Hepatitis Viruses, Signaling Events and Modulation of the Innate Host Response - Structure-Based Study of Viral Replication - page 109

protein has been found to up-regulate expression of the mitochondrial
outer membrane protein VDAC1 and to increase the mitochondrial
transmembrane potential. 98 This viral protein also provides protection
against apoptotic signals, though the mechanism still remains to be fully
elucidated.
Cell Survival Strategies
Besides inhibiting the innate apoptotic response of the host, many
viruses actively stimulate signaling pathways that promote survival
and proliferation of the infected cell. This aids in viral replication and
helps promote the establishment and persistence of viral infection.
Regulation of the MAP Kinase Pathway
The MAPK signaling pathway is initiated in response to external or
internal stimuli such as growth factors, stress, DNA damage, virus
infection, etc. In vertebrates, three MAPK pathways have been char-
acterized. 99 These are the extracellular signal-regulated kinases
(MAPK/ERK), the p38 MAPK and the stress-activated protein
kinase/c-jun (SAPK/JNK). All these pathways are based on a three-
kinase signaling module consisting of a MAPK that is activated by an
upstream MAPK kinase (MAPKK), which itself is activated by a
MAPK kinase kinase (MAPKKK). The prototype of the MAPK sig-
naling pathway is the Raf/MEK/ERK cascade, a major pathway for
cell growth and differentiation. Signaling through this pathway acti-
vates ERK; activated ERK1/2 translocates to the nucleus to activate
a variety of transcription factors such as Elk, c-Fos, c-Jun, STAT3,
etc., that can then regulate cell proliferation and differentiation.
Many viruses activate ERK in a bid to regulate cell survival, prolif-
eration and differentiation, and hepatitis viruses are no exception.
HBV activates epidermal growth factor receptor (EGFR) mediated
activation of the Raf/MEK/ERK pathway. On binding to EGF, the
cytoplasmic domain of EGFR undergoes autophosphorylation, leading
to its interaction with adaptor proteins Shc and Grb2 that mediate
Raf/MEK/ERK activation 100 (Fig. 6). Further, HBx transactivates the