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The open conformation of WASP regulates its nuclear localization and gene transcription in myeloid cells.
[wiskott-aldrich syndrome]
Mutations
in
the
gene
encoding
the
Wiskott-
Aldrich
syndrome
protein
(
WASP
)
are
responsible
for
Wiskott-
Aldrich
syndrome
and
WASP
is
a
major
actin
regulator
in
the
cytoplasm
.
Although
rare
gain-of-function
mutations
in
the
WASP
gene
are
known
to
result
in
X-
linked
neutropenia
(
XLN
)
,
the
molecular
pathogenesis
of
XLN
is
not
fully
understood
.
In
this
study
,
we
showed
that
all
reported
constitutively
activating
mutants
(
L
270
P
,
S
272
P
and
I
294
T
)
of
WASP
were
hyperphosphorylated
by
Src
family
tyrosine
kinases
and
demonstrated
higher
actin
polymerization
activities
compared
with
wild-
type
(
WT
)
WASP
.
Further
analysis
showed
a
tendency
of
activating
WASP
mutants
to
localize
in
the
nucleus
compared
with
WT
or
the
Y
291
F
mutant
of
WASP
.
In
addition
,
we
found
that
WASP
could
form
a
complex
with
nuclear
RNA-binding
protein
,
54
kDa
(
p
54
nrb
)
and
RNA
polymerase
II
(
RNAP
II
)
.
ChIP
assays
revealed
that
WASP
associated
with
DNA
,
although
the
affinity
was
relatively
weaker
than
RNAP
II
.
To
determine
whether
gene
transcription
was
affected
by
WASP
mutation
in
myeloid
cells
,
we
performed
microarray
analysis
and
found
different
expression
profiles
between
WT
and
L
270
P
WASP-transfected
K
562
cells
.
Among
the
genes
affected
,
granulocyte
colony-stimulating
factor
receptor
,
Runx
1
,
and
protein
tyrosine
phosphatase
receptor
c
were
included
.
ChIP
on
chip
analysis
of
genomic
DNA
showed
WT
and
L
270
P
WASP
had
a
highly
similar
DNA-binding
pattern
but
differed
in
binding
affinity
at
the
same
locus
.
Therefore
,
our
results
suggest
that
the
open
conformation
of
WASP
regulates
its
nuclear
localization
and
plays
requisite
roles
in
regulating
gene
transcription
that
would
contribute
to
the
outcome
in
the
nucleus
of
myeloid
cells
.
Diseases
Validation
Diseases presenting
"rare gain-of-function mutations"
symptom
wiskott-aldrich syndrome
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