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binds to and activates a serine/threonine kinase, called
Raf. Raf activation leads to activation of the mitogen-
activated protein kinase cascade (MAPK), eventually
resulting in translocation into the nucleus (Figure
7.23).
The potential importance of Ras-Raf signaling to
neuron survival is demonstrated in experiments where
the Ras protein is injected directly into cultured chick
DRG neurons. Although DRG neurons depend on
NGF for their survival, the Ras protein is sufficient to
prevent cell death (Borasio et al., 1989). Furthermore,
the same treatment promotes the survival of BDNF-
dependent nodose ganglion neurons and CNTF-
dependent ciliary ganglion neurons.
Which MAPKs are responsible for the positive
effects of NGF binding, and which ones produce the
negative effects following its withdrawal? In PC12
cells, there is evidence for both types of signal (Xia et
al., 1995). NGF promotes the survival of PC12 cells,
and this is accompanied by activation of several
MAPKs. Within six hours of NGF withdrawal, PC12
cells begin to die in great numbers, and there is a
prominent decrease in ERK activity. To test whether
ERK is responsible for the positive effect of NGF, PC12
cells were engineered to produce constitutively high
levels of ERK activity (Figure 7.24). These cells sur-
vived much better following NGF withdrawal. There
is also a MAPK signal, called JNK, that appears to turn
on following NGF withdrawal. In fact, PC12 cell death
will occur in the presence of NGF if JNK is constitu-
tively activated (Figure 7.24). Thus, NGF may upregu-
late proteins needed for cell survival through ERK,
while proteins needed for suicide are upregulated by
JNK.
How do activation of the two major kinase path-
ways, PI3K-Akt and MAPK, prevent cell death? Akt
can promote cell survival by inactivating pro-
apoptotic proteins in the cytoplasm and increasing
transcription of anti-apoptotic proteins. For example,
RSK phosphorylates, and inactivates, one of the pro-
apoptotic regulatory proteins in the Bcl-2 family. These
regulatory proteins are discussed below (see Regulat-
ing Death Proteins). The Ras-MAPK pathway pro-
motes survival in the fly using a similar strategy. When
active Ras is ectopically expressed in the developing
eye, it decreases the expression of pro-apoptotic pro-
teins and prevents normal cell death (Kurada and
White, 1998).
As discussed above, NGF withdrawal and the
p75 NTR lead to activation of the JNK-c-Jun pathway,
resulting in neuron death. Therefore, it seems impor-
tant for the survival pathway to suppress this system
as well. In fact, the active Ras-Raf pathway promotes
survival by blocking the JNK pathway (Figure 7.23),
Trk
Cysteine clusters
A
NT dimer
Ig-like domains
Binding
Tyrosine kinase
B
Dimerization and.....
autophosphorylation
P
P
P
P
P
P
P
P
P
P
C
Substrate binding and...
substrate phosphorylation
P
Shc
P
P
P
P
P
P
P
P
P
P
P
FIGURE 7.22 Neurotrophin-Trk receptor interaction. A. The bio-
logically active forms of neurotrophins are dimers of identical 13
kDa peptide chains. The neurotrophin dimer binds to the Trk
protein. B. The binding induces 2 Trk receptors to dimerize. The
ligand-receptor complex leads to transphosphorylation of tyrosine
residues on the cytoplasmic tail of neighboring receptors. (C) Cyto-
plasmic adaptor proteins (Shc) bind to specific phosphorylation
sites on the cytoplasmic tail, and these substrates are then
phosphorylated.
neurons alive (Figure 7.24). Specific blockade of either
PI3K or Akt activity kills the primary cultures of sym-
pathetic neurons even in the presence of NGF, while
constitutive activation of either kinase keeps the
neurons alive even in the absence of NGF (Crowder
and Freeman, 1998).
There is a second major pathway that also leads to
phosphorylation of cyoplasmic components and that
participates in cell survival. In this case, the adaptor
and docking proteins recruit a guanine nucleotide
exchange factor (SOS) to activate a membrane-associ-
ated G-protein called Ras (Figure 7.23). Ras is activated
when it exchanges a GDP for a GTP, whereupon it
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