Biology Reference
In-Depth Information
subunits to move apart from each other, leading to the separation
of the corresponding intracellular domains.
20
After the change in inte-
grin conformation, intracellular signaling proteins can bind to cytoplas-
mic tails and be activated.
In the integrins that have ligand-binding
and
β
α
I domains, a specific
glutamate residue in the
α
7 helix of the
α
I domain may act as an
intrinsic ligand for the
β
I domain.
21
In these integrins, the ligand at
first induces a change in the
α
I domain, followed by a similar change
in the
I domain.
Integrins are connected to many different signaling pathways,
which regulate cell growth, differentiation and survival. Therefore it
is logical to presume that also viruses binding to integrins can activate
cellular signaling. In our own studies with EV1 we noticed a rapid
phosphorylation of one of the mitogen-activated protein kinases
(MAP kinases), namely extracellular signal regulated kinase (ERK),
already after 5 to 30 min p.i. (Upla
et al
., 2004). MAP kinases are
activated, together with induction of immediate early genes, also dur-
ing the later stages of the replication cycle.
22,23
When we searched for
the upstream signaling proteins it became evident that members of
the PKC family activated ERK after EV1 binding, rather than the Ras
pathway. Inhibition of ERK activity had no effect on the EV1 entry,
but specific inhibitors of PKC-
β
were able to block the internalization
of the virus and its receptor. PKC-
α
was also moderately activated
during the internalization and the inhibition of its function totally
blocked EV1 internalization and infection.
24
α
Internalized EV1 is Found in Caveosomes
Virus entry into the host cell may occur via at least five different path-
ways (for a review see Refs. 25 and 26). Clathrin-dependent endocytic
pathway is the best characterized internalization route and it is often
referred to as the classical endocytic pathway. It mediates the consti-
tutive entry of clathrin-coated vesicles to cytoplasm, which after rapid
disintegration of the clathrin coat fuse with the peripheral early endo-
somes. The receptors that are attracted to enter through a clathrin-
dependent pathway usually contain an internalization signal in their
C-terminus, which then binds to the adaptors in the clathrin coat.
