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PTEN lipid phosphatase activity and proper subcellular localization are necessary and sufficient for down-regulating AKT phosphorylation in the nucleus in Cowden syndrome.
[cowden syndrome]
Germline
mutations
in
PTEN
are
associated
with
phosphatase
and
tensin
homolog
deleted
on
chromosome
10
(
PTEN
)
hamartoma
tumor
syndrome
including
Cowden
syndrome
(
CS
)
and
Cowden
-like
syndrome
(
CSL
)
that
predisposes
to
high
risks
of
benign
and
malignant
tumors
of
thyroid
and
breast
.
The
objective
of
the
study
was
to
analyze
the
subcellular
pattern
of
phosphorylated
(
P
)
-
AKT
expression
in
nonmedullary
thyroid
cancers
from
PTEN
hamartoma
tumor
syndrome
patients
and
to
investigate
whether
the
lack
of
PTEN
in
the
nucleus
and
/
or
lack
of
proper
PTEN
function
in
the
nucleus
affect
(
s
)
nuclear
AKT
activity
in
CS
patients
.
In
all
,
664
patients
with
CS
/
CSL
were
screened
for
PTEN
germline
mutations
and
nonmedullary
thyroid
cancers
.
Twenty
-
two
patients
who
have
both
pathogenic
PTEN
germline
mutations
and
nonmedullary
thyroid
cancers
were
selected
.
Thyroid
samples
from
these
patients
were
stained
for
PTEN
and
P-AKT
.
In
our
in
vitro
study
,
PTEN
was
knocked
down
or
overexpressed
in
both
thyroid
cancer
cells
and
breast
cancer
cells
,
and
nuclear
P-AKT
was
compared
with
the
control
.
Loss
of
PTEN
protein
was
found
in
thyroid
adenomas
and
carcinomas
from
all
22
(
100
%
)
PTEN
(
Mut
+
)
CS
/
CSL
patients
.
AKT
activation
was
identified
in
17
of
22
(
77
.
3
%
)
thyroid
adenoma
/
carcinoma
specimens
,
and
most
patients
(
63
.
7
%
)
have
activated
nuclear
AKT
.
Knockdown
of
PTEN
in
cells
containing
wild-
type
PTEN
enhanced
nuclear
P-AKT
,
whereas
expression
of
wild-
type
PTEN
,
but
not
phosphatase-dead
mutants
(
C
124
S
or
G
129
E
)
,
markedly
reduced
nuclear
P-AKT
in
PTEN
null
cells
.
We
also
showed
that
in
breast
cancer
but
not
thyroid
cancer
cells
,
PTEN
suppresses
nuclear
P-AKT
mainly
through
decreasing
P-AKT
nuclear
translocation
by
reducing
the
PIP
3
/
P-AKT
reservoir
in
the
cytoplasm
.
In
thyroid
cancer
cells
,
PTEN
suppresses
phosphorylation
of
AKT
already
resident
in
the
nucleus
.
PTEN
is
necessary
and
sufficient
for
inhibiting
AKT
activation
in
the
nucleus
through
its
intact
lipid
phosphatase
activity
and
proper
subcellular
localization
.
Diseases
Validation
Diseases presenting
"breast cancer"
symptom
acute rheumatic fever
aromatase deficiency
carcinoma of the gallbladder
child syndrome
cowden syndrome
cutaneous mastocytosis
dedifferentiated liposarcoma
esophageal squamous cell carcinoma
junctional epidermolysis bullosa
kindler syndrome
liposarcoma
lymphangioleiomyomatosis
oral submucous fibrosis
proteus syndrome
severe combined immunodeficiency
systemic capillary leak syndrome
von hippel-lindau disease
waldenström macroglobulinemia
werner syndrome
wiskott-aldrich syndrome
This symptom has already been validated