Transcript Chapter 11

Overview: The Cellular Internet
• Cell-to-cell communication is essential for
multicellular organisms
• Biologists have discovered some universal
mechanisms of cellular regulation
• The combined effects of multiple signals
determine cell response
• For example, the dilation of blood vessels is
controlled by multiple molecules
Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings
Evolution of 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
Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings
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
Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings
Fig. 11-4
Plasma membranes
Gap junctions
between animal cells
(a) Cell junctions
(b) Cell-cell recognition
Plasmodesmata
between plant cells
Fig. 11-2
 factor
Receptor
1
Exchange
of mating
factors

a
a factor
Yeast cell,
mating type a
2
Mating
3
New a/
cell
Yeast cell,
mating type 

a
a/
Fig. 11-3
1 Individual rodshaped cells
2 Aggregation in
process
0.5 mm
3 Spore-forming
structure
(fruiting body)
Fruiting bodies
• In many other cases, animal cells communicate
using local regulators, messenger molecules
that travel only short distances
• In long-distance signaling, plants and animals
use chemicals called hormones
Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings
Fig. 11-5
Long-distance signaling
Local signaling
Electrical signal
along nerve cell
triggers release of
neurotransmitter
Target cell
Secreting
cell
Local regulator
diffuses through
extracellular fluid
(a) Paracrine signaling
Endocrine cell
Neurotransmitter
diffuses across
synapse
Secretory
vesicle
Target cell
is stimulated
Blood
vessel
Hormone travels
in bloodstream
to target cells
Target
cell
(b) Synaptic signaling
(c) Hormonal signaling
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
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
Concept 11.2: Reception: A signal molecule binds
to a receptor protein, causing it to change shape
• The binding between a signal molecule
(ligand) and receptor is highly specific
• A shape change in a receptor is often the initial
transduction of the signal
• Most signal receptors are plasma membrane
proteins
Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings
Receptors in the Plasma Membrane
• Most water-soluble signal molecules bind to
specific sites on receptor proteins in the
plasma membrane
• There are three 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
• A G protein-coupled receptor is a plasma
membrane receptor that works with the help of
a G protein
• The G protein acts as an on/off switch: If GDP
is bound to the G protein, the G protein is
inactive
Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings
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
15.3 How Is a Response to a Signal Transduced
through the Cell?
Studies with human bladder cancer cells:
• They have an abnormal form of a G
protein called Ras. The protein was
permanently bound to GTP, causing
continuous cell division.
• Ras was thought to be an intermediary
between binding of growth factor to
receptor, and the cell’s response.
• Receptor tyrosine kinases are membrane
receptors that attach phosphates to tyrosines
• A receptor tyrosine kinase can trigger multiple
signal transduction pathways at once
Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings
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
• A ligand-gated ion channel receptor acts as a
gate when the receptor changes shape
• 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
Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings
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
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. 11-8-2
ormone
estosterone)
EXTRACELLULAR
FLUID
Plasma
membrane
Receptor
protein
UCLEUS
CYTOPLASM
Hormone
(testosterone)
EXTRACELLULAR
FLUID
Plasma
membrane
Receptor
protein
Hormonereceptor
complex
DNA
DNA
NUCLEUS
CYTOPLASM
Concept 11.3: Transduction: Cascades of molecular
interactions relay signals from receptors to target
molecules in the cell
• Signal transduction usually involves multiple
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
Protein Phosphorylation and Dephosphorylation
• In many pathways, the signal is transmitted by
a cascade of protein phosphorylations
• Protein kinases transfer phosphates from ATP
to protein, a process called phosphorylation
Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings
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
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
• 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
Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings
Small Molecules and Ions as Second Messengers
• The extracellular signal molecule (the first
messenger) that binds to the receptor can also
generate a second messenger along the
pathway
• 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
Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings
• The second messenger carries the signal from
the membrane receptor to the cytoplasm.
• Second messengers affect many cell processes,
amplifying the signal. They are short life
molecules
• Some of the most well known second
messengers are:
• cAMP
• IP3 and DAG
• Ca++
• Nitric Oxide (NO)
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
Calcium Ions and 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
Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings
Fig. 11-12
EXTRACELLULAR
FLUID
Plasma
membrane
Ca2+ pump
ATP
Mitochondrion
Nucleus
CYTOSOL
Ca2+
pump
Endoplasmic
reticulum (ER)
ATP
Key
High [Ca2+]
Low [Ca2+]
Ca2+
pump
• 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
Figure 15.13 The IP3/DAG Second-Messenger System
Concept 11.4: Response: Cell signaling leads to
regulation of transcription or cytoplasmic
activities
• The cell’s response to an extracellular signal is
sometimes called the “output response”
Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings
Nuclear and Cytoplasmic Responses
• Ultimately, a signal transduction pathway leads
to regulation of one or more cellular activities
• The response may occur in the cytoplasm or
may involve action in the nucleus
• Many signaling pathways regulate the
synthesis of enzymes or other proteins, usually
by turning genes on or off in the nucleus
• The final activated molecule may function as a
transcription factor
Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings
Fig. 11-14
Growth factor
Reception
Receptor
Phosphorylatio
n
cascade
Transduction
CYTOPLASM
Inactive
transcription
factor
Active
transcription
factor
P
Response
DNA
Gene
NUCLEUS
mRNA
Other pathways regulate
the activity of enzymes
Figure 15.14 A Signal Transduction Pathway Leads to the Opening of Ion Channels (Part 1)
Figure 15.14 A Signal Transduction Pathway Leads to the Opening of Ion Channels (Part 2)
• Signaling pathways can also affect the physical
characteristics of a cell, for example, cell shape
Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings
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
Signal Transduction
• Advantages of signal transduction pathway:
– Amplification: One molecule of receptor,
activated 100 molecules of second meesenger
which activates 1000 molecules of effecor
proteins down the cascade and so on.
– Specificity: Only a specific signal at the cell
membrane is transferred inside the cell.
–
Provide more opportunities of regulation:
Having many steps affecting different target
proteins also allows for a variety of responses by
different cells to the same signal.
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)
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-UN1
1
Reception
2
Transduction
3 Response
Receptor
Relay molecules
Signaling
molecule
Activation
of cellular
response