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have demonstrated that both gB and gH stimulate the activation of the cellular
transcription factors, NFκ-B and Sp1 (Yurochko et al. 1997a; Yurochko and Huang
1999). Other studies confirmed and expanded these results (Boyle et al. 1999;
Simmen et al. 2001; Wang et al. 2003, 2005; Boehme et al. 2004, 2006) and
together determined that HCMV fires cellular signal transduction pathways via the
actions of the major viral glycoproteins, gB and gH. Viral glycoprotein-mediated
signaling occurs in multiple cell types (fibroblasts, monocytes, endothelial cells,
etc.), suggesting that the capacity to induce cellular signaling is part of a central
theme in the viral infection strategy.
The recent identification of several cellular receptors for HCMV attachment/
entry that are found on multiple cell types supports this proposal: HCMV glycopro-
teins were recently shown to interact with the epidermal growth factor receptor
(EGFR; Wang et al. 2003, 2005), integrins (α
2
β
1
, α
6
β
1
, α
V
β
3
; Feire et al. 2004; Wang
et al. 2005), and toll-like receptor 2 (TLR2; Compton et al. 2003; Boehme et al.
2006). From a signaling standpoint, the engagement of these receptors by the virus
makes sense, as each receptor is biochemically integrated with the signaling
machinery. EGFR dimerizes upon ligand binding and then directs downstream sig-
naling events via the action of its intrinsic tyrosine kinase (Wang et al. 2003, 2005).
Integrins do not possess intrinsic kinase activity; however, upon their engagement
they interact with members of the Src family of tyrosine kinases to modulate down-
stream signaling events (Wang et al. 2003, 2005). Finally, like all TLRs, TLR2 is
part of a signaling network involving a cascade of players (Compton et al. 2003;
Boehme et al. 2006).
Mechanistically, it has been documented that gB and gH are responsible for the
engagement of the various cellular receptors (EGFR, the integrins, and TLR2) and
that, through this receptor/ligand interaction, they rapidly activate signal transduc-
tion pathways (Wang et al. 2003, 2005; Boehme et al. 2006). Wang et al. have
reported that gB interacts with EGFR and gH interacts with cellular integrins
(Wang et al. 2003, 2005), demonstrating that individual receptor/ligand events are
controlled by different viral gene products. gB and gH can also interact with TLR2
(Boehme et al. 2006), while gB may additionally interact with cellular integrins
(Feire et al. 2004). All three receptors appear to be present on most cell types, sug-
gesting an evolutionarily conserved mechanism may exist for viral binding and
receptor engagement during infection of multiple cell types. This possibility is sup-
ported by work showing that EGFR and/or integrins are central determinants of
signaling and/or attachment/entry in fibroblasts (Wang et al. 2003, 2005), cytotro-
phoblasts (Maidji E et al. 2007), endothelial cells (Bentz and Yurochko 2008) and
monocytes (Yurochko et al. 1992; Chan et al., unpublished data). Nevertheless, the
role these receptors play remains controversial, as it was recently reported that
EGFR was not required for attachment and signaling on some fibroblast, epithelial
and endothelial cell lines (Isaacson et al. 2007). Thus, it remains unclear if all three
receptors are utilized on all cell types infected or if different combinations are uti-
lized depending on the cell type. Overall, these findings suggest the following
general model (discussed in more detail below): gB and gH binding to cellular
receptors initiates the activation of multiple downstream players including the focal
