PLoS ONE,
Journal Year:
2024,
Volume and Issue:
19(7), P. e0305121 - e0305121
Published: July 31, 2024
Neurofibromatosis
type
2
is
a
genetic
disorder
that
results
in
the
formation
and
progressive
growth
of
schwannomas,
ependymomas,
and/or
meningiomas.
The
NF2
gene
encodes
Merlin
protein,
which
links
cell
cortical
elements
to
actin
cytoskeleton
regulates
number
key
enzymes
including
Group
I
p21-activated
kinases
(PAKs),
Hippo-pathway
kinase
LATS,
mTORC.
While
PAK1
PAK2
directly
bind
transmit
proliferation
survival
signals
when
mutated
or
absent,
inhibition
1
PAKs
alone
has
not
proven
sufficient
completely
stop
NF2-deficient
meningiomas
schwannomas
vivo
,
suggesting
need
for
second
pathway
inhibitor.
As
Hippo
also
activated
cells,
several
inhibitors
have
recently
been
developed
form
YAP-TEAD
binding
inhibitors.
These
prevent
activation
pro-proliferation
anti-apoptotic
effectors.
In
this
study,
we
show
PAK
slows
while
TEAD
promotes
apoptotic
death.
Finally,
demonstrate
efficacy
inhibitor
combinations
Schwannoma
lines.
Cancers,
Journal Year:
2023,
Volume and Issue:
15(20), P. 4956 - 4956
Published: Oct. 12, 2023
Yes-associated
Protein
(YAP)
and
its
paralog
Transcriptional
Coactivator
with
PDZ-binding
Motif
(TAZ)
are
major
regulators
of
gene
transcription/expression,
primarily
controlled
by
the
Hippo
pathway
cytoskeleton.
Integrating
an
array
chemical
mechanical
signals,
they
impact
growth,
differentiation,
regeneration.
Accordingly,
also
play
key
roles
in
tumorigenesis
metastasis
formation.
Their
activity
is
regulated
their
localization,
that
is,
pathway-
and/or
cytoskeleton-controlled
cytosolic
or
nuclear
sequestration.
While
many
details
such
prevailing
retention
models
have
been
elucidated,
much
less
known
about
actual
traffic:
import
export.
Although
size
not
far
from
cutoff
for
passive
diffusion
through
pore
complex
(NPC),
do
contain
any
classic
localization
(NLS)
export
signal
(NES),
evidence
has
accumulating
shuttling
involves
mediated
thus
regulatable/targetable
processes.
The
aim
this
review
to
summarize
emerging
information/concepts
nucleocytoplasmic
shuttling,
encompassing
relevant
structural
requirements
(NLS,
NES),
transport
receptors
(NTRs,
karyophererins),
NPC
components,
along
potential
mechanisms
regulation.
dissecting
vs.
often
challenging,
picture
suggests
YAP/TAZ
shuttles
across
via
multiple,
non-exclusive,
mechanisms,
constituting
a
novel
intriguing
facet
biology.
Trends in cancer,
Journal Year:
2023,
Volume and Issue:
10(3), P. 185 - 195
Published: Dec. 8, 2023
Colorectal
cancer
(CRC)
is
traditionally
considered
to
be
a
genetically
driven
disease.
However,
nongenetic
plasticity
has
recently
emerged
as
major
driver
of
tumour
initiation,
metastasis,
and
therapy
response
in
CRC.
Central
these
processes
discovered
cell
type,
the
revival
colonic
stem
(revCSC).
In
contrast
traditional
proliferative
CSCs
(proCSCs),
revCSCs
prioritise
survival
over
propagation.
play
an
essential
role
primary
formation,
metastatic
dissemination,
chemoresistance.
Current
evidence
suggests
that
CRC
tumours
leverage
intestinal
both
proliferate
(via
proCSCs)
when
unchallenged
survive
revCSCs)
cell-extrinsic
pressures.
Although
likely
represent
source
therapeutic
failure
CRC,
our
increasing
knowledge
this
important
fate
provides
novel
opportunities
for
intervention.
Journal of Biological Chemistry,
Journal Year:
2024,
Volume and Issue:
300(6), P. 107311 - 107311
Published: April 22, 2024
The
Hippo
signaling
pathway
plays
an
essential
role
in
organ
size
control
and
tumorigenesis.
Loss
of
signal
hyper-activation
the
downstream
oncogenic
YAP
are
commonly
observed
various
types
cancers.
We
previously
identified
STRN3-containing
PP2A
phosphatase
as
a
negative
regulator
MST1/2
kinases
(i.e.,
Hippo)
gastric
cancer
(GC),
opening
possibility
selectively
targeting
PP2Aa-STRN3-MST1/2
axis
to
recover
against
cancer.
Here,
we
further
discovered
1)
disulfiram
(DSF),
FDA-approved
drug,
which
can
similarly
block
binding
STRN3
core
enzyme
2)
CX-6258
(CX),
chemical
inhibitor,
that
disrupt
interaction
between
MST1/2,
both
allowing
reactivation
activity
inhibit
GC.
More
importantly,
found
these
two
compounds,
via
kinase-dependent
manner,
DNA
repair
sensitize
GC
towards
chemotherapy.
In
addition,
thiram,
structural
analog
DSF,
function
cell
proliferation
or
enhance
chemotherapy
sensitivity.
Interestingly,
inclusion
copper
ion
enhanced
such
effects
DSF
thiram
on
treatment.
Overall,
this
work
demonstrated
pharmacological
by
drug
compounds
potently
for
tumor
Pharmaceuticals,
Journal Year:
2023,
Volume and Issue:
16(4), P. 583 - 583
Published: April 13, 2023
The
Hippo
signaling
pathway
is
a
highly
conserved
that
plays
important
roles
in
the
regulation
of
cell
proliferation
and
apoptosis.
Transcription
factors
TEAD1-4
transcriptional
coregulators
YAP/TAZ
are
downstream
effectors
can
modulate
biology.
Dysregulation
this
implicated
tumorigenesis
acquired
resistance
to
therapies.
emerging
importance
YAP/TAZ-TEAD
interaction
cancer
development
makes
it
potential
therapeutic
target.
In
past
decade,
disrupting
as
an
effective
approach
for
treatment
has
achieved
great
progress.
This
followed
trajectory
wherein
peptidomimetic
YAP–TEAD
protein-protein
disruptors
(PPIDs)
were
first
designed,
by
discovery
allosteric
small
molecule
PPIDs,
currently,
direct
PPIDs.
YAP
TEAD
form
three
interfaces.
Interfaces
2
3
amenable
PPID
design.
One
(IAG933)
targets
interface
entered
clinical
trial
2021.
However,
general,
strategically
designing
molecules
PPIDs
targeting
interfaces
been
challenging
compared
with
inhibitor
development.
review
focuses
on
surface
discusses
challenges
opportunities
developing
potent
inhibitors
cancer.
