Campbell (8th ed.) p209-225
Cell Signaling and Communication – Part 2
The process that converts a signal on a cell’s surface into a cellular response involved a
series of steps that are collectively called signal transduction pathway. Interestingly,
the details of signal transduction in yeast and mammals are quite similar, showing that
these processes have been highly conserved through the process of evolution. As well,
similarities between signal transduction in plants and bacteria show that this is an ancient
process that has evolved along with live on Earth.
Signal Transduction Pathway – 3 Steps
Cascade of Events – each successive step in the
signal transduction pathway gets stronger.
1. Reception – the signal molecule attaches to a receptor protein or to a sugar
associated with a receptor glycoprotein. In doing so, the signal molecule is acting
as a ligand, a molecule that attaches to another molecule due to complimentary
shape and chemical nature. When the signal molecule attaches, the receptor
undergoes a conformational change (allosteric change) and its shape changes.
Note: Some receptors may be activated by environmental factors such as light,
pH, or temperature.
2. Transduction – relay molecules called second messengers become activated and
start a series of reactions in the cytoplasm that amplify. These reactions get more
intense at each step and are called a cascade.
3. Cellular Response – the final molecule in the signal transduction pathway will
lead to a nuclear response and/or a cytoplasmic response within the cell.
 Regulate gene expression in the nucleus by turning a gene on or off.
 Activate an enzyme to catalyze a specific chemical reaction.
 Open or close a gated channel protein within the cell membrane.
Three Types of Membrane Protein Reception
1. G-Coupled Reception
Approximately 60% of all
drugs currently on the market
interact with this type of
receptor protein. As a result,
it is important to understand
the different ways in which it
can function in order to
predict the affect of a drug.
2. Tyrosine-Kinase Reception
Abnormalities in the functioning
of this receptor have been linked
to uncontrolled cell division
associated with cancer.
Understanding the functioning of
this receptor could lead to drugs
that inhibit tumor growth.
3. Gated Channel Reception
Muscle and nerve cells as well as other cells in
animals use these types of channels to regulate
their functioning. Understanding the nervous
system and muscular system involves
understanding the action of these receptors.
G-Coupled Reception
1. No Signal Molecules Present
A signal molecule (ligand) is not
bound to the receptor protein. As well,
the G-protein is in its inactive form
(bound to GDP) and the enzyme is also
inactive.
2. Attachment of a Messenger Molecule and G-Protein Activation
The signal molecule (ligand) attaches
to the receptor protein in the
membrane and activates it. The
activated receptor causes GTP to bind
to the G-protein and for GDP to be
released from the G-protein. These two
changes activate the G-protein.
3. Activation of the Enzyme that Produces cAMP
The signal molecule (ligand) is released
from the receptor and the receptor is left
in its inactive form. This occurs after the
activated G-protein starts moving along
the surface of the membrane to the
enzyme (adenylyl cyclase). When the Gprotein binds to the enzyme, it activates
it by changing its conformation (shape).
The activated enzyme then causes ATP
to be converted into cAMP.
Adenylyl
Cyclase
The cAMP produced is the second
messenger molecule that is used to start
the cellular response (transduction).
Note: If the enzyme activated is guanylyl
cyclase, cGMP is the second messenger
molecule that is formed.
cAMP starts signal transduction
by activating kinase A
4. Return of G-protein to Resting Position
The G-protein acts as a GTPase
enzyme and eventually converts the
GTP it is carrying back to GDP and a
free phosphate molecule (Pi).
When this occurs, the G-protien
reverts back to its inactive state and
moves back to the receptor protein so
that it is ready for future responses to
signal molecules.
Note: The sequence of diagrams shown provides an account of the G-Receptor system
first discovered by Earl Sutherland in regard to his work on how epinephrine (adrenaline)
leads to glycogen breakdown in cells. However, there are variations in the molecules
involved and modes by which they function. Two examples are bulleted below that help
show that not all G-receptor systems are the same and that decoding the functioning of
these systems is difficult.

The enzyme that is activated by the G-protein may differ. If, guanylyl cyclase is
activated cGTP will be produced rather than cAMP.

