Cell signaling: Cell surface

receptors and signal transduction

Apr. 2022
Xuan-Hung Nguyen, Ph.D
Director of Center of Applied sciences, Regenerative medicine and Advance technologies (CARA)
Affiliate Faculty at College of Health Sciences, VinUniversity
 EUKARYOTIC GENE REGULATION_WHY?

Butterfly metamorphosis

• Respond to changing environmental

conditions
• Express only needed proteins at
particular times in life and cell cycle

• Define tissues and cells functions

~300/20,000 genes are active

in a typical cell
Urry et al., Campbell Biology. 2020. Pearson
 SENSE AND RESPOND TO THEIR
ENVIRONMENT_HOW?
Human body: 1014 cells
tyrosine kinase receptor
• Interpret the multitude of signals to coordinate their behaviors.
- During development embryonic cells exchange signals to
determine:
§ What: specialized role each cell will adopt
§ Where: position it will occupy
§ Fate: survive, divide, or die.
- Later in life: signals coordinates the growth, day-to-day
physiology and behavior
§ maintain homeostasis in response to environments
§ communicate to each other to “know” what to do: inform/signal;
get informed/receive signals
§ “process” and respond to the signals => cell specific activity

Alberts. Molecular biology of the cell. 6e, 2017

 SIGNAL TRANSDUCTION

1. Reception

2. Transduction

3. Response

Alberts. Molecular biology of the cell. 6e, 2017 Silverthorn et al. 2019. Human physiology: an integrated approach. 8th. Pearson
ENDOCRINE PARACRINE 1 signal à different effects
signal molecules/receptors/intracellular system
Acetylcholine
Heart cells: ⇩ firing rate
Salivary cells: Secretion
CONTACT SYNAPTIC
Muscle cells: contraction

(2) Integration/
(1) Modes (3) Timing
Coordination

General signaling principles

(4) Sensitivity (5) Modulate (6) Dynamic

range
• Hormones: very
low conc.

Amplification

• Neurotransmitters:
much higher conc.

Adaptation/desensitization
 Simple intracellular signaling pathway
?
1. Signal reception
• A cell can respond to a particular chemical signal only if the
cell has the appropriate receptor protein to bind that signal
• All signal pathways share the following features:
1. Ligand/ first messenger: signal molecule that binds to a protein
receptor and brings information to the target cell
2. Receptor: activates one or more intracellular signaling
molecules. ?
2. Signal transduction
3. The last signal molecule in the pathway creates a response by
modifying existing proteins or initiating the synthesis of new
proteins.

• Responses: changes in cell metabolism, motility, division,

differentiation, apoptosis, or phagocytosis…

?
3. Cellular response

Alberts. Molecular biology of the cell. 6e, 2017

Signaling principles
 Principle 1: Long or Short Range of Signals

• Signals Can Act over a Long or Short Range face-to-face Flyer

• 4 basic methods of cell-to-cell communication

- gap junctions: direct cytoplasmic transfer of signals
- contact-dependent signals: via surface molecules
- chemicals: via extracellular molecules, Auto-/Para-/Endo-crine
- long-distance communication: combination of chemical &
electrical signals carried by nerve cells and chemical signals < 1 msec

transported in the blood.

100 m/sec

• A given molecule can function as a chemical signal by more

than one method.

phone call, text

radio
message, or e-mail
Silverthorn et al. 2019. Human physiology: an integrated approach. 8th. Pearson
 Principle 2: Each Cell Is Programmed to Respond to
Specific Combinations of Extracellular Signals

• Hundreds of different signal molecules from environment:

free in extracellular fluid, embedded in extracellular
matrix, or bound to surface of neighboring cells.
• Each cell must respond very selectively to this mixture of
signals. HOW?
- 1 ligand may have multiple receptors
- express a limited set of receptors & intracellular signaling
systems out of the thousands that are possible
- unlimited number of combinations.
• The extracellular signal molecule alone is not the
message: the information conveyed by the signal depends
on how the target cell receives and interprets the signal

Alberts. Molecular biology of the cell. 6e, 2017

 Principle 3: Cell’s Response to a Signal Can Be
Fast or Slow but is specific
• Swift signal: < sec to mins
- signal affects the activity of proteins that are already present
inside the target cell, awaiting their marching orders
- Exp: acetylcholine stimulates a skeletal muscle cell to contract
(milliseconds); salivary gland cell to secrete (mins)
• Slow signal: mins to hrs
- response to these extracellular signals requires changes in
gene expression and the production of new proteins
- Exp: Cell growth and cell division
• Specific:
- receptor responds only to the appropriate signal (Binding site
of the receptor)
- intracellular signaling systems filter out noise, generating little
or no response to low levels of stimuli
Alberts. Molecular biology of the cell. 6e, 2017
 Principle 4: Signal amplification allows a small
amount of signal to have a large effect
• Meaning: Original signal is not only
transformed but also amplified à a small
amount of ligand to create a large effect
• Process:
- 1st messenger ligand binds receptor à
amplifier enzyme ON
- Amplifier enzyme activates several molecules
à each activate several more molecules as the
cascade proceeds
- Effects of the ligand have been amplified much
more than if there were a 1:1 ratio between
each step.

