Cell Communication

SIGNAL TRANSDUCTION
Overview: Cellular Messaging
Cell-to-cell communication is essential for both
multicellular and unicellular organisms

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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Figure 11.1
Concept 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
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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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 Plasmodesmata

between animal cells between plant cells
(a) Cell junctions

(b) Cell-cell recognition

 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
The ability of a cell to respond to a signal depends
on whether or not it has a receptor specific to that
signal

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Figure 11.5a

Local signaling

Target cell Electrical signal

along nerve cell
triggers release of
neurotransmitter.

Neurotransmitter
Secreting Secretory diffuses across
cell vesicle synapse.

Local regulator
diffuses through Target cell
extracellular fluid. is stimulated.

(a) Paracrine signaling (b) Synaptic signaling

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:
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

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Figure 11.6-1

EXTRACELLULAR CYTOPLASM
FLUID Plasma membrane

1 Reception

Receptor

Signaling
molecule
Figure 11.6-2

EXTRACELLULAR CYTOPLASM
FLUID Plasma membrane

1 Reception 2 Transduction

Receptor

Relay molecules in a signal transduction

pathway

Signaling
molecule
Figure 11.6-3

EXTRACELLULAR CYTOPLASM
FLUID Plasma membrane

1 Reception 2 Transduction 3 Response

Receptor
Activation
of cellular
response
Relay molecules in a signal transduction
pathway

Signaling
molecule
Various Responses

Note that more than one

response can result from the
reception of a single ligand
Concept 2: Reception: A signaling 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

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Receptors in the Plasma Membrane
Most water-soluble signal molecules bind to
specific sites on receptor proteins that span the
plasma membrane
There are three main types of membrane
receptors
G protein-coupled receptors
Receptor tyrosine kinases
Ion channel receptors

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 G-protein-coupled receptor (GPCRs) are the
largest family of cell-surface receptors
A GPCR 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

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Figure 11.7a

Signaling molecule binding site

Segment that
interacts with
G proteins

G protein-coupled receptor
Figure 11.7b

G protein-coupled Plasma Activated Signaling Inactive

receptor membrane receptor molecule enzyme

GTP
GDP GDP
CYTOPLASM
G protein Enzyme GDP GTP
1 (inactive) 2

Activated
enzyme

GTP
GDP
Pi

3 Cellular response 4
 Receptor tyrosine kinases (RTKs) are
membrane receptors that attach phosphates to
tyrosines
A receptor tyrosine kinase can trigger multiple
signal transduction pathways at once
Abnormal functioning of RTKs is associated with
many types of cancers

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Figure 11.7c

Signaling Ligand-binding site

molecule (ligand)
helix in the Signaling
membrane molecule

Tyr Tyr Tyr Tyr Tyr

Tyrosines Tyr
Tyr Tyr Tyr Tyr Tyr
Tyr
Tyr Tyr Tyr Tyr Tyr
Tyr

CYTOPLASM Receptor tyrosine Dimer

kinase proteins
1 (inactive monomers) 2

Activated relay
proteins

Cellular
P Tyr P Tyr Tyr P
Tyr Tyr Tyr P response 1
Tyr Tyr P Tyr Tyr P P Tyr Tyr P
Tyr Tyr P Tyr Tyr P P Tyr Tyr P Cellular
6 ATP 6 ADP
response 2
Activated tyrosine Fully activated
kinase regions receptor tyrosine
(unphosphorylated kinase Inactive
dimer) (phosphorylated relay proteins
3 4
dimer)
 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

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Figure 11.7d

1 2 3

Gate
closed Ions Gate Gate closed
Signaling open
molecule
(ligand)

Plasma
Ligand-gated
membrane
ion channel receptor Cellular
response
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 hormones of animals
An activated hormone-receptor complex can act
as a transcription factor, turning on specific
genes

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Figure 11.9-1
Hormone EXTRACELLULAR
(testosterone) FLUID

Plasma
membrane
Receptor
protein

DNA

NUCLEUS

CYTOPLASM
Figure 11.9-2
Hormone EXTRACELLULAR
(testosterone) FLUID

Plasma
membrane
Receptor
protein
Hormone-
receptor
complex

DNA

NUCLEUS

CYTOPLASM
Figure 11.9-3
Hormone EXTRACELLULAR
(testosterone) FLUID

Plasma
membrane
Receptor
protein
Hormone-
receptor
complex

DNA

NUCLEUS

CYTOPLASM
Figure 11.9-4
Hormone EXTRACELLULAR
(testosterone) FLUID

Plasma
membrane
Receptor
protein
Hormone-
receptor
complex

DNA

mRNA

NUCLEUS

CYTOPLASM
Figure 11.9-5
Hormone EXTRACELLULAR
(testosterone) FLUID

Plasma
membrane
Receptor
protein
Hormone-
receptor
complex

DNA

mRNA

NUCLEUS
New protein

CYTOPLASM
Concept 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

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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

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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

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 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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Figure 11.10

