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 .
TrkA is a high-affinity receptor for
NGF; TrkB is a high-affinity
receptor for BDNF and NT-4/5;
TrkC is a high-affinity receptor for
NT-3 , .
NGFR receptor binds NGF,
BDNF, NT-3, and
NT-4/5 , , .
High-affinity ligand-binding site is formed by a complex of
NGFR and Sortilin, a
co-receptor for NGF .
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
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
Gab1, allowing it to serve as a substrate for receptor
tyrosine kinases .
Moreover, activation of PI3K mediates the RAC-alpha
(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
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
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