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Overview: Cellular Messaging

Cell-to-cell communication is essential for both


multicellular and unicellular organisms
Biologists have discovered some universal
mechanisms of cellular regulation
Cells most often communicate with each other
via chemical signals
For example, the fight-or-flight response is
triggered by a signaling molecule called
epinephrine
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Cellular
communication
Types of signaling
Contact
Local
Paracrine Synaptic
Long-distance
Endocrine
system: via
hormones
Neuronal: via
elctricity
Cellular
communication
Types of signaling
Contact
Local
Paracrine Synaptic
Long-distance
Endocrine
system: via
hormones
Neuronal: via
elctricity
Cellular
communication
Types of signaling
Contact
Local
Paracrine Synaptic
Long-distance
Endocrine
system: via
hormones
Neuronal: via
elctricity
Cellular
communication
Types of signaling
Contact
Local
Paracrine Synaptic
Long-distance
Endocrine
system: via
hormones
Neuronal: via
electricity
Figure 11.1
Concept 11.1: External signals are converted
to responses within the cell
Concept 11.2: Reception: A signaling
molecule binds to a receptor protein, causing
it to change shape
Concept 11.3: Transduction: Cascades of
molecular interactions relay signals from
receptors to target molecules in the
cellConcept
11.4: Response: Cell signaling leads to
regulation of transcription or cytoplasmic
activities
Concept 11.5: Apoptosis integrates multiple cell-signaling
pathways



Concept 11.1: External signals are
converted to responses within the cell
Microbes provide a glimpse of the role of cell
signaling in the evolution of life
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Evolution of Cell Signaling
The yeast, Saccharomyces cerevisiae, has two
mating types, a and
Cells of different mating types locate each other
via secreted factors specific to each type
A signal transduction pathway is a series of
steps by which a signal on a cells surface is
converted into a specific cellular response
Signal transduction pathways convert signals on
a cells surface into cellular responses
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Communicati
on between
mating yeast
cells

How can
this be
analogized
to
people?
Exchange
of mating
factors
Receptor
factor
a factor
Yeast cell,
mating type a
Yeast cell,
mating type
Mating
New a/ cell
1
2
3
a
a
a/


How could we find out how long ago cell
communication evolved?

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How could we find out how long ago cell
communication evolved?


See if similar mechanisms are present in bacteria
and recently developed organisms like people.

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Individual
rod-shaped
cells
Spore-forming
structure
(fruiting body)
Aggregation
in progress
Fruiting bodies
1
2
3
0.5 mm
2.5 mm
The concentration of
signaling molecules
allows bacteria to sense
local population density
Local and Long-Distance Signaling
Cells in a multicellular organism communicate by
chemical messengers
Animal and plant cells have cell junctions that
directly connect the cytoplasm of adjacent cells
In local signaling, animal cells may communicate
by direct contact, or cell-cell recognition
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Figure 11.4
Plasma membranes
Gap junctions
between animal cells
Plasmodesmata
between plant cells
(a) Cell junctions
(b) Cell-cell recognition
Figure 11.5a
Local signaling
Target cell
Secreting
cell
Secretory
vesicle
Local regulator
diffuses through
extracellular fluid.
(a) Paracrine signaling using local regulators
(b) Synaptic signaling with
neurotransmitters
Electrical signal
along nerve cell
triggers release of
neurotransmitter.
Neurotransmitter
diffuses across
synapse.
Target cell
is stimulated.
Figure 11.5b
Long-distance signaling
Endocrine cell
Blood
vessel
Hormone travels
in bloodstream.
Target cell
specifically
binds
hormone.
(c) Endocrine (hormonal) signaling
The Three Stages of Cell Signaling:

1. Reception
2. Transduction
3. Response
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Animation: Overview of Cell Signaling
Right-click slide / select Play
Figure 11.6-1
Plasma membrane
EXTRACELLULAR
FLUID
CYTOPLASM
Reception
Receptor
Signaling
molecule
1
Figure 11.6-2
Plasma membrane
EXTRACELLULAR
FLUID
CYTOPLASM
Reception Transduction
Receptor
Signaling
molecule
Relay molecules in a signal transduction
pathway
2 1
Figure 11.6-3
Plasma membrane
EXTRACELLULAR
FLUID
CYTOPLASM
Reception Transduction Response
Receptor
Signaling
molecule
Activation
of cellular
response
Relay molecules in a signal transduction
pathway
3 2 1
Concept 11.2: Reception: A signaling
molecule binds to a receptor protein, causing
it to change shape

