Apoptosis and survival - NGF signaling pathway

NGF signaling

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 [1]. NGF binds to the tyrosine kinase receptor TrkA, which induces the recruitment of the complex of adapter molecules Shc/Grb2 [2], [3]. This complex activates PI3K regulatory subunits via another Grb2-associated protein Gab1 [4] 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 [5].

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

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

NGF stimulation of TrkA induces activation of phospholipase C PLC-gamma 1, which acts as a guanine nucleotide exchange factor for PIKE. [10] 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 [11]. 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 {15385964}. However, constitutively active nuclear AKT alone is not sufficient to protect DNA from degradation. It is suggested, that some other downstream effectors of nuclear PtdIns(3,4,5)P3 and nuclear AKT are necessary for the antiapoptotic effect of NGF in the nucleus.

Thus, both cytoplasmic and nuclear AKT kinases inhibit not only upstream signals of caspases activation, but also function downstream of them in the nucleus to serve as a final checkpoint before internucleosomal DNA fragmentation, which sufficiently protect neuronal cells from apoptosis [8].

References:

1. Brunet A, Datta SR, Greenberg ME
   Transcription-dependent and -independent control of neuronal survival by the PI3K-Akt signaling pathway. Current opinion in neurobiology 2001 Jun;11(3):297-305
2. Stephens RM, Loeb DM, Copeland TD, Pawson T, Greene LA, Kaplan DR
   Trk receptors use redundant signal transduction pathways involving SHC and PLC-gamma 1 to mediate NGF responses. Neuron 1994 Mar;12(3):691-705
3. Postigo A, Calella AM, Fritzsch B, Knipper M, Katz D, Eilers A, Schimmang T, Lewin GR, Klein R, Minichiello L
   Distinct requirements for TrkB and TrkC signaling in target innervation by sensory neurons. Genes & development 2002 Mar 1;16(5):633-45
4. Onishi-Haraikawa Y, Funaki M, Gotoh N, Shibuya M, Inukai K, Katagiri H, Fukushima Y, Anai M, Ogihara T, Sakoda H, Ono H, Kikuchi M, Oka Y, Asano T
   Unique phosphorylation mechanism of Gab1 using PI 3-kinase as an adaptor protein. Biochemical and biophysical research communications 2001 Oct 26;288(2):476-82
5. Datta SR, Brunet A, Greenberg ME
   Cellular survival: a play in three Akts. Genes & development 1999 Nov 15;13(22):2905-27
6. Neri LM, Borgatti P, Capitani S, Martelli AM
   The nuclear phosphoinositide 3-kinase/AKT pathway: a new second messenger system. Biochimica et biophysica acta 2002 Oct 10;1584(2-3):73-80
7. Borgatti P, Martelli AM, Tabellini G, Bellacosa A, Capitani S, Neri LM
   Threonine 308 phosphorylated form of Akt translocates to the nucleus of PC12 cells under nerve growth factor stimulation and associates with the nuclear matrix protein nucleolin. Journal of cellular physiology 2003 Jul;196(1):79-88
8. Ahn JY, Rong R, Liu X, Ye K
   PIKE/nuclear PI 3-kinase signaling mediates the antiapoptotic actions of NGF in the nucleus. The EMBO journal 2004 Oct 13;23(20):3995-4006
9. Ahn JY, Liu X, Cheng D, Peng J, Chan PK, Wade PA, Ye K
   Nucleophosmin/B23, a nuclear PI(3,4,5)P(3) receptor, mediates the antiapoptotic actions of NGF by inhibiting CAD. Molecular cell 2005 May 13;18(4):435-45
10. Ye K, Aghdasi B, Luo HR, Moriarity JL, Wu FY, Hong JJ, Hurt KJ, Bae SS, Suh PG, Snyder SH
    Phospholipase C gamma 1 is a physiological guanine nucleotide exchange factor for the nuclear GTPase PIKE. Nature 2002 Jan 31;415(6871):541-4
11. Ye K, Hurt KJ, Wu FY, Fang M, Luo HR, Hong JJ, Blackshaw S, Ferris CD, Snyder SH
    Pike. A nuclear gtpase that enhances PI3kinase activity and is regulated by protein 4.1N. Cell 2000 Dec 8;103(6):919-30