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Cell Communication
AP Biology
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Cell Signaling
 A signal transduction pathway is a series of
steps by which a signal on a cell’s surface is
converted into a specific cellular response
 Signal transduction pathways convert
signals on a cell’s surface into cellular
responses
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Signaling with Direct Contact
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Local vs. Long Distance Signaling
 Animal cells communicate using local
regulators
messenger molecules—travel short distances
Growth factors
 long-distance signaling
Hormones
Gases traveling through air in plants
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Local Signaling w/o Direct Contact
Interferon released
from viral infected
cells
Growth factors
Paracrine Signaling
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Synaptic Signaling
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Long-Distance Signaling
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Hormone Signaling
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Long-Distance Diffusion
Note how specificity is determined by
presence/absence of receptor protein
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Signaling, Free-Living Cells
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 factor
Receptor
1
Exchange
of mating
factors

a
a factor
Yeast cell,
Yeast cell,
mating type a
mating type 
2
Mating
3
New a/
cell

a
a/
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Cell-Cell Chemical Signaling
 Involves physical
movement of
ligands
Small molecule that
specifically binds to
larger molecule
Ligand reception by
proteins
Protein usually has
change in conformation
after binding
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Fig. 11-6-1
Signal Transduction
EXTRACELLULAR
FLUID
1 Reception
Receptor
Signaling
molecule
CYTOPLASM
Plasma membrane
Fig. 11-6-2
Signal Transduction
CYTOPLASM
EXTRACELLULAR
FLUID
Plasma membrane
1 Reception
2 Transduction
Receptor
Relay molecules in a signal transduction pathway
Signaling
molecule
Fig. 11-6-3
Signal Transduction
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
Signal Transduction
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Receptors in Plasma Membrane
 Most water-soluble
 Three main types:
G protein-coupled receptors
Receptor tyrosine kinases
Ion channel receptors
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G Proteins
 G protein-coupled receptor
plasma membrane receptor that works with
the help of a G protein
 G protein acts as an on/off switch:
If GDP is bound to the G protein, G protein
is inactive
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Fig. 11-7b
G-Protein-Linked Receptor
G protein-coupled
receptor
Plasma
membrane
Activated
receptor
Inactive
enzyme
Signaling
molecule
GDP
CYTOPLASM
GDP
Enzyme
G protein
(inactive)
GTP
2
1
Activated
enzyme
GTP
GDP
Pi
Cellular
response
3
4
Tyrosine Kinases
 Receptor tyrosine kinases
membrane receptors that attach phosphates
to tyrosines
can trigger multiple signal transduction
pathways at once
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Protein Kinase & Phosphatase
O
Protein Kinase
OH + ATP
Protein
Protein
O
P
O + ADP
O
Pi
H2O
Protein Phosphatase
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Response
Transduction
Phosphorylization
Receptor dimerization
Ligand Reception
Tyrosine Kinase Receptor
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Ligand Gated Ion Channel
 ligand-gated ion channel receptor
acts as gate when receptor changes shape
When signal molecule binds as a ligand to
receptor, gate allows specific ions, such as Na+
or Ca2+, through a channel in receptor
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Ion-Channel Receptor
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Reversibility
is assured by
pumping ions
back out
again (using
separate
protein)
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Intracellular Receptors
 Some receptor proteins are intracellular
found in cytosol or nucleus of target cells
 Small or hydrophobic chemical messengers
can readily cross membrane and activate receptors
 Examples of hydrophobic messengers
steroid and thyroid hormones of animals
 An activated hormone-receptor complex can
act as a transcription factor
turning on specific genes
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Fig. 11-8-1
Intracellular Receptor
Hormone
(testosterone)
EXTRACELLULAR
FLUID
Plasma
membrane
Receptor
protein
DNA
NUCLEUS
CYTOPLASM
Fig. 11-8-2
Intracellular Receptor
Hormone
(testosterone)
EXTRACELLULAR
FLUID
Plasma
membrane
Receptor
protein
Hormonereceptor
complex
DNA
NUCLEUS
