Page 96 - 80_01

José
María
Rojo,
Pilar
Portolés

PI3Kinase
inhibitors
are
specific
for
more
than
one
isoform,
or
that
PI3K
inhibitors

primarily
aimed
at
inhibiting
class
I
PI3Kinases
significantly
inhibit
PIKK
like

mTOR
or
DNA-­-PK
(9).

3.
CLASS
IA
AND
CLASS
IB
PI3KINASES:
STRUCTURE
AND
ACTIVATION,

CONTROL
BY
PHOSPHATASES

Class
I
PI3Kinases
are
heterodimers
formed
by
one
catalytic
of
110
kDa
and

one
regulatory
subunit
of
variable
size
(Figure
2).
According
to
the
nature
of
the

regulatory
subunit
they
bind
to,
and
the
mode
they
are
classically
activated,
class
I

PI3Kinases
are
further
divided
into
class
IA
(Figure
2A
and
B)
and
class
IB
(Figure

2C).
The
former
(catalytic
subunits
p110a,
p110ß,
and
p110d)
bind
to
any
of
five

regulatory
subunit
isoforms
(p85a,
p55a,
p50a,
p85ß,
and
p55?)
all
possessing

two
SH2
domains
separated
by
an
alpha-­-helix
inter-­-SH2
domain
(iSH2)
that

interacts
with
catalytic
subunits;
Class
IA
catalytic
subunits
are
characteristically

activated
through
tyrosine
kinase-­-dependent
mechanisms.
Phosphorylation
of
the

Tyr
residues
of
Tyr-­-x-­-x-­-Met
is
the
initial
step
inducing
binding
of
SH2
domains
that

are
conserved
in
all
class
IA
regulatory
isoforms.
The
p85,
but
not
the
p50
or
p55

regulatory
isoforms
have
additional
SH3,
proline
rich
and
BCR-­-homology
GTPase

activation
domain
(BH-­-domain)
that
might
mediate
binding
to
small
G
proteins
of

the
Rho/Rac/cdc42
family.

On
the
other
hand,
class
IB
catalytic
subunit
p110?
binds
to
regulatory

subunits
p101
and
p87
(Figure
2C).
Subunit
p101
is
the
main
subunit
in
most

tissues;
p101
and
p85
differentially
help
in
G
protein–coupled
receptor
(GPCR)-­-
induced
PI3K
activation,
such
that
interaction
of
p101
with
the
Gß?
chains
is

strong
and
efficient
in
recruitment
of
p110?
to
membranes
whereas
p87
interacts

weakly
with
Gß?
chains
and
recruitment
of
p110?
needs
additional
interactions

with
Ras-­-GTP
(10).

Class
I
catalytic
subunits
are
structured
in
domains
with
distinct
function

(Figure
2A-­-C);
these
include
a
N-­-terminal
adaptor
binding
domain
(ABD)
that

constitutively
bind
regulatory
subunits,
a
Ras-­-binding
domain,
the
C2
and
helical

domains
that
regulate
the
association
with
regulatory
subunits,
and
one
C-­-terminal

kinase
domain.
Interactions
of
class
IA
p110a
and
the
iSH2
and
amino-­-terminal

domain
of
regulatory
p85a
subunits
have
been
determined
in
detail
(11,12).
In
the

steady
state,
the
p110-­-p85
heterodimers
have
low
enzymatic
activity;
however,

binding
of
SH2
domains
to
phosphorylated
peptides
disrupt
the
inhibitory

interactions
including
the
one
between
the
p85
nSH2
domain
and
the
helical

domain
of
p110a
(12,13).
Given
the
inhibitory
nature
of
the
regulatory
subunits,
it

should
be
noted
that
there
are
clear
differences
among
catalytic
isoforms

concerning
their
interaction
strength
with
regulatory
subunits
(14).
In
addition,
at

94