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Cell Signaling
AP Chapter 11
Evolution of cell signaling
• Similarities in pathways in bacteria,
protists, fungi, plants, and animals
suggest an early evolution of signaling
pathways
• Multicellular better due to coordination
and control of pathways
http://www.youtube.com/watch?v=FsGwgiIv_NU
Boseman video
Bacteria communication
“bacteria talking to each other”
• Quorum sensingconcentration of signaling
molecules allows bacteria
to sense their local density
• Ex- Vibrio – glowing
bacteria (luciferase
enzyme) give off auto
inducers into their
environment
autoinducers
Quorum sensing can lead to the
formation of biofilms
Slime molds – chemical signaling
• Slime molds live as solitary amoebae.
• When slime mold cells begin to starve or dehydrate,
they release a pheromone-like chemical called cyclic
AMP. This messenger molecule alerts other slime
mold amoebae. They detect the cAMP and follow the
scent to join forces with the troubled amoebae
forming a large mass of cells.
Other slime mold amoebae detect
the cAMP and follow the scent to
join forces with the troubled
amoebae.
cAMP is an important chemical
word in the language of cells and
seems to be understood and
made by all cells, even our own.
Fruiting body formation in fungi
chemical signaling
Local and long-distance signaling
Direct cytoplasmic connections:
- gap junctions or plasmodesmata in
plant cells
- contact of surface molecules (cell-tocell recognition via receptors
Plasmodesmata in plant cells
Gap junctions in animal cells
Immune cells – direct contact
Local regulators – nearby cells
• paracrine signaling – only includes
cells of a particular organ
• synaptic signaling – between neurons
• Long distance
• endocrine signaling
• nerve transmission
3 stages of cell signaling
1. Reception
2. Transduction
3. Response
http://www.youtube.com/watch?v=qOVkedxDqQo
Boseman video on cell signaling pathways
Fig. 11-6-1
EXTRACELLULAR
FLUID
1 Reception
Receptor
Signaling
molecule
CYTOPLASM
Plasma membrane
Fig. 11-6-2
CYTOPLASM
EXTRACELLULAR
FLUID
Plasma membrane
1 Reception
2 Transduction
Receptor
Relay molecules in a signal transduction pathway
Signaling
molecule
Fig. 11-6-3
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
Reception
• Ligand – the signal molecule, fits like a
lock and key to receptor
• Most ligands bind to cell surface
receptors; some bind to intracellular
receptors
• Usually induces a shape change in
receptor protein’s shape
Types of receptors
Bind with water-soluble molecules on
membrane:
• G-Protein-linked Receptor
• Tyrosine Kinase Receptor
• Ligand-gated Ion Channel
Bind with hydrophobic receptors:
• Intracellular Receptors
G- Protein-Linked Receptors
• 7 protein helices that span the
membrane
• Binding of the ligand to the G-protein
receptor, activates a specific G protein
located on the cytoplasm side. How GDP becomes GTP.
• The activated G-protein activates a
membrane-bound enzyme which
continues on its pathway.
• The GTP goes back to GDP.
Animation: Membrane-Bound Receptors that Activate G
Proteins
Fig. 11-7a
Signaling-molecule binding site
Segment that
interacts with
G proteins
G protein-coupled receptor
Fig. 11-7b
Plasma
membrane
G protein-coupled
receptor
Activated
receptor
Signaling molecule
GDP
CYTOPLASM
GDP
Enzyme
G protein
(inactive)
GTP
2
1
Activated
enzyme
GTP
GDP
Pi
Cellular response
3
4
Inactive
enzyme
How important is the G-protein system?
• Used by hormones, neurotransmitters,
sensory reception, development….
• Many bacteria produce toxins that
interfere with with G-protein systems
• Up to 60% of medicines influence Gprotein pathways
Tyrosine kinase receptors
• Receptor tyrosine kinases are membrane
receptors that attach phosphates from ATP
to tyrosines (Remember kinase…ATP.)
• Once the receptors are activated, relay
proteins bind to them and become
activated themselves.
• A receptor tyrosine kinase can trigger
multiple signal transduction pathways at
once
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
Tyr
Receptor tyrosine
kinase proteins
CYTOPLASM
Dimer
1
2
Activated relay
proteins
Tyr
Tyr
Tyr
Tyr
P Tyr
P Tyr
Tyr
Tyr
P
6 ATP
Activated tyrosine
kinase regions
6 ADP
Tyr
Tyr
P Tyr
Tyr
P
Tyr
P Tyr
P Tyr
Tyr
P
P
P
P
Tyr P
Tyr
Fully activated receptor
tyrosine kinase
Inactive
relay proteins
3
4
Cellular
response 1
Cellular
response 2
Tyrosine Kinase Receptors
• Binding of the signal molecules
causes the two polypeptides to
join.
They are activated and act as
enzymes to phosphorylate the
tyrosines in the tails.