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Receptors in the Plasma Membrane
There are three main types of membrane
receptors
1. G protein-coupled receptors
2. Receptor tyrosine kinases
3. Ion channel receptors
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G protein-coupled receptors (GPCRs) are the largest family of cell-
surface receptors
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
Signaling molecule binding site
Segment that
interacts with
G proteins
Figure 11.7b
G protein-coupled
receptor
2 1
3 4
Plasma
membrane
G protein
(inactive)
CYTOPLASM
Enzyme
Activated
receptor
Signaling
molecule
Inactive
enzyme
Activated
enzyme
Cellular response
GDP
GTP
GDP
GTP
GTP
P
i

GDP
GDP
Note: the enzyme is activated
by shape change
Figure 11.8: The sturcutre of a G Protien-Coupled Receptor
Plasma
membrane
Cholesterol

2
-adrenergic
receptors
Molecule
resembling
ligand
2. Receptor tyrosine kinase
Signaling
molecule (ligand)
2 1
3 4
Ligand-binding site
helix in the
membrane
Tyrosines
CYTOPLASM Receptor tyrosine
kinase proteins
(inactive monomers)
Signaling
molecule
Dimer
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
P
P
P
P
P
P
P
P
P
P
P
P
Activated tyrosine
kinase regions
(unphosphorylated
dimer)
Fully activated
receptor tyrosine
kinase
(phosphorylated
dimer)
Activated relay
proteins
Cellular
response 1
Cellular
response 2
Inactive
relay proteins
6 ATP 6 ADP
Receptor tyrosine kinases (RTKs) are
membrane receptors that attach phosphates to
tyrosines

Benefit: A receptor tyrosine kinase can trigger
multiple signal transduction pathways at once

Tidbit: Abnormal functioning of RTKs is associated
with many types of cancers
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Figure 11.7d
Signaling
molecule
(ligand)
2 1 3
Gate
closed
Ions
Ligand-gated
ion channel receptor
Plasma
membrane
Gate
open
Cellular
response
Gate closed
A ligand-gated ion channel receptor acts as a gate when the
receptor changes shape
When a ligand binds to the receptor, the gate allows specific
ions, such as Na
+
or Ca
2+
, through a channel in the receptor

Intracellular Receptors
Intracellular receptor proteins are 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 (lipid soluble) hormones of
animals
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Figure 11.9-1
Hormone
(testosterone)
Receptor
protein
Plasma
membrane
DNA
NUCLEUS
CYTOPLASM
EXTRACELLULAR
FLUID
Figure 11.9-2
Hormone
(testosterone)
Receptor
protein
Plasma
membrane
Hormone-
receptor
complex
DNA
NUCLEUS
CYTOPLASM
EXTRACELLULAR
FLUID
Figure 11.9-3
Hormone
(testosterone)
Receptor
protein
Plasma
membrane
Hormone-
receptor
complex
DNA
NUCLEUS
CYTOPLASM
EXTRACELLULAR
FLUID
Figure 11.9-4
Hormone
(testosterone)
Receptor
protein
Plasma
membrane
Hormone-
receptor
complex
DNA
mRNA
NUCLEUS
CYTOPLASM
EXTRACELLULAR
FLUID
Figure 11.9-5
Hormone
(testosterone)
Receptor
protein
Plasma
membrane
EXTRACELLULAR
FLUID
Hormone-
receptor
complex
DNA
mRNA
NUCLEUS
CYTOPLASM
New protein
Concept 11.3: Transduction: Cascades of
molecular interactions relay signals from
receptors to target molecules in the cell
Signal transduction usually involves multiple steps
What are some benefits of a multistep pathway
a.k.a. cascade?

