Page 102 - 80_01

José
María
Rojo,
Pilar
Portolés

pathway.
Another
link
is
the
observation
of
genomic
amplification
of
genes
coding

for
p110a
(PIK3CA)
or
its
target
Akt
(AKT)
in
several
types
of
cancer
(reviewed
in

(39-­-41)).

Although
all
Class
I
PI3K
subunits
have
oncogenic
potential
in
vitro;
the

seminal
work
by
Samuels
et
al.
(42),
later
confirmed
by
abundant
data,
shows
that

the
p110a
catalytic
isoform
but
not
other
isoforms
is
mutated
with
high
frequency

in
colorectal
and
other
different
human
cancer
cells
(39-­-41)).
These
gain-­-of

function
mutations
of
the
PIK3CA
gene
are
located
in
the
ABD
and
C2
domains
of

p110a,
but
particularly
in
the
helical
and
catalytic
domains.
The
enzymatic
activity

is
increased
by
different
mechanisms
including
altered
interaction
between
the

ABD
and
kinase
domains
of
p110a,
between
the
C2
domain
and
the
p85
iSH2

domain,
between
the
p85
nSH2
domain
and
the
helical
and
kinase
domains,
or

between
the
kinase
domain
and
the
cell
membrane,
increasing
accessibility
to

phospholipid
substrates.
Mutations
in
the
PIK3R1
gene
coding
the
p85a
regulatory

subunit
have
been
also
described
in
different
cancer
cells.
They
are
clustered
in
the

inter-­-SH2
domain
of
p85
that
contacts
the
C2
domain
of
catalytic
subunits
or
in
the

nSH2
domain
that
interacts
with
the
helical
domain
of
catalytic
subunits;
both

might
interfere
inhibitory
interactions
between
subunits.
Interestingly,
these

cancer-­-derived
gain-­-of-­-function
mutations
in
p85a
function
through
the
p110a,

but
not
other
PI3K
catalytic
subunits
(43).
Last,
the
p110a
isoform
of
PI3K
in

endothelium
plays
a
role
in
tumor
growth
through
its
contribution
to
tumor

angiogenesis
(44).

Gain-­-of-­-function
E1021K
mutations
of
p110d
have
been
recently
reported

in
a
residue
of
the
catalytic
domain
similar
to
those
found
in
p110a,
but
these

mutations
are
surprisingly
associated
with
IgM
hyperglobulinemia
and

immunodeficiency
rather
than
cancer
(45).
However,
p110d
can
favour
tumor

growth
by
several
documented
mechanisms.
Firstly,
in
some
human
ovarian
and

colorectal
tumors
PIK3CD
transcripts
can
be
alternatively
spliced
to
generate
a
37

kDa
protein
(p37d)
that
maintains
the
ABD
and
RBD
domains
of
p110d.
This

protein
can
enhance
the
proliferation
and
invasive
properties
of
transformed
cells

(46).
In
second
place,
p110d
activation
can
indirectly
inhibit
the
activity
of
the

PTEN
phosphatase
by
a
mechanism
involving
RhoA
(47).
Enhanced
p110d

expression
in
solid
tumors
in
fact
suppresses
PTEN,
contributing
to
cell
growth

and
–likely-­-
to
cancer
progression
of
malignancies
of
hematopoietic
and
non-­-
hematopoietic
origin
(48,49).
The
complexity
of
PI3Kinase
activity
regulation
is

further
highlighted
by
the
ability
of
p85a
to
bind
to
and
to
activate
PTEN
in

transformed
cell
lines
(reviewed
in
(50)).

100