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Integrin linked kinase (ILK) regulates podosome maturation and stability in dendritic cells.
[wiskott-aldrich syndrome]
Podosomes
are
integrin-based
adhesions
fundamental
for
stabilisation
of
the
leading
lamellae
in
migrating
dendritic
cells
(
DCs
)
and
for
extracellular
matrix
(
ECM
)
degradation
.
We
have
previously
shown
that
soluble
factors
and
chemokines
such
as
SDF
1
-
a
trigger
podosome
initiation
whereas
integrin
ligands
promote
podosome
maturation
and
stability
in
DCs
.
The
exact
intracellular
signalling
pathways
that
regulate
the
sequential
organisation
of
podosomal
components
in
response
to
extracellular
cues
remain
largely
undetermined
.
The
Wiskott
Aldrich
Syndrome
Protein
(
WASP
)
mediates
actin
polymerisation
and
the
initial
recruitment
of
integrins
and
associated
proteins
in
a
circular
configuration
surrounding
the
core
of
filamentous
actin
(
F-
actin
)
during
podosome
initiation
.
We
have
now
identified
integrin
linked
kinase
(
ILK
)
surrounding
the
podosomal
actin
core
.
We
report
that
DC
polarisation
in
response
to
chemokines
and
the
assembly
of
actin
cores
during
podosome
initiation
require
PI
3
K
-
dependent
clustering
of
the
Wiskott
Aldrich
Syndrome
Protein
(
WASP
)
in
puncta
independently
of
ILK
.
ILK
is
essential
for
the
clustering
of
integrins
and
associated
proteins
leading
to
podosome
maturation
and
stability
that
are
required
for
degradation
of
the
subjacent
extracellular
matrix
and
the
invasive
motility
of
DCs
across
connective
tissue
barriers
.
We
conclude
that
WASP
regulates
DCs
polarisation
for
migration
and
initiation
of
actin
polymerisation
downstream
of
PI
3
K
in
nascent
podosomes
.
Subsequently
,
ILK
mediates
the
accumulation
of
integrin-associated
proteins
during
podosome
maturation
and
stability
for
efficient
degradation
of
the
subjacent
ECM
during
the
invasive
migration
of
DCs
.