Some G-proteins may inhibit rather than activate certain enzymes. In such cases
attachment of a signal molecule to a receptor and subsequent activation of a Gprotein may cause an enzyme to be turned off and for signal transduction to cease
functioning rather than be turned on.
Write the function for each of the molecules involved in the G-Protein-Linked
Receptor system using your textbook as a reference source.
Signal Molecule –
Receptor Protein –
GTP –
G-Protein –
Adenylyl Cyclase –
ATP –
cAMP –
Protein Kinase -
Diagrammatic Modeling
Vibrio cholerae is the bacterium that causes the disease cholera in humans. Use the
textbook to obtain information on how the toxins produced by the bacterium affect the
functioning of G-Reception in human cells and make a series of annotated diagrams that
shows the toxin’s action.
Textbook – Campbell (8th ed.) – p 217
Tyrosine-Kinase Reception
1. Signal Molecule Not Attached
The tyrosine kinase receptor exists as
two separate proteins in the cell
membrane before signal molecules
(ligands) attach to each of the proteins.
The tyrosine amino acids that extend
from the cytoplasmic regions of the
proteins are not phosphorylated at this
point.
2. Signal Molecules Attach to
Receptors
Each of the proteins must bind to a
signal molecule (ligand) in order for
them to join together (dimerization) and
become activated.
3. Phosphorylation of Tyrosine
Regions
The tyrosine amino acids that are in the
cytoplasmic region of the receptor
protein are phosphorylated, and the
receptor protein becomes fully activated.
4. Relay Proteins are Activated and
Start Signal Transduction
Inactive relay proteins in the cytoplasm
attach to the phosphorylated tyrosine
regions of the receptor and become
activated. Each of the relay proteins is
then capable of starting its own cellular
response (signal transduction).
Ligand Gated Channel Reception
1. Signal Molecule Not Attached
When the signal molecule (ligand) is
not attached to the ligand-gated
channel protein, the channel for ion
movement is closed.
2. Signal Molecule Attaches and
Channel Opens
When the signal molecule (ligand)
attaches to the channel receptor
protein, it undergoes a conformational
change (shape change) and ions can
move through it. The ions act as
second messenger molecules within
the cell and trigger a cellular response.
Note: Calcium ions (Ca2+) are a very
important second messenger molecule
in many cells and are typically found
in low concentration in the cellular
cytoplasm when a cell has not been
triggered by a signal molecule.
Compare and Contrast

How is the Tyrosine-Kinase Receptor system different from the G-Linked-Protein
Receptor system?

How do Ion-Gated Channels differ from both G-Linked-Protein Receptor systems
and Tyrosine-Kinase Receptor systems?
Cytoplasmic Protein Reception
In some cases, signal molecules are small and/or lipid
soluble. As a result, they can pass through the cell
membrane and enter the cytoplasm. This is true for
steroid hormones, which include testosterone, estrogen,
and cortisone. Once inside the cell, these signal
molecules bind to cytoplasmic receptor proteins to from a
hormone-receptor complex. This complex can then enter
into the nucleus and influence gene expression.
As well, many receptors that are stimulated
by environmental factors are located in the
cytoplasm. For example, the phytochrome
protein found in photosynthetic plant cells is
found in the cytoplasm and is activated by
light. It then is responsible for a series of
signal transduction responses.
Signal Transduction
Technically, signal transduction starts when a
second messenger molecule such as cAMP, cGMP,
IP3, DAG, or Ca2+ acts as an activated relay
molecule to activate the first kinase protein (kinase
A) in a series of reactions.
Once the first kinase protein has been activated, it
facilitates the phosphorylation of numerous second
kinase proteins so that they become activated. The
second kinase proteins facilitate the
phosphorylation and activation of numerous third
kinase molecules and so on. This series of
phosphorylation reactions increases in strength and
is called the phosphorylation cascade.
At the end of the cascade, a protein that can alter
cellular functioning is activated and this causes a
cellular response to occur.
Cyclic AMP (cAMP) is a second
Messenger molecule that
functions as an activated
relay molecule.
kinases activate
protein
phosphatases
(PP) deactivate
Types of Transduction Responses
1. Transduction may lead to a
single response or a branched
response that leads to
activation of two or more
pathways.
2. Different transduction pathways that are
operating at the same time may interact with each
other. As well, second messenger molecules can
stimulate or inhibit receptors that are stimulated
by a different signal molecule, especially gated ion
channels.
3. When a receptor is exposed to its own signal molecule
for an extended period of time, it may become
desensitized by one of the second messenger molecules
activated during transduction. Desensitization means that
signal molecules will have less effect on the receptor, and
is a type of negative feedback that occurs to slow the
response.
Desensitization
of Receptor
4. Many signal transduction pathways operate at the same time within cells and have
complex interactions with each other.
For example, the activated
cytoplasmic receptor
(phytochrome) in this plant
cell is stimulating another
receptor (calcium leak
channel protein) as well as
starting its own signal
transduction pathway via
kinase activation by cGMP.
Model of what a Signal Transduction Pathways Actually Looks Like
Molecules of different transduction responses may interact with each other leading to
complex interactions with complex regulatory mechanisms. Mapping and understanding
signal transduction pathways is a current focus of cell biology research.
Cellular Responses
At the end of the cascade of phosphorylation reactions involved in transduction, a
protein(s) is activated that causes a cellular response. Nuclear responses involve the
alteration of gene expression, while cytoplasmic responses involve the activation of an
enzyme or the opening of an ion channel.
Example 1 – Yeast Cells (Cytoplasmic Response - Enzyme Activation)
The attachment of a mating factor protein to a receptor protein in the yeast cell membrane
triggers a signal transduction pathway that ultimately leads to the activation an enzyme
that forms microfilaments. The microfilaments then cause membrane to change shape and
protrude so that two adjacent cells of opposite mating type may fuse together.
Example 2 – Mammalian Cells (Cytoplasmic Response –Enzyme Activation)
The hormone epinephrine (adrenaline) can bind to
membrane receptors and start signal transduction. The
ultimate cellular response that results is the activation
of glycogen phosphorylase, the enzyme which
functions to break down stored glycogen into glucose
for metabolic use.
Example 3 – Human Cells (Nuclear Response - Gene Expression)
Growth factors bind to receptors in the cell membrane and triggers signal transduction
reactions. The final kinase protein that is activated enters the nucleus and activates
transcription factor proteins. This leads to the expression of a gene that produces a
protein involved in cell growth and division.
Example 4 - Plant Leaves (Nuclear Response - Gene Expression)
In this case, sunlight is the environmental stimulus that activates phytochrome proteins to
set the signal transduction in motion. Ultimately, transcription factor proteins that are
responsible for turning on the expression specific genes within the DNA are activated.
The proteins produced by these activated genes are the enzymes responsible for
producing molecules involved in the de-etiolation (greening) process.
Campbell (8th ed.) - p822-823
Example 5 – Animal Embryonic Development (Nuclear Response - Gene Expression)
Signal molecules are released by cells
within the embryo which allow for
communication and coordination of
development. Signal molecules bind to
receptors of neighboring cells and signal
transduction occurs to result in specific gene
expression. This process in which a cell
releases signal molecules to influence a
neighboring cell’s specialization is called
induction.
In the diagram below, an embryonic
precursor cell (unspecialized embryo cell)
was triggered by signals from neighboring
cells to develop into a myoblast (muscle
cell). This involved signal reception,
transduction, and a cellular response. The
final molecule activated by transduction was the transcription factor called MyoD, which
then stared a nuclear response that involves expression of specific genes and production of
proteins necessary for differentiation (specialization) into a muscle cell.
Signals from
neighboring
cells trigger
differentiation.
Final Protein Activated
by Transduction
Nuclear
response
involves
changes in
gene
expression.
Campbell (8th ed.) – p367-369
Example 6 – Apoptosis in the C. elegans Worm (Nuclear Response – Gene Expression)
When a cell is functioning normally, the Ced-9 protein inhibits activity of proteins
involved in a signal transduction pathway that leads to the expression of proteins that
cause blebbing and apoptosis (cell death). However, when a membrane receptor comes in
contact with a death signaling molecule, the Ced-9 protein is inhibited and it no longer
functions to inhibit the signal transduction pathway. With the signal transduction
reactions turned on, proteins (proteases and nucleases) that are needed for blebbing and
apoptosis are produced.
Apoptosis in more advanced animals involves several different pathways and is more complex
than in C. elegans. Nonetheless, gene expression is altered so that proteins responsible for
degrading cellular components are produced.

