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Laminin-5-deficient human keratinocytes: defective adhesion results in a saltatory and inefficient mode of migration.
[junctional epidermolysis bullosa]
Laminin-
5
is
a
major
adhesion
protein
of
the
skin
basement
membrane
and
crucially
involved
in
integrin-mediated
cell
substrate
attachment
of
keratinocytes
,
which
is
important
for
hemidesmosomal
anchorage
as
well
as
for
keratinocyte
migration
during
epidermal
wound
healing
.
To
investigate
its
role
in
keratinocyte
migration
,
we
analyzed
laminin-
5
-
deficient
cells
of
patients
with
a
lethal
variant
of
junctional
epidermolysis
bullosa
.
Normal
migrating
keratinocytes
adopted
monopolar
morphology
with
a
distinct
front
lamella
and
employed
a
continuous
mode
of
translocation
.
In
contrast
,
laminin-
5
-
deficient
cells
assumed
a
stretched
bipolar
shape
with
two
lamella
regions
and
migrated
in
a
discontinuous
,
saltatory
manner
characterized
by
significantly
decreased
directional
persistence
and
reduced
migration
velocity
.
The
distinct
morphology
as
well
as
the
migratory
phenotype
apparently
resulted
from
a
defect
in
the
formation
of
cell
substrate
adhesions
that
were
completely
missing
in
the
cell
body
and
less
stable
in
the
lamella
regions
.
Accordingly
in
normal
keratinocytes
,
a
bipolar
shape
and
a
saltatory
migration
mode
were
inducible
by
blocking
laminin-
5
-
mediated
substrate
adhesion
.
Our
findings
clearly
point
to
an
essential
role
of
laminin-
5
in
forming
dynamic
cell
substrate
adhesion
during
migration
of
epidermal
keratinocytes
and
provide
an
explanation
for
the
cellular
mechanisms
that
underlie
the
lethal
form
of
junctional
epidermolysis
bullosa
.