Page 98 - 80_01

José
María
Rojo,
Pilar
Portolés

catalytic
subunits
by
small
GTPases
of
the
Ras
family,
with
a
clear
selectivity
of
the

different
catalytic
subunits
for
activation
by
distinct
Ras
family
members
(16).

The
signaling
outcome
of
PI3K
is
also
controlled
by
the
activity
of

PtdIns(3,4,5)P3
phosphatases
that
are
essential
to
correct
lymphocyte
function

(17-­-19)
(Figure
1,
3).
The
PtdIns(3,4,5)P3
3-­-phosphatase
Phosphatase
and
Tensin

Homologue
(PTEN)
controls
PtdIns(3,4,5)P3
levels
by
generating
PtdIns(4,5)P2;

PTEN
is
particularly
important
to
control
basal
levels
of
PtdIns(3,4,5)P3.
The

PtdIns(3,4,5)P3
5-­-phosphatases
SHP-­-1
and
SHP-­-2
(SH2
domain-­-containing
Inositol

Phosphatase-­-1
and
-­-2)
dephosphorylate
PtdIns(3,4,5)P3
levels
yielding

PtdIns(3,4)P2.
Interestingly,
SHP-­-1,
2
bind
to
surface
molecules
of
lymphocytes

that
are
essential
to
negatively
control
immune
responses
including
CTLA-­-4,
PD-­-1,

and
BTLA
(17).

Figure
3.
A
diagram
of
class
I
PI3K-­-mediated
signaling
in
T
(CD4+)
lymphocytes.
Class
IA
PI3K
are

recruited
to
the
cell
membrane
and
activated
upon
binding
of
ligands
for
cytokine
and
antigen

receptors
or
CD28
family
costimulator
molecules
like
CD28
or
ICOS.
Class
IB
subunits
are

characteristically
recruited
and
activated
upon
binding
of
chemokines
to
their
G
protein-­-coupled

receptors.
Enhanced
levels
of
PtdIns(3,4,5)P3
(PIP3)
favor
the
recruitment
and
activation
of

proteins
containing
PH
domains
including
Ser
and
Thr
kinases
like
PDK1
and
Akt,
Tec
family

protein
Tyr
kinases
(Itk),
phospholipases
like
PLC-­-?,
or
GEF
like
Vav.
Akt
is
activated
by

phosphorylation
of
Thr308
and
Ser473
by
PIP3–dependent
activated
PDK1
and
mTORC2,

respectively.
Akt
has
an
array
of
different
targets
involved
in
many
cell
functions.
One
major

effector
of
Akt
is
the
mTORC1
complex
containing
the
Ser/Thr
kinase
mTOR
and
Raptor.
This
is

achieved
by
inactivation/phosphorylation
of
the
tuberous
sclerosis
1
and
2
complex
(TSC1-­-TSC2)

that
blocks
RHEB
(Ras
homologue
enriched
in
brain),
a
small
GTPase
and
mTOR
activator.
Through

phosphorylation
of
other
substrates
like
ATG13
(autophagy-­-related
protein
13),
S6K,
4E-­-BP1,
or

HIF-­-1a,
mTORC1
controls
important
cell
processes
including
autophagy
or
cell
metabolism.
Akt

also
regulate
apoptosis
through
Bcl-­-2-­-associated
death
promoter
(BAD)
protein
phosphorylation,

the
transcription
of
genes
controled
by
FOXO
transcription
factors,
or
Glycogen
synthase
kinase

(GSK)
3-­-mediated
effects
on
cell
cycle
and
metabolism.
mTORC2
and
PDK1
also
phosphorylate
the

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