Biology Reference
In-Depth Information
bind to the src homology 3 (SH3) domains found in a diverse group
of signal-transducing molecules,
105
including Grb2
106
and the p85
subunit of PI3K
107
leading to subversion of signaling through the
Raf/MEK/ERK and PI3K/Akt pathways. The NS5A-Grb2 interac-
tion also results in down-regulation of IFN expression,
108
while its
interaction with PKR leads to inhibition of PKR, an effector of the
interferon pathway. Thus HCV adopts a dual strategy for survival by
activating MAPK on one hand and inhibiting the interferon response
on the other. The HEV ORF3 protein also has PXXP motifs and binds
to SH3 domains of multiple proteins, including Src, Grb2, Hck, Fyn,
PLC-
and the p85 regulatory subunit of PI3K
109
; these proteins are
upstream modulators of Raf/MEK/ERK, PI3K/Akt and PLC-
γ
/PKC
signaling pathways. Increased activity of ERK has been observed in
ORF3 expressing cells and this was shown to be due to its binding to
and inhibition of a MAPK phosphatase.
110
γ
Regulation of the PI3 Kinase/Akt (PKB) Pathway
On binding their cognate cell surface receptors, extracellular signals
like growth factors recruit a large number of cytoplasmic signaling
molecules, phosphatidylinositol-3-kinase (PI3K) being one of
them.
111,112
Recruitment of PI3K to the cell membrane by growth fac-
tors or other docking molecules activates downstream effectors such
as the kinase PDK1 and its substrate Akt (also called protein kinase
B, PKB). By recruiting and activating signaling complexes, PI3K
triggers complex cellular events such as cell cycle entry, cell survival
and migration. Akt is a serine/threonine kinase that on activation
phosphorylates a number of downstream effectors including other
kinases and transcription factors. Activation of Akt results in the
phosphorylation and inhibition of pro-apoptotic signals from pro-
teins such as BAD,
113
caspase 9,
114
and Forkhead,
115,116
while pro-
B
117
(Fig. 6). In its
non-phosphorylated state, BAD translocates from the cytosol to the
mitochondria and promotes apoptotic death by binding and inhibit-
ing anti-apoptotic proteins Bcl2 and Bcl-X
L
. Activated Akt phospho-
rylates BAD, retaining it in the cytosol and thereby preventing
moting cell survival signals mediated by NF
κ
