Pathway Map Details
Apoptosis and survival_NGF signaling pathway
Object list (links open in MetaCore):
IP3, PtdIns(3,4,5)P3, PIKE, Caspase-3, Shc, 126.96.36.199, DAG, AKT, 188.8.131.52, GRB2, PI3K cat class IA, ICAD, AKT, 184.108.40.206, Nucleophosmin, PI3K reg class IA, H-Ras, BAD, NGF, PtdIns(4,5)P2, PtdIns(3,4,5)P3, TrkA, Caspase-9, 4.1N, PtdIns(4,5)P2, PtdIns(4,5)P2, PLC-gamma 1, DNA, GAB1, SOS, PI3K cat class IA, DFF40
NGF (nerve growth factor) activates a variety of cascades in neuron cells. One of them, PI3K (phosphoinositide-3-kinase)/ AKT (serine/threonine-protein kinases) pathway, is particularly important for mediating neuronal survival under a wide variety of circumstances . NGF binds to the tyrosine kinase receptor TrkA, which induces the recruitment of the complex of adapter molecules Shc/Grb2 , . This complex activates PI3K regulatory subunits via another Grb2 -associated protein Gab1  or via SOS (guanine nucleotide exchange factor)/ H-RAS (p21 protein). In both cases, this event activates PI3K catalytic subunit. Thus PI3K is recruited to the vicinity of the plasma membrane, where the catalytic subunits of PI3K generate the phosphoinositide 3,4,5-trisphosphate ( PtdIns(3,4,5)P3 ), which, in turn, leads to the membrane translocation of AKT and activation of its signaling cascades. AKT inhibits apoptosis 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 their proapoptotic functions .
Antiapoptotic actions of NGF was also shown to be mediated through nuclear PtdIns(3,4,5)P3 and nuclear AKT by PI3K enhancer PIKE . Nucleophosmin (nucleolar phosphoprotein B23) also mediates the antiapoptotic effects of NGF by inhibiting DNA fragmentation activity of caspase-activated DNase ( DFF40 ) .
NGF stimulation of TrkA induces activation of phospholipase C PLC-gamma 1, which acts as a guanine nucleotide exchange factor for PIKE.  PIKE is the brain-specific nuclear GTPase that interacts with nuclear PI3K to stimulate its lipid kinase activity. Activation of nuclear PI3K by PIKE is inhibited by the NGF-stimulated 4.1N (band 4.1-like protein 1) translocation to the nucleus and its interaction with PIKE . Thus, PIKE physiologically modulates activation of nuclear PI3K by NGF.
Nuclear PI3K activates nuclear AKT through nuclear PtdIns(3,4,5)P3. Activated AKT by unknown mechanism can inhibit Caspase-activated DNase DFF40 DNA fragmentation activity .
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