Silverthorn et al. 2019. Human physiology: an integrated approach. 8th. Pearson Alberts. Molecular biology of the cell. 6e, 2017
 Principle 5: intracellular signaling systems
incorporate feedback loops
• Feedback loops: output of a process acts back to regulate that same
process
• Positive feedback: the output stimulates its own production
- transient extracellular signal can induce long-term changes
- Exp: The signals trigger muscle-cell specification turn on the transcription
of muscle-specific transcription regulatory proteins à transcription of
their own genes & various other muscle-cell proteins à the decision to
become a muscle cell is made permanent
• Negative feedback: the output inhibits its own production
- abbreviates & limits the level of the response à the system less sensitive
to perturbations
- Exp: shut down of immune stimulation
• Feedback loops can operate exclusively within a cell or involve the
secretion of extracellular signals
Alberts. Molecular biology of the cell. 6e, 2017
 Principle 6: Cells Can Adjust Their Sensitivity
to a Signal
Adaptation/desensitization: prolonged exposure to a stimulus decreases the cells’ response
to that level of stimulus.

Alberts. Molecular biology of the cell. 6e, 2017

ENDOCRINE PARACRINE 1 signal à different effects
signal molecules/receptors/intracellular system
Acetylcholine
Heart cells: ⇩ firing rate
Salivary cells: Secretion
CONTACT SYNAPTIC
Muscle cells: contraction

(2) Integration/
(1) Modes (3) Timing
Coordination

General signaling principles

(4) Sensitivity (5) Modulate (6) Dynamic

range
• Hormones: very
low conc.

Amplification

• Neurotransmitters:
much higher conc.

Adaptation/desensitization
Signal transduction
 BIOLOGICAL SIGNAL TRANSDUCTION
1. Reception
• Signal molecules: (i) electrical & (ii) chemical
• Cell surface receptors: 3 major classes
- Ion-channel coupled receptors
- G-protein-coupled receptors 2. Transduction

- Enzyme-coupled receptors.

• Intracellular signaling molecules:

- Small chemicals: second messengers (cAMP, cGMP, Ca2+, diacylglycerol)
- Proteins: protein kinases, GTP-binding protein, other (ubiquitination…)

• Cellular responses: altered

- metabolism: metabolic enzymes
- cell shape or movement: motor proteins for muscle contraction and cytoskeletal movement
- gene expression: proteins that regulate gene activity and protein synthesis 3. Response

Alberts. Molecular biology of the cell. 6e, 2017

 RECEPTION – SIGNAL MOLECULES
• Diversity: hundreds kinds of extracellular molecules but only
2 basic types
- Electrical signals: changes in a cell’s membrane potential
- Chemical signals: molecules secreted by cells into the
extracellular fluid

• Specificity: receptor responds only to the appropriate signal

(Binding site of the receptor)
• Receptor-ligand binding is brief and reversible with certain
affinity
• Signal binding induces a shape change of the receptor
initiating transduction of the signal
• Competition: Agonist vs. Antagonist
à stimulatory vs. inhibitory

Silverthorn et al. 2019. Human physiology: an integrated approach. 8th. Pearson Alberts. Molecular biology of the cell. 6e, 2017
 RECEPTION – RECEPTORS

The number of different types of receptors in each of these 3 classes is greater than the
number of extracellular signals that act on them
Alberts. Molecular biology of the cell. 6e, 2017
 Ion-Channel-Coupled Receptors
• Where? Most of these receptors are neurotransmitter receptors found in
nerve and muscle
• Characteristics?
- speed: the most rapid intracellular responses (within milliseconds)
- signal: chemical, electrical, or mechanical

• Effect?
- Altering the cell’s permeability to an ion
- transduce a chemical signal directly into an electrical signal
• Exp? Acetylcholine-gated cation channel of skeletal muscle
- Neurotransmitter acetylcholine released from an adjacent neuron binds to the
acetylcholine receptor and opens the channel.
- K+ OUT & Na+ IN along their electrochemical gradients.
- à muscle contraction.

