Cell Signaling Ch 11
• There are three main receptorsin the p.m. for signaling pathways,
• G-protein coupled receptors,
• Tyrosine-kinase receptors
• second messengers (cAMP, Ca2+, and IP3);
– discuss all in terms of the three stages of cell signaling» 1. reception,
» 2. transduction
» 3. response (don't forget to discuss the importance of protein
phosphorylation
• Discuss the importance of cell signaling in nerve impulse
transmission.
• Intracellular receptors
• Discuss the importance of cell communication used by the
endocrine system, is there any overlap with the nervous system?
• What role does cell signaling play in apoptosis? When and where is
apoptosis appropriate?
External signals are converted to
responses within the cell
• Saccharomyces
cerevisiae mating
between alpha and
beta cells using
chemical signals
Did you know Bacteria can talk?
•
http://www.ted.com/talks/bonnie_bassler_on_how_bacteria_communicate.html
Bacteria Quorum
• Bacteria sense density of bacteria
populations by detecting concentration of
chemicals
– Inter species
– Intra species
– All bacteria have the same chemical (old)
**Allows for coordination of activity
bioluminescence
biofilm
Hormones: diverse sizes,shapes
• Animals: endocrine
signaling (gland
>circulatory>target)
• Plant growth
regulators: may travel
in vessels but usually
move through cells or
diffuse through air as
a gas
Gap junctions
between animal cells
Plasmodesmata
between plant cells
(b) Cell-cell recognition
Fig. 11-5ab
Local signaling
Electrical signal
along nerve cell
triggers release of
neurotransmitter
Target cell
Secreting
cell
Local regulator
diffuses through
extracellular fluid
(a) Paracrine signaling
Growth hormones are local
regulators
Neurotransmitter
diffuses across
synapse
Secretory
vesicle
Target cell
is stimulated
(b) Synaptic signaling
Ach is signal ligand for muscle action
potential )allows Na) to rush in
Fig. 11-5c
Long-distance signaling
Long
Distance
signaling:
hormones
and nerves
Endocrine cell
Blood
vessel
Hormone travels
in bloodstream
to target cells
Target
cell
(c) Hormonal signaling
Fig. 11-6-3
Signal Transduction Pathway: process; how an external signal binds
to cell’s surface is converted to a specific cellular response thru a series of
steps
CYTOPLASM
EXTRACELLULAR
FLUID
Plasma membrane
1 Reception
2 Transduction
3 Response
Receptor
Activation
of cellular
response
Relay molecules in a signal transduction pathway
Signaling
molecule
Relay race
very similar pathways between
yeast and bacteria
mammals and plants
Suggest early versions of signaling used before the 1st multicellular organism (1bya)
What happens when a cell encounters
a ligand (signaling molecule)?
• 1. molecule must be recognized by a
specific receptor
• 2. Signal (info being carried) must be
changed into another form
(TRANSDUCED)
• 3. inside cell (AMPLIFY, DIVERSIFY)
The Three Stages of Cell
Signaling: A Preview
• Earl W. Sutherland discovered how the
hormone epinephrine acts on cells
• Sutherland suggested that cells receiving
signals went through three processes:
– Reception
– Transduction
– Response
Animation: Overview of Cell Signaling
Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings
Sutherland: epinephrine
• Epinephrine: breaks down glycogen (liver, muscle)
releasing glucose 1P and glucose 6P
• Can make ATP in liver or remove P and glucose can
enter bloodstream
• Epinephrine and
glycogen
phosphorylase and
glycogen into tube =
NO CATABOLISM
• Infer: epinephrine
must not interact
directly with enzyme
and needs intact cells
(plasma membrane)
• http://www.rpi.edu/de
pt/bcbp/molbiochem/
MBWeb/mb1/part2/gl
ycogen.htm
• Diseases involving
phosphorylase,
glycogen; muscle
(McArdle syndrome,
glycogen storage
disease type V)
Receptors in the Plasma
Membrane
• Most water-soluble signal molecules bind to
specific sites on receptor proteins in the
plasma membrane
• 3 main types of membrane receptors:
– G protein-coupled receptors
– Receptor tyrosine kinases
– Ion channel receptors
Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings
Fig. 11-7a
Signaling-molecule binding site
Although
receptors vary
in binding sites
for ligands and
diff G proteins
Similar
structure with 7
alpha helices
Evidence
evolved early
due to the
presence in
diverse
organisms
Segment that
interacts with
G proteins
•The G protein acts as an on/off
switch:
•If GDP is bound to the G protein,
•the G protein is inactive
G protein-coupled receptor
Fig. 11-7b
GTP high energy molecule
Yeast mating factors, epinephrine, hormones and neurotransmitters
Plasma
membrane
G protein-coupled
receptor
Activated
receptor
Signaling molecule
Inactive
enzyme
GDP
CYTOPLASM
GDP
Enzyme
G protein
(inactive)
GTP
2
1
Activated
enzyme
GTP
GDP
Pi
Cellular response
3
4
G coupled receptor systems diverse: embryonic development, sensory
reception, (vision and smell)
Whooping cough, cholera, botulism make people sick by making toxins that
Fig. 11-7c
Ligand-binding site
Signaling
molecule (ligand)
Signaling
molecule
 Helix
Tyrosines
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Receptor tyrosine
kinase proteins
CYTOPLASM
1
Tyr
Dimer
Tyrosine kinases are enzymatic:
kinase transfers P
2
One tyr complex can activate more
than 10 diff cellular responses
Activated relay
proteins
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
P Tyr
P Tyr
6 ATP
Activated tyrosine
kinase regions
6 ADP
P Tyr
Tyr
P
Tyr P
Tyr P
P Tyr
Tyr
P
P Tyr
P Tyr
Tyr
P
P
Tyr
Fully activated receptor
tyrosine kinase
Inactive
relay proteins
3
4
Cellular
response 1
Cellular
response 2
Tyrosine Kinases
• More than one signal transduction
pathway can be triggered at once
• Allows for cell regulation and coordination
for growth and repro
• A single ligand binding event can trigger
multiple pathways = *** key difference
between tyr kinase and G proteins
• Tyr
• kinase abnormalities can lead to cancer
Fig. 11-7d
1 Signaling
molecule
(ligand)
Gate
closed
Ions
•A ligand-gated ion channel
•When a signal molecule
•receptor acts as a gate when
binds as a ligand to the
• the receptor changes shape
2
Ligand-gated
ion channel receptor
Plasma
membrane
receptor, the gate allows
specific ions, such as
Gate open
Na+ or Ca2+, through
Ligand gated ion channels
are very important in
nervous system
a channel in the receptor
Cellular
response
NT released form the
presynaptoc cell are ligands 3
for the Na channels on the
post synaptic cell in order to
start an daciton potential
Gate closed
Intracellular Receptors
• Some receptor proteins are intracellular,
found in the cytosol or nucleus of target cells
• Small or hydrophobic chemical messengers
can readily cross the membrane and
activate receptors
• Examples of hydrophobic messengers are
the steroid and thyroid hormones of animals
• An activated hormone-receptor complex can
act as a transcription factor, turning on
specific genes
Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings
Fig. 11-8-5
Hormone
(testosterone)
EXTRACELLULAR
FLUID
Plasma
membrane
Receptor
protein
Hormonereceptor
complex
DNA
mRNA
NUCLEUS
CYTOPLASM
New protein
Cascades of molecular
interactions relay signals from
receptors to target molecules in
• Signal transduction usually involves multiple
the
cell
steps
• Multistep pathways can amplify a signal: A
few molecules can produce a large cellular
response
• Multistep pathways provide more
opportunities for coordination and regulation
of the cellular response
Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings
Signal Transduction Pathways
• The molecules that relay a signal from
receptor to response are mostly proteins
• Like falling dominoes, the receptor activates
another protein, which activates another,
and so on, until the protein producing the
response is activated
• At each step, the signal is transduced into a
different form, usually a shape change in a
protein
Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings
Fig. 11-9
Signaling molecule
•Protein kinases transfer
phosphates from ATP to
