Download Cellular Communicaüon

Cellular
Communica-on
Communication in the Work Place
•  Why is communication important in the
workplace community? What are some
reasons we need to communicate?
•  Why is it important to ensure proper
communication?
How could you communicate with someone…?
In the office next to you?
In the Provost’s office?
At Berkley?
One of our faculty visiting Japan?
To get information to everyone in your
department?
How does a breakdown in
communication impact the
functioning of the business?
•  What happens if one department continues to
hire without permission?
•  What happens if income is not brought in?
Cell
Communica,on
is
Important
for
Cells
What are some reasons cells need to communicate?
Why ensure proper communication?
Yeast
image
courtesy
of
Dr.
Maxim
Zakhartsev
and
Doris
Petroi,
Frog
image
courtesy
of
Carole
LaBonne
Types of Communication Needed
Between cells to generate
Within the
What
does
life
do?
It
makes
copies
of
itself.
It
creates
order.
subunits
A
T
length
DNA
“Structure”
Figure
17‐1
Molecular
Biology
of
the
Cell
(©
Garland
Science
2008)
System of Checks and Balances
Designed to coordinate proper
Cell cycle progression
Weiss lab studies the spatial and
temporal coordination of growth
and division
Errors
in
cell
communica,on
result
in
disease
Cancer…uncontrolled
cell
prolifera,on
and
migra,on.
Gene,c
muta,ons
of
proteins
that
regulate
signal
pathways
control
cell
division.
Hyperac,va,on
of
proteins
encouraging
division
or
not
enough
from
nega,ve
regula,on
(suppressor)
Abelson
tyrosine
kinase
signaling
has
been
implicated
in
leukemia
Diabetes
(abnormally
high
blood
sugar
levels)
occur
as
a
result
of
errors
in
the
levels
of
insulin
produc,on,
a
failure
of
insulin
receptor
signaling
or
components
of
its
relay
pathway.
How do cells communicate?
Signal
pathways
allow
communica,on
across
barriers
Figure
10‐1
Molecular
Biology
of
the
Cell
(©
Garland
Science
2008)
Signal
pathways
allow
amplifica,on
of
the
signal
Responses
to
signaling
molecule
vary
based
on
receptor
type
and
cell
type
Different
receptors
Same
receptor,
Different
Cell
Type
SIGNAL
INTEGRATION
* NOT
SHOWN
HERE
ARE
INHIBITORY
SIGNALS
Cell-to-cell communication is necessary because…
• Transfers
the
signal
from
the
membrane
to
machinery
elici-ng
response
• 
Amplifies
the
signal…a
small
ini-al
s-mulus
may
be
enhanced
• 
Single
signal
may
ac-vate
mul-ple
targets
• 
Allows
several
levels
for
integra-on/regula-on
of
signals
Cell
Communica-on
Cell signaling pathways provide cells with adaptability
to changing environmental conditions and cellular demands.
Cell-to-cell communication is necessary for disease
prevention and regulating complex behaviors
input
Stimulus, signal,
Target
integration
output
response
How is signaling between cells
accomplished?
In
response
to
s,mulus,
the
ini-a-ng
cell
produces
signaling
molecule
(i.e.
an
ac,vated
protein,
small
pep,des,
amino
acids,
nucleo,des,
steroids,
lipids,
and
gases)
*1
Recipient
cell
needs
receptor
(whether
on
cell
surface
or
internal
protein)
Variables influencing signaling: Distance
*1
Specificity:
Neighbors
w/
receptors
Time**:
Variable
Direct
contact
All
distances
Fast
Slower
(diffusion)
**lasting on the order of milliseconds in the case of ion flux, but some can take even days (as is the case with gene expression), to complete.
Variables influencing signaling: Localization of
signal receptors
*1
• 
Cell-surface receptors: Enzyme linked
receptors, G-protein linked receptors,
and ion-channel-linked receptor
• 
Receptors are found intracellularly and
upon ligand binding migrate to the
nucleus where the ligand-receptor
complex directly affects gene
transcription.
Variables influencing signaling: Signal Type
*2
Methods
of
transmiang
signal
within
the
cell
•  conforma,onal
changes
•  gene
regula,on
•  protein
modifica,on
•  genera,on
of
2nd
messenger
•  amplifica,on
of
signal
•  protein
degrada,on
•  change
in
localiza,on
•  protein
binding
(adapters)
•  gradient
differences
Conforma,on
changes
•  Ligand binding induces a change in the shape
or conforma,on of the receptor
•  changes in conformation either result in the
activation of an enzymatic activity contained
within the receptor or expose a binding site for
other proteins/DNA/RNA within the cell.
Conformational change and gene
regulation
*DNA binding regulates gene expression
*1
Protein
modifica,ons
Many chemical modifications change binding properties of the protein
The two branches of the inositol
phospholipid pathway
Receptor
point
muta,on cause
active conformation even in the
absence of ligand-binding ("constitutively active").
