Page 94 - 80_01

José
María
Rojo,
Pilar
Portolés

1.
INTRODUCTION

This
review
focuses
on
the
use
and
possible
applications
of

phosphoinositide-­-3
kinase
(PI3K)-­-specific
inhibitors
to
modulate
immune

responses,
with
an
emphasis
on
T
lymphocyte-­-dependent
adaptive
responses.

Phosphoinositide-­-3
kinases
(PI3Ks)
are
enzymes
that
phosphorylate
the

OH-­-
group
at
the
D3-­-position
of
the
inositol
ring
of
inositol-­-containing
lipids

(PtdIns)
located
in
inner
leaflet
of
membrane
bilayers.
In
this
way,
they
generate

intracellular
phosphorylated
inositol
lipids
(PtdInsP)
that
serve
to
anchor
cytosolic

enzymes
facilitating
interaction
with
their
substrates
and/or
their
activation,

initiating
different
cell
signaling
cascades
(Figure
1)
(reviewed
in
(1-­-5)).
This
is

mediated
by
membrane
translocation
of
different
effector
proteins
that
possess

domains,
like
the
Pleckstrin
homology
domain
(PH),
the
Phox
homology
domain

(PX)
or
the
FYVE
domain,
specific
for
distinct
phosphorylated
inositides
(Figure
1).

These
effector
proteins
are
involved
in
the
regulation
of
many
essential
cell

functions
including
cell
survival,
growth,
and
proliferation.
Not
surprisingly,

different
signals
essential
to
the
function
of
cells
of
the
immune
system
activate

PI3K
activity.
For
instance,
in
lymphocytes
PI3K
activity
is
enhanced
upon
antigen

activation,
engagement
of
costimulatory
molecules,
binding
of
cytokines
or

quimiokines
to
their
receptors,
or
integrin-­-mediated
adhesion.
Thus,
PI3Ks
are

prime
targets
for
immunomodulatory
strategies.

Differences
in
protein
structure,
regulation
of
activity,
and
lipid
substrate

preference
define
three
different
classes
of
PI3K,
namely
class
I,
class
II
and
class

III
PI3K
(Figure
1,
2).
In
mammals
there
are
eight
different
PI3K
isoforms.
Of
them,

four
are
class
I
PI3Ks
(p110a,
p110ß,
p110?
and
p110d),
three
belong
to
class
II

PI3K
(PI3K-­-C2a,
PI3K-­-C2ß,
PI3K-­-C2?)
and
the
vacuolar
sorting
protein
34
(VPS34)

is
the
only
class
III
PI3K.
Class
I
are
PI3Kinases
specific
for
PtdIns(4,5)P2
and
play
a

major
role
in
signal
transduction
induced
by
receptors
that
activate
protein

tyrosine
kinases
(class
IA
PI3K)
or
by
receptors
coupled
to
small
GTPases
(class
IB

PI3K).
Class
II
and
III
PI3Kinases
phosphorylate
PtdIns.
Class
II
have
a
role
in

signal
transduction,
but
many
aspects
of
their
biology
are
not
well
known;
Class
III

have
a
role
in
vesicle
trafficking.

92