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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
2011 Pearson Education, Inc.
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
2011 Pearson Education, Inc.
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?
2011 Pearson Education, Inc.
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
2011 Pearson Education, Inc.
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
2011 Pearson Education, Inc.
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
2011 Pearson Education, Inc.
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
2011 Pearson Education, Inc.
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
2011 Pearson Education, Inc.
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
2011 Pearson Education, Inc.
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
2011 Pearson Education, Inc.
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
2011 Pearson Education, Inc.
Signal Amplification
Enzyme cascades amplify the cells response
At each step, the number of activated products is
much greater than in the preceding step
2011 Pearson Education, Inc.
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
2011 Pearson Education, Inc.
Concept 11.5: Apoptosis integrates multiple
cell-signaling pathways
Apoptosis is programmed or controlled cell
suicide
WHY IS THIS FUNCTION CRITICAL?
2011 Pearson Education, Inc.
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
2011 Pearson Education, Inc.
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
2011 Pearson Education, Inc.
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
2011 Pearson Education, Inc.
Apoptosis may be involved in some diseases (for
example, Parkinsons and Alzheimers);
interference with apoptosis may contribute to
some cancers
2011 Pearson Education, Inc.
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