*ligand
induces
conforma,onal
change
in
receptor
that
causes
dissocia,on
of
GDP
and
associa,on
of
GTP
with
trimeric
G‐protein
α
subunit
*1
Protein
degrada,on
In Notch-mediated
signaling, activation of
Notch can cause the
Notch protein to be
altered by a protease. Gradient
signaling
Some signaling transduction pathways respond
differently depending on the amount of
signaling received by the cell. For instance the
hedgehog
protein activates different genes
depending on the amount of hedgehog protein
present.
Robert Holmgren’s lab studies
Mayo group studies hormone regulation
of the reproductive tissues such as
ovaries and pituitary
Act via 2nd
messengers
Receptors
with
kinase
ac,vity
Protein
modifica,on,
adaptor
proteins,
amplifica,on,
mul,ple
targets,
2nd
messengers,
…gene
regula,on
*2
Different
regions
of
the
protein
may
be
important
for
separate
pathways
*
*Other activated regions required to interact with adapter
proteins. Adapter proteins facilitate interactions with other proteins,
*2
Signal
needs
to
be
reversible…need
to
reset
once
s,mulus
ends
*2
Protein
degrada,on,
removal
of
modifica,ons,
conversion
of
2nd
messengers
*2
• Mul-ple
inputs
influencing
transduc-on
• Mul-ple
levels
that
can
be
regulated
Loops
and
feedback
Negative feedback: the response
negates the stimulus and shuts
the response off
Positive feedback: the response
reinforces the stimulus
Notch
Ac,va,on
Myt1
Ngn3
Endocrine
differen,a,on
Muta,ons
•  Some
muta,ons
influence
produc,on
of
a
protein
(stop
a
protein
from
being
made
at
all
or
cause
it
to
be
made
all
the
,me)
•  Other
muta,ons
influence
when
a
protein
is
ac,ve
versus
off
or
whether
the
protein
func,ons
to
perform
its
task
properly
3 Strike Rule
Mutations happen all the time but normally cell detects mutation
and repairs it. If it can’t repair there are pathways that tell the cell
to commit suicide
Most mutations occur in genes that regulate the following pathways:
cell division
programmed cell death
DNA repair
Oncogenes
•  Proto‐oncogene:
normal,
good
gene
•  Oncogene:
mutated
gene
leading
to
unregulated
cell
growth
(Usually
acquired
muta,ons
by
chromosome
rearrangement,
gene
duplica,on,
muta,on)
•  i.e.
Chronic
Myeloid
leukemia
(CML)
is
a
rearrangement
that
forms
BCR‐ABL
gene
•  (Tyrosine
Kinase)…treat
with
ima,nib/
dasa,nib
Tumor
Suppressors
•  Genes
that
normally
slow
down
cell
division,
DNA
repair
mistakes
and
tell
cells
when
to
undergo
programmed
cell
death
•  Inac,va,on
of
these
genes
results
in
unregulated
growth
and
cancer
•  i.e.
p53
(found
in
%50
of
human
cancer,
70%
colon
cancers,
30‐50%
breast
cancer,
50%
lung
cancers),
BRCA1,
BRCA2
P53
is
part
of
apopto,c
pathway
Inactivates p53
Drug
interac,ons
Molecules
that
bind
to
a
receptor
but
do
not
produce
an
effect
are
called
antagonists,
whereas
those
that
bind
to
a
receptor
and
induce
a
response
are
termed
agonists.
The
ligand
is
frequently
referred
to
as
a
hormone
or
drug.
Blood
glucose
Eat a meal
Stretch receptors
*Pax4 expression converts
Alpha cells to insulin producing
Beta cells
CNS
Pancreas
Insulin
Type
2
diabetes
a
resistance
to
the
ac,on
of
insulin
in
target
cells
‐ especially
in
muscle,
‐ fat
and
liver
cells.
Target tissues
Glucose uptake
Blood Glucose
Type
1
diabetes
is
caused
by
a
lack
of
insulin
output
*
Tyrosine
kinase
inhibitors
(TKIs)
Therapeu,c
strategies
include:
 blocking
kinase‐substrate
interac,on
 inhibi,ng
the
enzyme's
ATP
binding
site
 blocking
extracellular
receptors
on
tumour
cells.
Breast
cancer
is
the
second
leading
cause
of
cancer
deaths
in
women
in
the
US
Approximately
15‐30%
of
breast
cancers
are
HER2‐posi,ve
In
25‐30%
of
pa,ents
with
metasta,c
breast
cancer,
HER2
is
overexpressed
due
to
amplifica,on
of
the
HER2
gene
*American
Cancer
Society.
Cancer
Facts
and
Figures
2009.
hlp://www.cancer.org.
Accessed
May
5,
2009.
cetuximab
targets
ERBB1
for
treatment
of
colorectal
cancer.
Y kinase inhibitor used for small lung cancer treatment
Compe,,ve
inhibitors
prevent
ligand
binding
by
blocking
site