Human White Blood Cells – Old Macrophage Lysis
Normal Cell
Blebbing occurs during Apoptosis

Mouse Paw Development – Apoptosis is responsible for the removal of cells that
form webbing between digits.
Note: Apoptosis is a critical mechanism for correct development in almost all
animals. Cells are laid down and then removed by apoptosis during the
development process.

Neurodegenerative Diseases (Alzheimer’s Disease and Parkinson’s Disease) Apoptosis is of nerve cells is thought to contribute to loss of functional nerve
tissue.

Cancer – Apoptosis does not function in cancer cells which continually divide
and are immortal.
Note: Mechanisms for apoptosis have high degree of similarity in all animals. This shows
that apoptosis has been conserved in the process of evolution and has been an important
aspect of animal development.
Signal Transduction and Disease
Changes that lead to unnecessary activation or suppression of a signal transduction
pathway can lead to disruption of homeostasis and disease. To counter these changes,
drugs may be used to activate, suppress, or block a signal transduction pathway. As more
signal transduction pathways are mapped, the use of drugs engineered to regulate signal
transduction pathways will increase.
Problem - Signal transduction pathway is too active or has been turned-on when it
should not be turned-on.

Solution – Administer drugs that serve as inhibitors and block either the receptor
protein or any of the kinase proteins involved in transduction.

Example - Heart Disease
Problem – When adrenaline is released from the adrenal glands in times of stress,
it binds to receptors found mainly in the smooth muscle cells comprising the
blood vessels. The binding of adrenaline leads to a response that involves
contraction of the smooth muscle cells (vasoconstriction) and increased blood
pressure.
Drug Therapy - Alpha-blocker and beta-blocker molecules attach to the same
receptors to which adrenaline binds, but do no not lead to transduction and a
response. As a result, alpha-blockers and beta-blockers diminish the affect of
adrenaline when it is present due to stress and reduce vasoconstriction to keep
blood pressure more stable.
Problem – Signal transduction is not functioning or is functioning too slowly.

Solution - Administer drugs that stimulate receptors or amplify action of specific
molecules involved in transduction.

Example - Diabetes
Problem – Beta-cells in the Islets of Langerhans glands that lie on top of the
pancreas fail to make sufficient insulin. Insulin is a stimulatory molecule for the
signal transduction pathway that leads to cellular glucose intake.
Drug Therapy – Administer artificial human insulin (produced by genetic
engineering techniques) at specific times of the day to regulate blood sugar levels
Article - Signal Transduction as a Drug-Discovery Platform
Nature Biotechnology 18, IT37 - IT39 (2000)
Abstract - Mapping the key signaling molecules in biochemical pathways will be
central to future drug discovery efforts.