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Concept 11.3: Transduction: Cascades of
molecular interactions relay signals from
receptors to target molecules in the cell
Signal transduction usually involves multiple steps,
a.k.a. cascade?
Benefit 1: can amplify a signal: (A few molecules
can produce a large cellular response)
Benefit 2: provide more opportunities for
coordination and regulation of the cellular response
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Protein Phosphorylation and
Dephosphorylation is the cascades signal
Protein kinases transfer phosphates from ATP to
protein, a process called phosphorylation
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 or up or down, as required

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Receptor
Signaling molecule
Activated relay
molecule
Inactive
protein kinase
1
Active
protein
kinase
1
Active
protein
kinase
2
Active
protein
kinase
3
Inactive
protein kinase
2
Inactive
protein kinase
3
Inactive
protein
Active
protein
Cellular
response
ATP
ADP
ATP
ADP
ATP
ADP
PP
PP
PP
P
P
P
P
i

P
i

P
i

Figure 11.10
upstream/downstream
regulation
Small Molecules and Ions as Second
Messengers
The extracellular signal molecule (ligand) that
binds to the receptor is a pathways first
messenger
Second messengers are small, nonprotein, water-
soluble molecules or ions that spread throughout a
cell by diffusion
Cyclic AMP and calcium ions are common second
messengers
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Figure 11.11
Adenylyl cyclase Phosphodiesterase
Pyrophosphate
AMP
H
2
O
ATP
P
i
P
cAMP
What other organic molecule do
cAMP resemble?
Why?
Figure 11.12
G protein
First messenger
(signaling molecule
such as epinephrine)
G protein-coupled
receptor
Adenylyl
cyclase
Second
messenger
Cellular responses
Protein
kinase A
GTP
ATP
cAMP
Calcium I ons and I nositol Triphosphate (I P
3
)

Calcium ions (Ca
2+
) act as a second messenger in
many pathways
Calcium is an important second messenger
because cells can regulate its concentration
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Figure 11.13
Mitochondrion
EXTRACELLULAR
FLUID
Plasma
membrane
Ca
2

pump
Nucleus
CYTOSOL
Ca
2

pump
Ca
2

pump
Endoplasmic
reticulum
(ER)
ATP
ATP
Low [Ca
2
] High [Ca
2
] Key
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Animation: Signal Transduction Pathways
Right-click slide / select Play
G protein
EXTRA-
CELLULAR
FLUID
Signaling molecule
(first messenger)
G protein-coupled
receptor
Phospholipase C
DAG
PIP
2

IP
3
(second messenger)
IP
3
-gated
calcium channel
Endoplasmic
reticulum (ER)
CYTOSOL
Ca
2

GTP
Figure 11.14-1: Calcium and IP
3
in signaling pathways
Figure 11.14-2
G protein
EXTRA-
CELLULAR
FLUID
Signaling molecule
(first messenger)
G protein-coupled
receptor
Phospholipase C
DAG
PIP
2

IP
3
(second messenger)
IP
3
-gated
calcium channel
Endoplasmic
reticulum (ER)
CYTOSOL
Ca
2

(second
messenger)
Ca
2

GTP
Figure 11.14-3
G protein
EXTRA-
CELLULAR
FLUID
Signaling molecule
(first messenger)
G protein-coupled
receptor
Phospholipase C
DAG
PIP
2

IP
3
(second messenger)
IP
3
-gated
calcium channel
Endoplasmic
reticulum (ER)
CYTOSOL
Various
proteins
activated
Cellular
responses
Ca
2

(second
messenger)
Ca
2

GTP
Concept 11.4: Response: Cell signaling leads to
regulation of transcription or cytoplasmic
activities
The final activated molecule in the signaling
pathway may have a response in the cytoplasm
(e.g. changing shape of cytoskeleton or regulating
enzymes) or function as a transcription factor

