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Crk adaptors negatively regulate actin polymerization in pedestals formed by enteropathogenic Escherichia coli (EPEC) by binding to Tir effector.
[wiskott-aldrich syndrome]
Infections
by
enteropathogenic
Escherichia
coli
(
EPEC
)
cause
diarrhea
linked
to
high
infant
mortality
in
developing
countries
.
EPEC
adheres
to
epithelial
cells
and
induces
the
formation
of
actin
pedestals
.
Actin
polymerization
is
driven
fundamentally
through
signaling
mediated
by
Tir
bacterial
effector
protein
,
which
inserts
in
the
plasma
membrane
of
the
infected
cell
.
Tir
binds
Nck
adaptor
proteins
,
which
in
turn
recruit
and
activate
N-WASP
,
a
ubiquitous
member
of
the
Wiskott-
Aldrich
syndrome
family
of
proteins
.
N-WASP
activates
the
Arp
2
/
3
complex
to
promote
actin
polymerization
.
Other
proteins
aside
from
components
of
the
Tir-
Nck-
N-WASP
pathway
are
recruited
to
the
pedestals
but
their
functions
are
unknown
.
Here
we
investigate
the
function
of
two
alternatively
spliced
isoforms
of
Crk
adaptors
(
CrkI
/
II
)
and
the
paralog
protein
CrkL
during
pedestal
formation
by
EPEC
.
We
found
that
the
Crk
isoforms
act
as
redundant
inhibitors
of
pedestal
formation
.
The
SH
2
domain
of
CrkII
and
CrkL
binds
to
phosphorylated
tyrosine
474
of
Tir
and
competes
with
Nck
to
bind
Tir
,
preventing
its
recruitment
to
pedestals
and
thereby
inhibiting
actin
polymerization
.
EPEC
infection
induces
phosphorylation
of
the
major
regulatory
tyrosine
in
CrkII
and
CrkL
,
possibly
preventing
the
SH
2
domain
of
these
proteins
from
interacting
with
Tir
.
Phosphorylated
CrkII
and
CrkL
proteins
localize
specifically
to
the
plasma
membrane
in
contact
with
EPEC
.
Our
study
uncovers
a
novel
role
for
Crk
adaptors
at
pedestals
,
opening
a
new
perspective
in
how
these
oncoproteins
regulate
actin
polymerization
.
Diseases
Validation
Diseases presenting
"diarrhea"
symptom
acute rheumatic fever
adrenomyeloneuropathy
benign recurrent intrahepatic cholestasis
cutaneous mastocytosis
esophageal carcinoma
fabry disease
familial mediterranean fever
hirschsprung disease
kabuki syndrome
legionellosis
lymphangioleiomyomatosis
omenn syndrome
pendred syndrome
phenylketonuria
primary effusion lymphoma
primary hyperoxaluria type 1
scrub typhus
systemic capillary leak syndrome
triple a syndrome
typhoid
von hippel-lindau disease
waldenström macroglobulinemia
wiskott-aldrich syndrome
This symptom has already been validated