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Class
I
phosphoinositide
3-­-kinases
in
immunity…

PKC?
activated
by
diacylglicerol
(DAG),
or
Serum-­-
and
glucocorticoid-­-inducible
kinase
(SGK)
1.

PLC-­-?
is
recruited
to
PI3P3
containing
membranes
to
generate
IP3
and
DAG;
IP3
induces
enhanced

cytoplasmic
Ca2+
levels
and
activation
of
NF-­-AT
transcription
factors.
DAG
activates
not
only
NF-­-?B

through
PKC?,
but
RasGRP
that
activates
the
Ras
proteins,
thus
enhancing
PI3K
and
other
Ras-­-
dependent
signals
including
the
MAPK
pathway.

One,
then,
faces
a
situation
where
class
I
PI3K,
an
enzyme
essential
to
many

cell
functions
is
regulated
at
many
levels,
particularly:
i)
by
the
expression
levels
of

each
regulatory
and
catalytic
isoform
of
PI3K,
of
the
different
PtdIns(3,4,5)P3

phosphatases,
and
the
different
activator
and
effector
proteins
of
PI3K;
and
ii)
by

the
nature
of
the
signals
that
activate
PI3K
activity
in
different
cells
and
conditions.

The
final
outcome
of
the
cell
response
will
depend
on
the
integration
of
all
these

factors.
Furthermore,
differences
among
different
cells
and
tissues
concerning

these
factors
allow
for
distinct
pharmacological
effects
of
PI3Kinase
inhibitors
and

a
selective
intervention
in
different
pathological
situations.

As
a
general
rule,
the
expression
of
class
IA
p110a
and
p110ß
is
broad,

whereas
class
IA
p110d
and
class
IB
p110?
are
mainly
expressed
by
cells
of

hematopoietic
origin.
Among
class
I
PI3K,
lymphocytes
express
readily
detectable

amounts
of
class
IA
p110d
and
class
IB
p110?
catalytic
subunits
that
are

characteristic
of
leukocytes.
Interestingly,
in
T
lymphocytes
class
IA
p110a
is

expressed
at
levels
similar
to
p110d,
but
expression
of
p110ß
is
low
(14).
The

particular
function
for
the
different
class
IA
regulatory
subunit
isoforms
is
not

clearly
established.
Among
class
IA
regulatory
subunits,
T
lymphocytes
express

low
amounts
of
p85ß
and
p55?
chains
((14),
and
unpublished
data),
so
p85a
and

its
splicing
variants
p55a
and
p50a
are
the
main
regulatory
subunits
(14).
There

are
clear
variations
in
the
abundance
of
these
isoforms
in
resting
and
activated
T

cells.
Thus,
resting
CD4+
T
lymphocytes
have
similar
levels
of
p85a
and
p50a,
but

the
levels
of
p50a
is
strongly
reduced
upon
activation;
low
levels
of
p50a
are
also

common
in
T
cell
lines
(14).
In
turn,
p50a
subunits
bind
better
than
p85a
to

phosphorylated
Tyr-­-x-­-x-­-Met
motifs
(14)
and
are
preferentially
recruited
to

immunological
synapses
together
with
ICOS
(20).
However,
the
functional
meaning

of
these
differences
is
far
from
clear.

4.
CLASS
IA
AND
CLASS
IB
PI3KINASES:
MAIN
MOLECULAR
MEDIATORS

In
lymphocytes
class
I
PI3Kinases
are
activated
through
different
receptors

((21,22),
Figure
3).
The
activity
of
Src
and
Syk
tyrosine
kinases
is
triggered
by

ligand
binding
to
antigen
receptor
complexes
(BCR
in
B
lymphocytes,
TCR/CD3
in

T
lymphocytes).
This
activation
leads
to
phosphorylation
of
adaptor
proteins
like

LAT
and
TRIM
in
T
cells
or
BCAP
in
B
cells.
Class
IA
PI3Kinases
are
typically

recruited
to
membranes
and
activated
upon
phosphorylation
of
Y-­-x-­-x-­-M
motifs
in

these
proteins
(i.e.
in
TRIM)
or
by
means
of
adaptor
proteins
like
Grb-­-2
or
Cbl.
Co-­-

97