protein, a process called
phosphorylation
Receptor
Activated relay
molecule
Inactive
protein kinase
1
Active
protein
kinase
1
Inactive
protein kinase
2
ATP
ADP
Pi
•Protein
phosphatases remove
the phosphates from
proteins, a process
called
dephosphorylation
This
phosphorylation
and
dephosphorylation
system acts as a
molecular switch,
turning activities on
and off
P
Active
protein
kinase
2
PP
Inactive
protein kinase
3
Pi
ATP
ADP
Active
protein
kinase
3
PP
Inactive
protein
P
ATP
P
ADP
Pi
PP
Active
protein
Cellular
response
Small Molecules and Ions as Second
Messengers
• The extracellular signal molecule that binds to the
receptor is a pathway’s “first messenger”
• Second messengers are small, nonprotein,
water-soluble molecules or ions that spread
throughout a cell by diffusion
• Second messengers participate in pathways
initiated by G protein-coupled receptors and
receptor tyrosine kinases
• Cyclic AMP and calcium ions are common second
messengers
Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings
Fig. 11-10
Cyclic AMP (cAMP) is one of the most widely used second messengers
Adenylyl cyclase
Phosphodiesterase
Pyrophosphate
P
ATP
Pi
cAMP
AMP
Adenylyl cyclase, an enzyme in the plasma membrane, converts ATP to
cAMP in response to an extracellular signal
Fig. 11-11
First messenger
•Many signal
molecules trigger
formation of
cAMP
G protein-coupled
receptor
Other components of
cAMP pathways are G
proteins, G proteincoupled receptors, and
protein kinases
cAMP usually activates
protein kinase A, which
phosphorylates various
other proteins
Adenylyl
cyclase
G protein
GTP
ATP
cAMP
•Further
regulation of
cell
metabolism is
provided by
G-protein
systems that
inhibit
adenylyl
cyclase
Second
messenger
Protein
kinase A
Cellular responses
Fig. 11-12
EXTRACELLULAR
FLUID
Plasma
membrane
Ca2+ pump
ATP
Mitochondrion
Calcium ions
(Ca2+) act as a
second
messenger in
many pathways
Nucleus
CYTOSOL
Ca2+
pump
Endoplasmic
reticulum (ER)
ATP
Key
High [Ca2+]
Low [Ca2+]
Ca2+
pump
Calcium is an
important
second
messenger
because cells
can regulate its
concentration
• A signal relayed by a signal transduction
pathway may trigger an increase in calcium
in the cytosol
• Pathways leading to the release of calcium
involve inositol triphosphate (IP3) and
diacylglycerol (DAG) as additional second
messengers
Animation: Signal Transduction Pathways
Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings
Fig. 11-13-3
EXTRACELLULAR
FLUID
Signaling molecule
(first messenger)
G protein
DAG
GTP
G protein-coupled
receptor
PIP2
Phospholipase C
IP3
(second messenger)
IP3-gated
calcium channel
Endoplasmic
reticulum (ER)
CYTOSOL
Various
proteins
activated
Ca2+
Ca2+
(second
messenger
)
Cellular
responses
Signaling pathways : Output
Response
• Nuclear or cytoplasmic responses
• Regulate the activity of other enzymes
• can affect the physical characteristics of a
cell, for example, cell shape
Fig. 11-14
Growth factor
Receptor
Response: Cell signaling
leads to regulation of
transcription or cytoplasmic
activities
Ultimately, leads
Reception to regulation of
one or more
cellular activities
Phosphorylatin
cascade
Transduction
The cell’s
response to an
extracellular
signal is
sometimes
called the
“output
response
CYTOPLASM
Inactive
transcription
factor
Active
transcription
factor
P
DNA
Many signaling
pathways regulate
the synthesis of
enzymes or other
proteins, usually
by turning genes
Response
on or off in the
nucleus
Gene
NUCLEUS
mRNA
The response
may occur in the
cytoplasm or may
involve action in
the nucleus
The final activated
molecule may act
as a transcription
factor
Fig. 11-15
Reception
Binding of epinephrine to G protein-coupled receptor (1 molecule)
Transduction
Inactive G protein
Active G protein (102 molecules)
Inactive adenylyl cyclase
Active adenylyl cyclase (102)
ATP
Cyclic AMP (104)
Inactive protein kinase A
Active protein kinase A (104)
Inactive phosphorylase kinase
Active phosphorylase kinase (105)
Inactive glycogen phosphorylase