CYTOPLASM
Fig. 11-8-3
Intracellular Receptor
Hormone
(testosterone)
EXTRACELLULAR
FLUID
Plasma
membrane
Receptor
protein
Hormonereceptor
complex
DNA
NUCLEUS
CYTOPLASM
Fig. 11-8-4
Intracellular Receptor
Hormone
(testosterone)
EXTRACELLULAR
FLUID
Plasma
membrane
Receptor
protein
Hormonereceptor
complex
DNA
mRNA
NUCLEUS
CYTOPLASM
Fig. 11-8-5
Intracellular Receptor
Hormone
(testosterone)
EXTRACELLULAR
FLUID
Plasma
membrane
Receptor
protein
Hormonereceptor
complex
DNA
mRNA
NUCLEUS
CYTOPLASM
New protein
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Intracellular Receptor
Transduction
 molecules that relay a signal from
receptor to response are mostly proteins
 reception activates another protein,
which activates another, …..until protein
producing response is activated
 At each step, signal is transduced into a
different form, usually a shape change in
a protein
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Protein Phosphorylation & Dephosphorylation
 In many pathways, signal is transmitted by
cascade of protein phosphorylations
 Protein kinases transfer phosphates from ATP
to protein, a process called phosphorylation
 Protein phosphatases remove phosphates from
proteins, a process called dephosphorylation
 phosphorylation and dephosphorylation
system acts as molecular switch, turning
activities on and off
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Phosphorylation
Cascade
Signaling
molecule
Receptor
Activated relay
molecule
Inactive
protein kinase
1
Activates protein kinase
Active
protein
kinase
1
Inactive
protein kinase
2
Active PK1 transfers P
From ATP to inactive PK2
ATP
Active
protein
kinase
2
ADP
Pi
PP
Inactive
ATP
protein kinase
3
Protein phosphatases
(PP) catalyze removal
of P to make them
inactive again
P
ADP
Pi
Active
protein
kinase
3
PP
Inactive
protein
P
ATP
P
ADP
Pi
PP
Active
protein
Cellular
response
Small Molecules & Ions Second Messengers
 first messenger
extracellular signal molecule that binds to receptor
 Second messengers
small, non-protein, water-soluble molecules or
ions that spread throughout a cell by diffusion
participate in pathways initiated by G protein-coupled
receptors and receptor tyrosine kinases
Cyclic AMP and calcium ions are common second
messengers
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Cyclic AMP
 cAMP
widely used second messengers
 Adenylyl cyclase
enzyme in plasma membrane
converts ATP to cAMP in response to
extracellular signal
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Cyclic AMP (cAMP)
Note
reversibility
“Second”
Messenger
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Second
messengers
are not
proteins
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cAMP
 Many signal molecules trigger formation of cAMP
 Other components of cAMP pathways are
G proteins
G protein-coupled receptors
protein kinases
 cAMP usually activates protein kinase A, which
phosphorylates various other proteins
 Further regulation of cell metabolism is provided
by G-protein systems that inhibit adenylyl
cyclase
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cAMP as a 2nd Messenger
Fig. 11-11
First messenger
Adenylyl
cyclase
G protein
G protein-coupled
receptor
GTP
ATP
cAMP
Second
messenger
Protein
kinase A
Cellular responses
Cell Signaling - Disease
 Cholera
Caused by Vibrio cholerae in contaminated
water
Toxin secreted by V. cholerae in small
intestine
Toxin modifies G protein involved in salt/water
secretion
Can no longer hydrolyze GTP
Always active - stimulates cAMP production
Intestinal cells secrete water/ions
Severe diarrhea
often lethal due to dehydration and salt imbalance
Cell Signaling - Cholera
Intestinal Lumen
H2O, ions
Ext
Int
GTP
active
Intestinal Cell
GDP
Toxin
inactive
cAMP
Copyright © 2005 Pearson Education, Inc., publishing as Benjamin Cummings
H2O, ions
Net
Effect
Calcium Ions & Inositol Triphosphate (IP3)
 Calcium ions (Ca2+)
act as a second messenger in many
pathways
 Calcium is an important second
messenger because cells can regulate its
concentration
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Fig. 11-12
EXTRACELLULAR
FLUID
Active transport of Ca2+
ions out of cell
Active transport into
lumen of ER and
mitochondrion
Plasma
membrane
Ca2+ pump
ATP
Mitochondrion
Nucleus
CYTOSOL
Ca2+
pump
Endoplasmic
reticulum (ER)
Signal transduction
results in release of
Ca from ER
ATP
Key
High [Ca2+]
Low [Ca2+]
Ca2+
pump
Calcium Ions & Inositol Triphosphate (IP3)
 Signal relayed by signal transduction
pathway may trigger increase in calcium
in the cytosol
 Pathways leading to release of calcium
involve inositol triphosphate (IP3) and
diacylglycerol (DAG) as additional
second messengers
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Ca2+-mediated Signal Amp.
