Pharmaceuticals,
Год журнала:
2017,
Номер
10(1), С. 11 - 11
Опубликована: Янв. 20, 2017
The
history
of
protein
kinase
CK2
is
crowded
with
paradoxes
and
unanticipated
findings.
Named
after
a
(casein)
that
not
among
its
physiological
substrates,
remained
in
search
targets
for
more
than
two
decades
discovery
1954,
but
it
later
came
to
be
one
the
most
pleiotropic
kinases.
Being
active
absence
phosphorylation
and/or
specific
stimuli,
looks
unsuitable
participate
signaling
cascades,
“lateral”
implication
variety
pathways
now
soundly
documented.
At
variance
many
“onco-kinases”,
constitutively
active,
no
oncogenic
mutant
known;
still
high
activity
correlates
neoplasia.
Its
pleiotropy
essential
role
may
cast
doubts
on
actual
“druggability”
CK2;
however,
inhibitor
Phase
II
clinical
trials
treatment
cancer,
cell
clones
viable
are
providing
information
about
mechanism
by
which
cancer
becomes
addicted
levels.
A
phosphoproteomics
analysis
these
null
cells
suggests
less
pronounced
expected
supports
idea
phosphoproteome
generated
this
flexible
rigidly
pre-determined.
Proceedings of the National Academy of Sciences,
Год журнала:
2014,
Номер
111(15), С. 5520 - 5525
Опубликована: Март 26, 2014
The
family
with
sequence
similarity
20,
member
C
(Fam20C)
has
recently
been
identified
as
the
Golgi
casein
kinase.
Fam20C
phosphorylates
secreted
proteins
on
Ser-x-Glu/pSer
motifs
and
loss-of-function
mutations
in
kinase
cause
Raine
syndrome,
an
often-fatal
osteosclerotic
bone
dysplasia.
is
potentially
upstream
regulator
of
phosphate-regulating
hormone
fibroblast
growth
factor
23
(FGF23),
because
humans
FAM20C
KO
mice
develop
hypophosphatemia
due
to
increase
full-length,
biologically
active
FGF23.
However,
mechanism
by
which
regulates
FGF23
unknown.
Here
we
show
that
directly
Ser(180),
within
R(176)XXR(179)/S(180)AE
subtilisin-like
proprotein
convertase
motif.
This
phosphorylation
event
inhibits
O-glycosylation
polypeptide
N-acetylgalactosaminyltransferase
3
(GalNAc-T3),
promotes
cleavage
inactivation
furin.
Collectively,
our
results
provide
a
molecular
dynamically
regulated
phosphorylation,
glycosylation,
proteolysis.
Furthermore,
findings
suggest
cross-talk
between
secretory
pathway
may
be
important
are
regulated.
Scientific Reports,
Год журнала:
2020,
Номер
10(1)
Опубликована: Окт. 9, 2020
Abstract
The
Spike
protein
of
the
novel
coronavirus
SARS-CoV2
contains
an
insertion
680
S
PRRA
R↓SV
687
forming
a
cleavage
motif
RxxR
for
furin-like
enzymes
at
boundary
S1/S2
subunits.
Cleavage
is
important
efficient
viral
entry
into
target
cells.
absent
in
other
CoV-s
same
clade,
including
SARS-CoV1
that
caused
2003
outbreak.
However,
analogous
was
present
more
distant
Middle
East
Respiratory
Syndrome
MERS-CoV.
We
show
crucial
third
arginine
left
middle
position,
comprising
R
xR
required
furin
recognition
vitro,
while
general
common
with
MERS-CoV
not
sufficient
cleavage.
Further,
we
describe
surprising
finding
two
serines
edges
insert
PRRAR↓
V
can
be
efficiently
phosphorylated
by
proline-directed
and
basophilic
kinases.
Both
phosphorylations
switch
off
furin’s
ability
to
cleave
site.
Although
phospho-regulation
secreted
proteins
still
poorly
understood,
further
studies,
supported
recent
report
ten
vivo
sites
SARS-CoV2,
could
potentially
uncover
regulatory
mechanisms
SARS-CoV2.
Biochemical Journal,
Год журнала:
2014,
Номер
460(2), С. 141 - 156
Опубликована: Май 13, 2014
The
term
‘casein
kinase’
has
been
widely
used
for
decades
to
denote
protein
kinases
sharing
the
ability
readily
phosphorylate
casein
in
vitro.
