Page 100 - 80_01

José
María
Rojo,
Pilar
Portolés

stimulatory
molecules
like
CD28
and
ICOS
in
T
cells
and
CD19
in
B
cells
also

possess
Y-­-x-­-x-­-M
motifs
that
can
be
phosphorylated
to
directly
recruit
PI3Kinases.

Cytokine
receptors
indirectly
induce
recruitment
and
activation
of
class
IA
PI3K
by

means
of
different
adaptor
proteins.
For
instance,
in
IL-­-2
signaling
IL-­-2
receptors

(IL-­-2R)
recruits
class
IA
PI3K
upon
phosphorylation
of
Tyr338
of
the
ß
chain
that

allows
binding
of
the
protein
adaptors
SHP2
and
Gab2,
as
well
as
the
Shc
and
Grb

adaptors
that
facilitate
the
formation
of
Grb-­-Gab2
o
Grb-­-2-­-SHPS.
On
the
other

hand,
the
PI3Kinase
class
IB
p110?
catalytic
subunits
are
activated
by
the ß?

subunits
of
G-­-coupled
protein
chemokine
receptors
having
seven
trans-­-membrane

peptide
sequences.
However,
this
separation
among
PI3K
subclasses
is
not

absolute,
as
on
one
hand
class
IA
p110ß
signaling
through
G-­-coupled
receptors
has

been
observed
((23),
reviewed
in
(5)),
and
in
T
lymphocytes
tyrosine
kinases
like

Lck
and
ZAP-­-70
can
associate
p110?
class
IB
subunits
upon
antigen
receptor

activation
(24).
This
is
further
complicated
in
lymphocytes,
where
p110?
mediate

PI3K-­-dependent
chemokine
signals
in
T
lymphocytes,
but
p110d
perform
the
same

functions
in
B
lymphocytes
by
mechanisms
not
well
understood
(25,26),
but
that

might
involve
tyrosine
kinases
or
Ras
members
activated
by
quimiokines
(5).

Upon
PI3K
activation
PtdIns(3,4,5)P3
is
generated
that
can
be

dephosphorylated
by
the
action
of
SHIP
phosphatases
to
yield
PtdIns(3,4)P2.
Both

PtdIns(3,4,5)P3
and
PtdIns(3,4)P2
recruit
proteins
with
plectstrin
homology
(PH)

domains
to
cell
membranes,
usually
the
plasma
membrane.
Recruited
proteins
can

then
be
activated
to
initiate
signaling
cascades.
These
proteins
can
vary,
as
PH

domains
have
certain
selectivity
concerning
their
interaction
strength
with
these

phosphoinositides.
In
lymphocytes
they
include
serine
threonine
kinases
like
the

phosphoinositide-­-dependent
kinase
1
(PDK1)
or
Akt
(PKB),
Tec
family
tyrosine

kinases
like
Itk
(in
T
lymphocytes)
or
Btk
(in
B
lymphocytes),
adaptor
proteins
like

GAB2,
and
small
GTPase
positive
(Guanine
nucleotide
exchange
factors
(GEF)
like

Vav)
or
negative
(GTPase
activating
factors
(GAP))
regulatory
proteins.

4.a.
Targets
of
PI3K:
PDK1,
Akt
and
mTOR.

In
many
cell
types
and
in
lymphocytes
too,
the
serine
threonine
kinase
Akt

plays
a
key
mediator
role
in
PI3K
activated
signals
(3,18,27-­-29).
Membrane-­-
recruited
Akt
is
activated
upon
phosphorylation
in
residue
Thr308
by
PDK1
that
is

also
recruited
through
PH
domains
and
activated
by
tyrosine
kinases
of
the
src-­-
family
kinases
like
Lck
(30).
Akt
P-­-Thr308
then
phosphorylates
substrates
like

Caspase
9,
BAD
or
IKKa
to
prevent
apoptosis,
GSK3ß
to
favour
proliferation,
and

the
mTORC1
complex
(the
Rapamycin
sensitive
complex
of
mechanistic
target
of

Rapamycin
(mTOR)
containing
Raptor)
or
its
negative
regulator
TSC1/2
to
favour

protein
synthesis
and
cell
growth.
Akt
is
fully
activated
by
phosphorylation
of

Ser423
by
kinases
generically
termed
PDK2.
The
main
PDK2
is
mTORC2,
the

Rapamycin-­-insensitive
complex
of
mTOR
containing
Rictor.
mTORC2
activation
is

98