7].

Antiapoptotic actions of NGF was also shown to be mediated through nuclearPtdIns(3,4,5)P3 and nuclear AKT by PI3K enhancer PIKE [8]. Nucleophosmin (nucleolar phosphoprotein B23) also mediates theantiapoptotic effects of NGF by inhibiting DNA fragmentation activity ofcaspase-activated DNase ( DFF40 ) [9].

NGF stimulation of TrkA induces activation of phospholipase CPLC-gamma 1, which acts as a guanine nucleotide exchange factor for PIKE.[10] 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 [11]. 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 [8].