Pathway Map Details
Development_Neurotrophin family signaling
Object list (links open in MetaCore):
Bax, NT-3, RAP-1A, C3G, GRB2, NRAGE, SHP-2, GAB2, ERK1/2, MEK2, c-Jun, Elk-1, NT-4/5, JNK1-3, MEK1, c-Raf-1, SH2B, TrkB, XIAP, Rac1, H-Ras, PtdIns(3,4,5)P3, TrkC, CrkL, Sortilin, MEKK1, p53, SOS, GAB1, NGF, NGFR, PtdIns(4,5)P2, 18.104.22.168, B-Raf, BDNF, TrkA, PI3K cat class IA, PI3K reg class IA, AKT, Shc
Neurotrophin family signaling
Factors of the neurotrophin family ( NGF, BDNF and neurotrophins NT-3 and NT-4/5 ), promote neuronal survival or death. The best characterized receptors for these trophic factors are the tropomyosin-related tyrosine kinase receptors TrkA, TrkB, and TrkC, and a member of the tumor necrosis factor receptor family NGFR .
The NGFR receptor physically binds to the Trk receptors , and complexes of NGFR with TrkA or TrkB increase their ligand affinity and selectivity. Whether the association of NGFR with TrkC influences neurotrophin affinity is not known , .
Many investigations indicate that the survival-promoting signals of neurotrophins are generated by activation of Trk receptors and that their death-promoting signals are generated by activation of NGFR , .
Neurotrophin binding to TrkA, TrkB and TrkC induces receptor dimerization and autophosphorylation, which leads to the recruitment of the complex signaling molecules, including Shc ,  and SH2-B . These signaling molecules then initiate activation of multiple signaling pathways.
Tyrosyl phosphorylation of Shc by Trk-receptors enables Shc to recruit Grb2-SOS complexes to the plasma membrane.  This results in the activation of RAS/RAF/MEK/ERK pathway and promotes cell proliferation , .
SH2-B also can bind Grb2 and mediate the same RAS/RAF/MEK/ERK pathway in developing neurons .
In addition to H-RAS, RAP-1A is likely to play an important role in the sustained activation of Raf/MEK/ERK kinases. Formation of a long-lived complex containing C3G/CrkL/Shp2/Gab2 induces RAP-1A activation and continuing MEK1/2 and ERK1/2 activation with simultaneous inhibition of H-RAS .
Another Grb2 -associated protein Gab1 undergoes tyrosine phosphorylation in response to NGF stimulation. Phosphoinositide-3-kinase regulatory subunit ( PI3K reg (p85) ) binds Gab1, allowing it to serve as a substrate for receptor tyrosine kinases .
Moreover, activation of PI3K mediates the RAC-alpha serine/threonine-protein kinase ( AKT ) signaling, which plays the leading role in promoting neuron survival .
NGFR receptor, in contrast, has been repeatedly implicated in neuronal death. Apoptosis of neuronal cell lines, glia and a variety of primary neurons in vitro is mediated by ligand activation of NGFR , , . Sortilin is a type I transmembrane protein expressed in a wide variety of tissues, but is most abundant in the central nervous system during development and in adults. NGFR and Sortilin form a receptor complex that binds NGF at the cell surface. Both receptors appear to be required to transduce apoptotic effects .
Some NGFR-associated proteins may play an important role in apoptosis induction. Neurotrophin receptor-interacting MAGE homolog ( NRAGE) binds NGFR in vitro and in vivo. NRAGE associates with the plasma membrane when NGF is bound to NGFR. NRAGE blocks the physical association of NGFR with TrkA, which facilitates cell cycle arrest and induces neuron apoptosis . Intracellular signaling events associated with cell death are less well understood than the survival-promoting cascades initiated by Trk receptor activation. Upon activation, NGFR assembles a signaling complex that may include NRAGE and other proteins and adaptors. Rac1  and H-Ras  are likely to be activated, which leads to MEKK1/JNK/P53/BAX signaling. This pathway appears to be crucial for NGF - NGFR induced apoptosis .
It seems unlikely, that neurotrophin receptors have such opposite effects on neuronal survival and act independently, as each receptor can engage survival-promoting or death-promoting signaling pathways. There is evidence of crosstalk between signaling pathways engaged by NGFR and Trk receptors, although correct mechanisms are not well understood .
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