Silverthorn et al. 2019. Human physiology: an integrated approach. 8th. Pearson

 G protein-coupled receptors (GPCRs)
• Where? practically every cell type in the body.
• Characteristics?
- > 700 GPCRs in human: include light and smell receptors
- structure: 7-(pass)-transmembrane domain receptors
- cytoplasmic tail of the receptor is linked to G protein, a 3-part (𝜶,𝜷,𝜸)
membrane transducer; 𝜶 binds Guanosine nucleotides (GDP or GTP)
- signals: proteins, small peptides, or derivatives of amino acids or fatty acids
play a roles as hormones, growth factors, olfactory molecules, visual
pigments, and neurotransmitters
• Effect? one-third of all drugs used today work through GPCRs
dissociation of activated α subunit
- open an ion channel in the membrane
- activate amplifier enzymes (adenylyl cyclase or phospholipase C)

Alberts. Molecular biology of the cell. 6e, 2017

How GPCR transduce
signals?
- open an ion channel in the membrane
- activate amplifier enzymes:
• (i) adenylyl cyclase or
• (ii) phospholipase C
 Regulate Ion Channels
• 20 different types of mammalian G proteins.

heart pacemaker cells

• The heartbeat controlled by two sets of nerves: one speeds the
heart up, the other slows it down.
- The nerves that signal a slowdown in heartbeat releases acetylcholine
- acetylcholine binds GPCR on surface of the heart pacemaker cells.
- à activate G protein.
norepinephrine
+
- βγ complex binds K channel à open channel à slows the heart rate
- Gα inactivates itself by hydrolyzing its bound GTP à terminate original
signal à K+ channel recloses

acetylcholine

Alberts. Molecular biology of the cell. 6e, 2017

 GPCRs Activate amplifier enzymes
• adenylyl cyclase OR
• Enzymes activated by G proteins increase the concentrations of small
• phospholipase C
intracellular signaling molecules
- adenylyl cyclase: generate cAMP
- phospholipase C: generate inositol trisphosphate (IP3) and diacylglycerol (DAG)
IP3: promotes the accumulation another cytosolic signaling molecule (Ca2+)
• Adenylyl cyclase and phospholipase C are activated by different types of G
proteins à different extracellular signals
• cGMP
• Each activated enzyme generates many 2nd messenger molecules à • IP3, DAG, Ca2+
signal amplification

Alberts. Molecular biology of the cell. 6e, 2017

 GPCR-ADENYLYL CYCLASE SIGNAL TRANSDUCTION

• Most commonly, Gα subunit

switches on adenylyl cyclase à
dramatic and sudden increase in
the synthesis of cAMP from ATP
• To terminate the signal, cAMP
phosphodiesterase, rapidly
converts cAMP to AMP
cAMP-dependent
protein kinase (PKA)
mediates most of the
effects of cAMP

Silverthorn et al. 2019. Human physiology: an integrated approach. 8th. Pearson

 WHEN WE ARE FRIGHTENED OR EXCITED

• adrenal gland releases epinephrine hormone (adrenaline)

• adrenaline circulates in bloodstream & binds to adrenergic receptors
(in different cell types) à prepare the body for sudden action
• skeletal muscle:
- adrenaline increases cAMP à breakdown glycogen (polymerized storage
form of glucose) within seconds of epinephrine binding to receptor
- activate PKA to promote glycogen breakdown and inhibit glycogen
synthesis à maximizes the amount of glucose available as fuel for
anticipated muscular activity.

• fat cells:
- adrenaline stimulates the breakdown of fat to fatty acids.
- fatty acids be exported to fuel ATP production in other cells

Alberts. Molecular biology of the cell. 6e, 2017

 α subunit controls response time
• Gα controls the amount of time that the α subunit and βγ complex
remain “switched on”—and hence available to relay signals—also
determines how long a response lasts.
• Gα has an intrinsic GTPase activity, and it eventually hydrolyzes its
bound GTP to GDP à returning the whole G protein into origina/
inactive conformation
• GTP hydrolysis and inactivation usually occur within seconds after the
G protein has been activated.

Alberts. Molecular biology of the cell. 6e, 2017

 BACTERIAL TOXINS ALTERS G PROTEINS ACTIVITIES

• CTFR channel in the gut:

- CTFR is expressed on the apical membrane of epithelial
cells
- cAMP + PKA à phosphorylation of CTFR à open the
channel
• Cholera: Vibrio cholerae multiplies in intestine,
produces a protein called cholera toxin
- cholera toxin enters endothelial intestinal cells &
modifies the Gα subunit
- Modified Gα cannot hydrolyzing its bound GTP

What is the consequence? cholera toxin

https://www.frontiersin.org/articles/10.3389/fphys.2021.690247/full
 BACTERIAL TOXINS ALTERS G PROTEINS ACTIVITIES

• Cholera: Vibrio cholerae multiplies in intestine,

produces a protein called cholera toxin
- Modified Gs cannot hydrolyzing its bound GTP à G
protein is locked in activate GTP-bound state &
stimulates adenylyl cyclase à prolonged/excessive
outflow of Cl–
- Na+ follows through sodium channels to neutralize
the charge.
- NaCl draws water into the gut by osmotic force à
catastrophic diarrhea and dehydration.
• The diarrhea producing effects of cholera toxin
helps the disease-causing bacteria move from
host to host.