Active glycogen phosphorylase (106)
Response
Glycogen
Glucose-1-phosphate
(108 molecules)
Fig. 11-16
RESULTS
∆Fus3
Wild-type (shmoos)
∆formin
CONCLUSION
1
Mating
factor G protein-coupled
receptor
Shmoo projection
forming
Formin
P
Fus3
GTP
GDP
Phosphorylation
cascade
2
Actin
subunit
P
Formin
Formin
P
4
Fus3
Fus3
P
Microfilament
5
3
Fine-Tuning of the Response
• Multistep pathways have two important
benefits:
– Amplifying the signal (and thus the response)
– Contributing to the specificity of the response
Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings
Signal Amplification
• Enzyme cascades amplify the cell’s
response
• At each step, the number of activated
products is much greater than in the
preceding step
Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings
The Specificity of Cell Signaling and
Coordination of the Response
• Different kinds of cells have different
collections of proteins
• These different proteins allow cells to detect
and respond to different signals
• Even the same signal can have different
effects in cells with different proteins and
pathways
• Pathway branching and “cross-talk” further
help the cell coordinate incoming signals
Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings
Fig. 11-17
Signaling
molecule
Receptor
Relay
molecules
Response 1
Cell A. Pathway leads
to a single response.
Response 2
Response 3
Cell B. Pathway branches,
leading to two responses.
Activation
or inhibition
Response 4
Cell C. Cross-talk occurs
between two pathways.
Response 5
Cell D. Different receptor
leads to a different response.
Fig. 11-18
Signaling Efficiency: Scaffolding Proteins and Signaling Complexes
Signaling
molecule
Plasma
membrane
Receptor
Scaffolding
proteins are large
relay proteins to
which other relay
proteins are
attached
Three
different
protein
kinases
Scaffolding
protein
Scaffolding proteins can increase the signal transduction efficiency by grouping
together different proteins involved in the same pathway
Termination of the Signal
• Inactivation mechanisms are an essential
aspect of cell signaling
• When signal molecules leave the receptor,
the receptor reverts to its inactive state
Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings
Concept 11.5: Apoptosis
(programmed cell death) integrates
multiple cell-signaling pathways
• Apoptosis is programmed or controlled cell
suicide
• A cell is chopped and packaged into
vesicles that are digested by scavenger
cells
• Apoptosis prevents enzymes from leaking
out of a dying cell and damaging
neighboring cells
Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings
Fig. 11-19
2 µm
Apoptosis in the Soil Worm
Caenorhabditis elegans
• Apoptosis is important in shaping an
organism during embryonic development
• The role of apoptosis in embryonic
development was first studied in
Caenorhabditis elegans
• In C. elegans, apoptosis results when
specific proteins that “accelerate” apoptosis
override those that “put the brakes” on
apoptosis
Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings
Fig. 11-20
Ced-9
protein (active)
inhibits Ced-4
activity
Mitochondrion
Ced-4 Ced-3
Receptor
for deathsignaling
molecule
Inactive proteins
(a) No death signal
Ced-9
(inactive)
Cell
forms
blebs
Deathsignaling
molecule
Active Active
Ced-4 Ced-3
Activation
cascade
(b) Death signal
Other
proteases
Nucleases
Apoptotic Pathways and the
Signals That Trigger Them
• Caspases are the main proteases (enzymes
that cut up proteins) that carry out apoptosis
• Apoptosis can be triggered by:
– An extracellular death-signaling ligand
– DNA damage in the nucleus
– Protein misfolding in the endoplasmic reticulum
Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings
Fig. 11-21
•Apoptosis evolved early in animal evolution and is
essential for the development and maintenance of
all animals
Interdigital tissue
•Apoptosis may be involved in some diseases (for
example, Parkinson’s and Alzheimer’s); interference
with apoptosis may contribute to some cancers
1 mm