The receptor protein is now
recognized by relay proteins,
triggering different effects.
Ligand-gated ion channel
• A ligand-gated ion channel receptor
acts as a gate
• When a signal molecule binds as a
ligand to the receptor, the gate allows
specific ions, such as Na+ or Ca2+,
through a channel in the receptor
• Ex- in neurotransmitters and nervous
signal transmission
Fig. 11-7d
1 Signaling
molecule
(ligand)
Gate
closed
Ligand-gated
ion channel receptor
2
Ions
Plasma
membrane
Gate open
Cellular
response
3
Gate closed
Ligand-Gated Ion Channels
http://msjensen.cehd.umn.edu/1135/Links/Animations/Flash/0003-swf_receptors_link.swf
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
Fig. 11-8-5
Hormone
(testosterone)
EXTRACELLULAR
FLUID
Plasma
membrane
Receptor
protein
Hormonereceptor
complex
DNA
mRNA
NUCLEUS
CYTOPLASM
New protein
Intracellular Receptors
http://highered.mcgraw-hill.com/olc/dl/120109/bio46.swf
Signal Transduction
• Allow for amplification of signals
• Signal coordination and regulation
• Involves
1) second messengers (cAMP and Ca+2)
2) relay proteins such as protein
kinases
How does epinephrine work?...an
example of cAMP messenging
•
Epinephrine acts via cyclic AMP (cAMP) as
a second messenger.
•
An activated G protein activates the
enzyme adenylyl cyclase (THINK CYCLING!)
which turns ATP to cAMP.
• Then cAMP can activate other inactive
molecules to reach the desired product.
action of epinephrine Video | DnaTube.com - Scientific Video Site
Fig. 11-10
Adenylyl cyclase
Phosphodiesterase
Pyrophosphate
P
ATP
Pi
cAMP
AMP
Fig. 11-11
First messenger
Adenylyl
cyclase
G protein
G protein-coupled
receptor
GTP
ATP
cAMP
Second
messenger
Protein
kinase A
Cellular responses
cAMP second messenger
systems
Membrane Structure
• Calcium ions also act as second
messengers.
One example is activating an enzyme
phospholipase C to produce two more
messengers which will open Ca channels.
The signal receptor may be a G protein or a
tyrosine kinase receptor.
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
RELAY PROTEINS
• Enzymes called protein kinases are also
important links in transduction.
• A protein kinase catalyzes the transfer of
PHOSPHATE GROUPS from ATP to another
protein to activate it.
• Amplification is possible in these type of
pathways.
Fig. 11-9
Signaling molecule
Receptor
Activated relay
molecule
Inactive
protein kinase
1
Active
protein
kinase
1
Inactive
protein kinase
2
ATP
ADP
Pi
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
This can get pretty complicated!
Cell Responses
• Alteration of metabolism
• Rearrangement of cytoskeleton
• Modulation of gene activity
Fig. 11-14
Growth factor
Reception
Receptor
Phosphorylatio
n
cascade
Modulating
Gene
Activity
Transduction
CYTOPLASM
Inactive
transcription
factor
Active
transcription
factor
P
Response
DNA
Gene
NUCLEUS
mRNA
Fig. 11-15
Reception
Binding of epinephrine to G protein-coupled receptor (1 molecule)
Transduction
Inactive G protein
Active G protein (102 molecules)
Alteration of
Metabolism
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
Rearrangement
Wild-type (shmoos)
Of cytoskeleton
∆Fus3
∆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
The Specificity of Cell Signaling and
Coordination of the Response
• Different kinds of cells have different
collections of proteins which allow cells
to detect and respond to different
signals.
• Even the same signal can have different
effects in cells with different proteins and
pathways
Fig. 11-17
Signaling
molecule
Same signal
- different
effects in
cells with
different
proteins and
pathways
Pathway
branching and
“cross-talk”
further help the
cell coordinate
incoming
signals
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.
Signaling Efficiency: Scaffolding Proteins
and Signaling Complexes
• Scaffolding proteins are large relay
proteins to which other relay proteins are
attached
• Scaffolding proteins can increase the
signal transduction efficiency by
grouping together different proteins
involved in the same pathway
Fig. 11-18
Signaling
molecule
Plasma
membrane
Receptor
Three
different
protein
kinases
Scaffolding
protein
Disruptions in cell signaling
pathways
• Bacterial infections (cholera, anthrax,
pertussis)
• Animal toxins
• Hormone imbalances (diabetes)
• Cancer
• Plant diseases
Boseman video on disruptions
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
• Apoptosis is important in shaping an
organism during embryonic development
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
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
• Apoptosis evolved early in animal
evolution and is essential for the
development and maintenance of all
animals
• Apoptosis may be involved in some
diseases (for example, Parkinson’s and
Alzheimer’s); interference with apoptosis
may contribute to some cancers
Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings
Fig. 11-21
Interdigital tissue
1 mm