Signaling molecule

Receptor
Activated relay
molecule

Inactive
protein kinase
1 Active
protein
kinase
1

Inactive
protein kinase ATP
2 ADP P
Active
protein
PP kinase
Pi 2

Inactive
protein kinase ATP
3 ADP P
Active
protein
PP kinase
Pi 3
Inactive
protein ATP
ADP P
Active Cellular
PP
protein response
Pi
Figure 11.10a

Activated relay
molecule

Inactive
protein kinase
1 Active
protein
kinase
1

Inactive
protein kinase ATP
2 ADP P
Active
protein
PP kinase
Pi 2

Inactive
protein kinase ATP
ADP P
3 Active
protein
PP kinase
Pi 3
Inactive
protein ATP
ADP P
Active
protein
PP
Pi
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
Second messengers participate in pathways
initiated by GPCRs and RTKs
Cyclic AMP and calcium ions are common second
messengers
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Cyclic AMP
Cyclic AMP (cAMP) is one of the most widely
used second messengers
Adenylyl cyclase, an enzyme in the plasma
membrane, converts ATP to cAMP in response to
an extracellular signal

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Figure 11.11

Adenylyl cyclase Phosphodiesterase

Pyrophosphate H2O
P Pi

ATP cAMP AMP

 Many signal molecules trigger formation of cAMP
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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Figure 11.12

First messenger
(signaling molecule
such as epinephrine)
Adenylyl
G protein cyclase

G protein-coupled GTP
receptor

ATP
Second
cAMP 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

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Figure 11.13
EXTRACELLULAR Plasma
FLUID membrane

Ca2
ATP pump
Mitochondrion

Nucleus

CYTOSOL

Ca2
pump
Endoplasmic
Ca2 reticulum
ATP pump (ER)

Key High [Ca2 ] Low [Ca2 ]

 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

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Figure 11.14-1

EXTRA-
CELLULAR Signaling molecule
FLUID (first messenger)

G protein

DAG
GTP
G protein-coupled PIP2
Phospholipase C
receptor
IP3
(second messenger)

IP3-gated
calcium channel

Endoplasmic Ca2
reticulum (ER)

CYTOSOL
Figure 11.14-2

EXTRA-
CELLULAR Signaling molecule
FLUID (first messenger)

G protein

DAG
GTP
G protein-coupled PIP2
Phospholipase C
receptor
IP3
(second messenger)

IP3-gated
calcium channel

Endoplasmic Ca2
reticulum (ER)
Ca2
(second
CYTOSOL messenger)
Figure 11.14-3

EXTRA-
CELLULAR Signaling molecule
FLUID (first messenger)

G protein

DAG
GTP
G protein-coupled PIP2
Phospholipase C
receptor
IP3
(second messenger)

IP3-gated
calcium channel

Various Cellular
Endoplasmic Ca2 proteins
reticulum (ER) responses
activated
Ca2
(second
CYTOSOL messenger)
Concept 4: Response: Cell signaling leads to
regulation of transcription or cytoplasmic
activities
The cells response to an extracellular signal is
sometimes called the output response

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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 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 in the signaling
pathway may function as a transcription factor

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Figure 11.15
Growth factor Reception
Receptor

Phosphorylation
cascade
Transduction

CYTOPLASM

Inactive Active
transcription transcription
factor factor Response
P

DNA

Gene

NUCLEUS mRNA
 Other pathways regulate the activity of enzymes
rather than their synthesis

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Figure 11.16
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)
 Signaling pathways can also affect the
overall behavior of a cell, for example,
changes in cell shape

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Fine-Tuning of the Response
There are four aspects of fine-tuning to consider
Amplifying the signal (and thus the response)
Specificity of the response
Overall efficiency of response, enhanced by
scaffolding proteins
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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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

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Figure 11.18

Signaling
molecule

Receptor

Relay
Activation
molecules
or inhibition

Response 1 Response 2 Response 3 Response 4 Response 5

Cell A. Pathway leads Cell B. Pathway branches, Cell C. Cross-talk occurs Cell D. Different receptor
to a single response. leading to two responses. between two pathways. leads to a different
response.
Figure 11.18a

Signaling
molecule

Receptor

Relay
molecules

Response 1 Response 2 Response 3

Cell A. Pathway leads Cell B. Pathway branches,

to a single response. leading to two responses.
Figure 11.18b

Activation
or inhibition

Response 4 Response 5

Cell C. Cross-talk occurs Cell D. Different receptor

between two pathways. 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
In some cases, scaffolding proteins may also help
activate some of the relay proteins

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Figure 11.19

Signaling Plasma
molecule membrane

Receptor

Three
different
protein
kinases
Scaffolding
protein
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 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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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

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 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, Parkinsons and Alzheimers);
interference with apoptosis may contribute to
some cancers

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Figure 11.UN01

1 Reception 2 Transduction 3 Response

Receptor
Activation
of cellular
response
Relay molecules

Signaling
molecule
Figure 11.UN02