These
fall
into
three
main
classes:
two
of
them,
later
renamed
as
CK1
(casein
kinase
1,
also
known
CKI)
and
CK2
(also
CKII),
are
pleiotropic
members
kinome
functionally
unrelated
casein,
whereas
G-CK,
or
genuine
kinase,
responsible
phosphorylation
Golgi
apparatus
lactating
mammary
gland,
only
identified
recently
with
Fam20C
[family
sequence
similarity
20C;
DMP-4
(dentin
matrix
protein-4)],
a
member
four-jointed
family
atypical
kinases,
being
many
secreted
proteins.
In
hindsight,
therefore,
is
misleading
every
instance;
case
CK2,
it
because
not
physiological
substrate,
G-CK/Fam20C/DMP-4,
just
one
out
plethora
its
targets,
rather
marginal
at
that.
Strikingly,
altogether,
albeit
representing
minimal
proportion
whole
kinome,
appear
be
generation
up
40–50%
non-redundant
phosphosites
currently
retrieved
human
phosphopeptides
database.
present
review,
short
historical
explanation
will
provided
accounting
usage
same
misnomer
classes
together
an
update
our
current
knowledge
these
enzymes,
while
playing
very
distinct
biological
roles.
Although
numerous
extracellular
phosphoproteins
have
been
identified,
the
protein
kinases
within
secretory
pathway
only
recently
discovered,
and
their
regulation
is
virtually
unexplored.
Fam20C
physiological
Golgi
casein
kinase,
which
phosphorylates
many
secreted
proteins
critical
for
proper
biomineralization.
Fam20A,
a
paralog,
essential
enamel
formation,
but
biochemical
function
of
Fam20A
unknown.
Here
we
show
that
potentiates
kinase
activity
promotes
phosphorylation
matrix
in
vitro
cells.
Mechanistically,
pseudokinase
forms
functional
complex
with
Fam20C,
this
enhances
pathway.
Our
findings
shed
light
on
molecular
mechanism
by
collaborate
to
control
provide
first
insight
into
phosphorylation.
Proceedings of the National Academy of Sciences,
Год журнала:
2014,
Номер
111(44), С. 15723 - 15728
Опубликована: Окт. 20, 2014
Significance
Proteoglycans
are
cellular
proteins
modified
with
long
chains
of
repeating
sugar
residues
connected
to
serine
within
the
protein
core
by
a
short
tetrasaccharide
linker.
perform
critical
functions
such
as
formation
extracellular
matrix,
binding
diverse
array
molecules,
and
regulation
cell
motility,
adhesion,
cell–cell
communication.
We
show
here
that
family
sequence
similarity
20,
member
B
(Fam20B)
is
xylose
kinase
phosphorylates
residue
proteoglycan
linkage.
Xylose
phosphorylation
dramatically
stimulates
activity
galactosyltransferase
II
(GalT-II,
B3GalT6),
an
enzyme
adds
galactose
growing
Cells
lacking
Fam20B
cannot
extend
linkage
thus
have
immature
nonfunctional
proteoglycan,
phenotype
remarkably
similar
Ehlers-Danlos
syndrome
caused
inactivating
GalT-II
mutations.
Screening
gene
function
in
vivo
is
a
powerful
approach
to
discover
novel
drug
targets.
We
present
high-throughput
screening
(HTS)
data
for
3
762
distinct
global
knockout
(KO)
mouse
lines
with
viable
adult
homozygous
mice
generated
using
either
gene-trap
or
homologous
recombination
technologies.
Bone
mass
was
determined
from
DEXA
scans
of
male
and
female
at
14
weeks
age
by
microCT
analyses
bones
16
age.
Wild-type
(WT)
cagemates/littermates
were
examined
each
KO.
Lethality
observed
an
additional
850
KO
lines.
Since
primary
HTS
are
susceptible
false
positive
findings,
cohorts
intriguing
bone
examined.
Aging,
ovariectomy,
histomorphometry
strength
studies
performed
possible
non-skeletal
phenotypes
explored.
Together,
these
screens
identified
multiple
genes
affecting
mass:
23
previously
reported
(Calcr,
Cebpb,
Crtap,
Dcstamp,
Dkk1,
Duoxa2,
Enpp1,
Fgf23,
Kiss1/Kiss1r,
Kl
(Klotho),
Lrp5,
Mstn,
Neo1,
Npr2,
Ostm1,
Postn,
Sfrp4,
Slc30a5,
Slc39a13,
Sost,
Sumf1,
Src,
Wnt10b),
five
extensively
characterized
(Cldn18,
Fam20c,
Lrrk1,
Sgpl1,
Wnt16),
preliminary
characterization
(Agpat2,
Rassf5,
Slc10a7,
Slc26a7,
Slc30a10)
three
undisclosed
coding
potential
osteoporosis