Page 101 - 80_01

Class
I
phosphoinositide
3-­-kinases
in
immunity…

also
PI3K
dependent
and
involves
its
association
with
ribosomes,
yet
the
exact

mechanisms
are
not
known
(29).
At
least
another
well
established
PDK2
activity

for
Ser423
Akt
phosphorylation
is
mediated
by
the
DNA-­-PK
(7,31,32).
Doubly

phosphorylated
Akt
P-­-Thr308Ser423
efficiently
phosphorylates
forkhead

transcription
factor/forkhead
box
(FOXO)
transcription
factors
FOXO1/2
to
inhibit

their
function,
with
important
consequences
in
lymphocytes
(27,33).

4.b.
Targets
of
PI3K:
GEFs
and
Tec.

The
control
by
PI3Ks
of
the
actin
cytoskeleton
dynamics
mediated
by
GEF

stimulation
of
the
Rac
and
Rho
GTPases
is
well
established
(21).One
typical
GEF
is

Vav,
that
is
activated
by
Src
and
Syk
family
tyrosine
kinases
but
also
depends
on
its

PH
and
Dbl-­-homology
domains
for
activity
(34).

With
one
exception,
Tec
family
tyrosine
kinases
including
BTK
and
Itk

expressed
in
B
and
T
lymphocytes
possess
an
N
terminus
PH
domain
followed
by

TH,
SH3,
SH2,
and
kinase
domains
(35,36).
The
PH
domain
is
determinant
to

recruitment
of
these
Tec
kinases
to
membranes,
where
they
can
further
interact

with
specific
Tyr-­-phosphorylated
substrates
and
activated
by
Src
family
and

autophosphorylation.
Tec
family
tyrosine
kinases
have
phospholipase
C
enzymes

like
PLC?
as
important
substrates
within
signalosomes
generated
upon
receptor

activation.
PLC?
then
splits
PtdIns(4,5)P2
into
Diacylglicerol
and
Ins(1,4,5)P3
that

in
turn
are
necessary
to
activate
the
Ser/Thr
kinases
PKC?
and
hence
the

Ras/MAPK
and
the
IKK/NF?B
pathways,
or
the
Ins(1,4,5)P3-­-Ca2+-­-dependent

activation
of
NFAT
family
of
transcription
factors
(Figure
3).

4.c.
Targets
of
PI3K:
PDK1-­-dependent,
Akt-­-independent.

PDK1
can
associate
to
and
activate
additional
substrates
that
are
not

dependent
on
Akt
including
the
Ser/Thr
kinases
PKC?
(37)
and
the
cAMP-­-
dependent
kinase
PKA
(38),
with
important
functional
consequences
to

lymphocyte
activation.

Of
note,
although
the
different
pathways
initiated
by
PI3K
activation
have

specific
targets,
they
can
be
also
connected
to
reinforce
others.
For
instance,
PKC?-­-
mediated
activation
of
IKK/NF?B
is
targeted
in
a
PI3-­-dependent
manner
through

PDK1-­-,
mTORC2-­-
and
Tec-­-dependent
mechanisms.

5.
CLASS
I-­-PI3KINASES:
RELEVANCE
TO
CANCER

The
clues
for
an
association
of
PI3K
and
tumor
development
and
growth

come
from
different
sources.
On
one
hand,
some
oncogenic
retroviruses
possess

genes
derived
from
those
encoding
p110a
and
AKT.
On
the
other,
the

PtdIns(3,4,5)P3
phosphatase
PTEN
is
a
tumor
suppressor
gene
frequently
mutated

in
human
tumors
with
the
consequence
of
a
constitutive
activation
of
the
PI3K

99