Fig. 11-13-1
EXTRACELLULAR
FLUID
Signaling molecule
(first messenger)
G protein
DAG
GTP
G protein-coupled
receptor
Phospholipase C
PIP2
IP3
(second messenger)
IP3-gated
calcium channel
Endoplasmic
reticulum (ER)
CYTOSOL
Ca2+
Fig. 11-13-2
EXTRACELLULAR
FLUID
Signaling molecule
(first messenger)
G protein
DAG
GTP
G protein-coupled
receptor
Phospholipase C
PIP2
IP3
(second messenger)
IP3-gated
calcium channel
Endoplasmic
reticulum (ER)
CYTOSOL
Ca2+
Ca2+
(second
messenger)
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
Ca2+-mediated Signal Amp.
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Releasing Ca2+ is a
means of greatly
amplifying signal
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Response
 Cell signaling leads to regulation of
transcription activities or
cytoplasmic activities
 cell’s response to extracellular signal
sometimes called “output response”
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Nuclear & Cytoplasmic Responses
 signal transduction pathway leads to
regulation of one or more cellular activities
 response may occur in
cytoplasm or
may involve action in nucleus
 Many signaling pathways regulate synthesis
of proteins
usually by turning genes on or off in nucleus
 final activated molecule may function as
transcription factor
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Fig. 11-14
Growth factor
Reception
Nuclear Response
Receptor
Phosphorylation
cascade
Transduction
CYTOPLASM
Inactive
transcription
factor
Active
transcription
factor
P
Response
DNA
Gene
NUCLEUS
mRNA
Signaling pathways can
affect physical characteristics
of a cell--cell shape
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 Response
 Multistep pathways have two important
benefits:
Amplifying signal
and therefore the response
Contributing to specificity of response
 Signal Amplification
Enzyme cascades amplify cell’s response
At each step, number of activated products is
much greater than in preceding step
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Signal Amplification (Cascade)
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Signal Amplification (Cascade)
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Signal-Transduction Cascade
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)
Specificity & Coordination of Response
 Different kinds of cells have different
collections of proteins
allow cells to detect & respond to different
signals
 Even same signals can have different
effects in cells with different proteins and
pathways
 Pathway branching and “cross-talk”
further help cell coordinate incoming
signals
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Fig. 11-17a
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.
Fig. 11-17b
Activation
or inhibition
Response 4
Cell C. Cross-talk occurs
between two pathways.
Response 5
Cell D. Different receptor
leads to a different response.
Signaling Efficiency
 Scaffolding proteins
large relay proteins to which other relay
proteins are attached
can increase signal transduction efficiency
Groups together different proteins involved
in same pathway
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Fig. 11-18
Signaling
molecule
Plasma
membrane
Receptor
Three
different
protein
kinases
Scaffolding
protein
Termination of Signal
 Inactivation mechanisms are an
essential aspect of cell signaling
 When signal molecules leave receptor
it reverts to inactive state
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Apoptosis
 Programmed or controlled cell suicide
integrates multiple cell-signaling pathways
Cell chopped & packaged into vesicles that are
digested by scavenger cells
prevents enzymes from leaking out of dying cell
and damaging neighboring cells
 Caspases
main proteases that carry out apoptosis
 can be triggered by:
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An extracellular death-signaling ligand
DNA damage in the nucleus
Protein misfolding in the endoplasmic reticulum
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Fig. 11-20a
Ced-9
protein (active)
inhibits Ced-4
activity
Mitochondrion
Receptor
for deathsignaling
molecule
Ced-4 Ced-3
Inactive proteins
(a) No death signal
Fig. 11-20b
Ced-9
(inactive)
Cell
forms
blebs
Deathsignaling
molecule
Active Active
Ced-4 Ced-3
Activation
cascade
(b) Death signal
Other
proteases
Nucleases
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Fig. 11-21
Interdigital tissue
1 mm
Fig. 11-UN1
1
Reception
2
Transduction
3 Response
Receptor
Relay molecules
Signaling
molecule
Activation
of cellular
response
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