Healthcare and Medicine Reference
In-Depth Information
A
PI3 kinase and...
Akt pathway
P
Grb2 SOS
Shc
P
P
P
P
P
P
P
P
P
P
P
PI3K
Akt1
B
Ras activation and...
MAPK pathway
P
Shc
Grb2 SOS
P
P
Ras
GTP
Raf
P
P
P
P
P
P
P
P
MEK
P
P
ASK
P
ERK
P
JNK
PI3K
Akt1
RSK
P
P
c-Jun
CREB
P
P
Nucleus
Bcl-2
P
FIGURE 7.23 Trk intracellular signaling. A. The first pathway leads to activation of the Akt Kinase. Two
proteins (Grb-2, Gab-1) are recruited to the receptor complex, resulting in the activation of a phosphatidyli-
nositol-3 kinase (PI3K). PI3K generates phosphoinositide phophases that activate the serine/threoninee
kinase, Akt. B. The second pathway leads to activation of the mitogen-activated protein kinase (MAPK)
cascade. In this pathway, a membrane-associated G-protein, Ras, first becomes activated through GDP-GTP
exchange, mediated by a guanine nucleotide exchange factor (Sos). The activated Ras phosphorylates several
substrates, including a serine/threonine kinase, Raf. Raf can inhibit a proapoptotic pathway consisting of
two kinases (ASK, JNK) and a trascription factor (c-Jun). Raf also initiates the MAPK cascade, concluding
with the activation of ribosomal S6 protein kinase (RSK). Both Akt and RSK can phosphorylate the tran-
scription factor, cyclic AMP response element binding protein (CREB). CREB enters the nucleus and increases
the expression of antiapoptoptic proteins, such as Bcl-2.
possibly through phosphorylation of a JNK-activator.
Thus, when sympathetic neurons are transfected with
constitutively active Ras, the level of JNK and c-Jun
declines, and the neurons survive in the absence of
NGF. This pathway appears to play role in the survival
mechanism during in vivo maturation. The genetic
elimination of p53, which is known to be a down-
stream effector of c-Jun, results in increased survival of
SCG neurons (Mazzoni et al., 1999; Aloyz et al., 1998;
Kanamoto et al., 2000).
The PI3K-Akt and MAPK pathways also promote
survival at the level of gene transcription. The tran-
scription factor, cyclic AMP response element binding
protein (CREB), is phosphorylated by RSK2. The acti-
vated CREB enters the nucleus and binds to DNA and
increases the expression of a pro-apoptotic regulatory
protein (Bcl-2) that is discussed below (see Regulating
Death Proteins). The mechanism appears to support
the in vitro survival of both sympathetic neurons
through NGF activation of TrkA, and cerbellar granule
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