https://www.scirp.org/journal/paperinformation.aspx?paperid=89167
 INCREASED cAMP ALTERS GENE TRANSCRIPTION

• cAMP can change the transcription of specific genes (take hours to

develop fully).
• Exp: In cells that secrete the peptide hormone somatostatin
- cAMP activates the gene that encodes this hormone.
- CRE element: short cis-regulatory sequence in the regulatory region of
genes activated by cAMP.
- CREB protein: transcription regulator binds CRE.
- cAMP activate PKA; PKA phosphorylates CREB à recruits a transcriptional
coactivator CBP à turn on the transcription of the target genes
- CREB can transform a short cAMP signal into a long-term change in a cell,
a process that, in the brain, is thought to play an important part in some
forms of learning and memory.

Alberts. Molecular biology of the cell. 6e, 2017

 GPCR-PHOSPHOLIPASE C SIGNAL TRANSDUCTION

PKC phosphorylates a set

of intracellular proteins
that varies depending on
the cell type

Alberts. Molecular biology of the cell. 6e, 2017

 CALCIUM AS AN INTRACELLULAR MESSENGER

• Extremely low concentration (10–7 M) of cytosolic Ca2+

in unstimulated cell as compared to its concentration in
extracellular fluid (about 10–3 M) and ER.
• Fertilization: when a sperm fertilizes an egg cell, Ca2+
channels open à ↑ cytosolic Ca2+ à egg
• Muscle contraction: signal from a nerve à ↑ cytosolic
Ca2+ à muscle contraction
• Secretion: Ca2+ triggers secretion in many secretory
cells, including nerve cells
• Ca2+ stimulates all these responses by binding to and
influencing the activity of various Ca2+-responsive
proteins.
enzyme release of Ca2+ binds troponin
transporter insulin from à muscle
gated ion channels pancrea contraction

Silverthorn et al. 2019. Human physiology: an integrated approach. 8th. Pearson

Enzyme-coupled receptors
- Protein kinases: serine-; thereonine-; tyrosine- kinases
- 30-50% of human protein contain covalently attached phosphate
- Human genome encoding for: 520 protein kinases; 150 protein phosphatase
- A typical human cell use hundreds of distinct types of protein kinases at any moment
 ENZYME-COUPLED RECEPTORS
• Where? found in all the cells
receptor tyrosine kinases (RTKs)
• Characteristics?
- speed:
§ slow (hs): effects required the induction of gene expression
§ rapid: reconfigurations of the cytoskeleton, changing the cell’s
shape and movement
- signal: signal proteins at very low concentrations (about 10–9 to
10–11 M).
• Effect?
- responses to extracellular signal proteins that regulate the
growth, proliferation, differentiation, and survival of cells Tyrosine kinase (TK) transfers a phosphate
group from ATP to a tyrosine of a protein
• Exp? abnormalities in enzyme-coupled receptors have a
major role in the development of most cancers

Silverthorn et al. 2019. Human physiology: an integrated approach. 8th. Pearson

 ENZYME-COUPLED RECEPTORS
Ca

phospholipase C Ras-GEF PI 3-kinase

sc
ad
es
and

PKC MAP kinase Akt kinase

Am
pli
fic
at
ion

Responses
Silverthorn et al. 2019. Human physiology: an integrated approach. 8th. Pearson
EGFR and Personalized
medicine
 EGFR
receptor tyrosine kinases
EGFR Growth factors Cetuximab
C o l o r e c ta l C a n c e r Cell membrane

EGFR is upregulated in colorectal cancer cells Dimerization

P P Cytoplasm
• Binding of Cetuximab to EGFR blocks the EGFR
phosphorylation

phosphorylation and activation of

receptor-associated tyrosine kinase à
inhibits cell growth

• Cetuximab’s inhibitory effect is more

pronounced on tumor cells than on
normal cells.

https://www.creativebiolabs.net/cetuximab-overview.htm
 EGFR

Colorectal Cancer

Cetuximab
Cell membrane

P P Cytoplasm

RAS-RAF-MAPK: cell proliferation

PI3K-PTEN-AKT: cell survival and motility-invasion

Bardelli and Siena. J. Clin. Oncol. B. 2010

Signal termination
 SUMMARY OF SIGNAL TRANSDUCTION
1. Reception

2. Transduction

3. Response

Alberts. Molecular biology of the cell. 6e, 2017 Silverthorn et al. 2019. Human physiology: an integrated approach. 8th. Pearson
FAS-INDUCED APOPTOSIS

Lee et al., 2006. EMBO J

 GLUCOSE SIGNALING

tyrosine kinase receptor

https://www.cellsignal.com/pathways/insulin-receptor-signaling-pathway