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Figure 11.15
Growth factor
Receptor
Reception
Transduction
CYTOPLASM
Response
Inactive
transcription
factor
Active
transcription
factor
DNA
NUCLEUS
mRNA
Gene
Phosphorylation
cascade
P
Cytoplasmic
response to a
signal:
the stimulation
of glycogen
breakdown by
epinephrine.
Reception
Transduction
Response
Binding of epinephrine to G protein-coupled receptor (1 molecule)
Inactive G protein
Active G protein (10
2
molecules)
Inactive adenylyl cyclase
Active adenylyl cyclase (10
2
)
ATP
Cyclic AMP (10
4
)
Inactive protein kinase A
Active protein kinase A (10
4
)
Inactive phosphorylase kinase
Active phosphorylase kinase (10
5
)
Inactive glycogen phosphorylase
Active glycogen phosphorylase (10
6
)
Glycogen
Glucose 1-phosphate
(10
8
molecules)
Signaling pathways can also affect the
overall behavior of a cell, for example,
changes in cell shape
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Wild type yeast (with shmoos) Fus3 formin
Mating
factor
activates
receptor.
Mating
factor
G protein-coupled
receptor
Shmoo projection
forming
Formin
G protein binds GTP
and becomes activated.
2
1
3
4
5
P
P
P
P
Formin Formin
Fus3
Fus3 Fus3
GDP
GTP
Phosphory-
lation
cascade
Microfilament
Actin
subunit
Phosphorylation cascade
activates Fus3, which moves
to plasma membrane.
Fus3 phos-
phorylates
formin,
activating it.
Formin initiates growth of
microfilaments that form
the shmoo projections.
RESULTS
CONCLUSION
What is this showing?
Figure 11.17a
Wild type (with shmoos)
Fine-Tuning of the Response
There are four aspects of fine-tuning to consider:
1. Amplification of the signal (and thus the
response)
2. Specificity of the response
3. Overall efficiency of response, enhanced by
scaffolding proteins
4. Termination of the signal
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Signal Amplification
Enzyme cascades amplify the cells response
At each step, the number of activated products is
much greater than in the preceding step
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Figure 11.18 The specificity of cell signaling.
Signaling
molecule
Receptor
Relay
molecules
Response 1
Cell A. Pathway leads
to a single response.
Response 2 Response 3 Response 4 Response 5
Activation
or inhibition
Cell B. Pathway branches,
leading to two responses.
Cell C. Cross-talk occurs
between two pathways.
Cell D. Different receptor
leads to a different
response.
Figure 11.19
Signaling
molecule
Receptor
Plasma
membrane
Scaffolding
protein
Three
different
protein
kinases
Signaling Efficiency: Scaffolding Proteins
and Signaling Complexes
Termination of the Signal
Inactivation mechanisms are an essential aspect
of cell signaling
If ligand concentration falls, fewer receptors will be
bound
Unbound receptors revert to an inactive state
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Concept 11.5: Apoptosis integrates multiple
cell-signaling pathways
Apoptosis is programmed or controlled cell
suicide
WHY IS THIS FUNCTION CRITICAL?
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Concept 11.5: Apoptosis integrates multiple
cell-signaling pathways
Apoptosis is programmed or controlled cell
suicide
Components of the cell are chopped up and
packaged into vesicles that are digested by
scavenger cells
Apoptosis prevents enzymes from leaking out of a
dying cell and damaging neighboring cells
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Figure 11.20: white blood cell apoptosis
2 m
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 studied in Caenorhabditis elegans
In C. elegans, apoptosis results when proteins that
accelerate apoptosis override those that put the
brakes on apoptosis
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Figure 11.21
Mitochondrion
Ced-9
protein (active)
inhibits Ced-4
activity
Receptor
for death-
signaling
molecule
Ced-4 Ced-3
Inactive proteins
(a) No death signal
Death-
signaling
molecule
Ced-9
(inactive)
Cell
forms
blebs
Active
Ced-4
Active
Ced-3
Other
proteases
Nucleases
Activation
cascade
(b) Death signal
Apoptotic Pathways and the Signals That
Trigger Them
Caspases are the main proteases (what are
these?) 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
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Apoptosis may be involved in some diseases (for
example, Parkinsons and Alzheimers);
interference with apoptosis may contribute to
some cancers

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Figure 11.22: apoptosis in paw development of the mouse
Interdigital tissue
Cells undergoing
apoptosis
Space between
digits
1 mm
REVIEW
Reception
1 2 3 Transduction Response
Receptor
Signaling
molecule
Relay molecules
Activation
of cellular
response