Page 95 - 80_01

Class
I
phosphoinositide
3-­-kinases
in
immunity…

Figure
1.-­-
A
summary
of
phosphoinositide
phosphorylation/dephosphorylation
steps
in
the
cell

membrane
is
shown.
These
phosphoinositides
recruit
proteins
endowed
with
phosphorylated

inositol
lipid-­-binding
protein
domains
that
serve
to
cell
signaling.
Phosphorylation
and

dephosphorylation
steps
are
indicated
by
red
and
blue
arrows,
respectively;
steps
where
PI3K

kinases
intervene
are
shadowed
in
red;
Inositol
phosphate
phosphatases
are
shadowed
in
blue;

effector
protein
domains
binding
to
different
phosphorylated
inositol
lipids
are
in
yellow.

Abbreviations:
FAB1:
PtdIns(3)P
5-­-kinase;
FYVE:
Fab
1
YOTB
Vac
1
and
EEA1
domain;
INPP4:

Inositol
polyphosphate
4-­-phosphatase;
INPP5:
Inositol
polyphosphate
5-­-phosphatase;
MTM:

Myotubularin;
PH:
Plecstrin
homology
domain;
PI3K:
Phosphoinositide-­-3
kinase;
PLC:

Phospholipase
C;
PROPPIN:
ß-­-propeller
that
bind
phosphoinositide
species
domain;
PtdInsP:

Phosphorylated
inositol
lipids;
PTEN:
Phosphatase
and
Tensin
Homologue;
PX:
Phox
homology

domain;
SHIP:
SH2
domain-­-containing
inositol
5’-­-phosphatase.

2.
CLASS
I,
II,
III
PI3K,
AND
PI3K-­-LIKE
KINASES

Of
interest
to
the
development
and
effect
of
PI3K-­-specific
inhibitors,
PI3Ks

have
sequence
similarity
with
a
number
of
other
related
serine
and
threonine

protein
kinases
collectively
known
as
“PI3K-­-like
protein
kinases”,
or
PIKK.
These

PIKK
play
a
role
in
the
cellular
response
to
stresses
like
DNA
damage
or
replication

block,
mRNA
splicing
errors
and
nutrient
deprivation.
Importantly,
PIKK
include

one
of
the
main
downstream
effectors
of
class
I
PI3K
activation
in
lymphocytes,

namely
the
mechanistic
target
of
the
immunosuppressant
Rapamycin
(mTOR),
but

also
the
ataxia-­-telangiectasia
mutated
protein
(ATM),
the
ataxia-­-
and
Rad3-­-related

protein
(ATR),
and
the
DNA-­-dependent
protein
kinase
catalytic
subunit
(DNA-­-
PKcs)
(6,7).
DNA-­-PK
is
required
for
the
activation
of
the
non-­-homologous
end-­-
joining
pathway
to
repair
double-­-strand
DNA
breaks
induced
by
ionizing
radiation.

Furthermore,
DNA-­-PK
activates
protein
kinase
B
(Akt),
another
primer
target
of

class
I
PI3K,
and
is
particularly
important
to
lymphocyte
biology
as
its
mutation
is

a
cause
for
severe
combined
immunodeficiency
(8).
Structural
homology
among

PI3K
isoforms,
or
between
PI3K
and
PIKK
(6)
has
the
consequence
that
frequently,

93