Cell Signalling

(Part 1)

Prof. Dr. Selma YILMAZER

Medical Biology Department
 Cell Signalling
• All cells
• receive signals from their surroundings and
• respond to signals.

• Behavior of each cell must be carefully

regulated to meet the needs of the organism as
a whole

• This is accomplished by a variety of signalling

molecules and their receptors
 Cell Signalling

• This is accomplished by a variety of signalling

molecules and their receptors

• 1-Signalling molecules
• 2-Receptors
(Signal molecules are produced and secreted from one
cell and bind to receptors expressed by the other cells)
 Cell Signalling
• The binding of signaling molecules to
their receptors
• initiates a series of intracellular reactions (signal
transduction) that
• regulate the cell behaviour;
• metabolism,
• movement,
• proliferation
• differentiation
• apoptosis
 Overview of cell signalling
EXTRACELLULAR CYTOPLASM
FLUID
Plasma membrane

1 Reception 2 Transduction 3 Response

Receptor

Activation
of cellular
response

Relay molecules in a signal transduction pathway

Signal
molecule
 Stage One: Reception
EXTRACELLULAR CYTOPLASM
FLUID
Plasma membrane

1 Reception

Receptor The receptor and signaling molecules

fit together (lock and key model, just
like enzymes!)

Signaling
molecule

• The signaling molecule (a ligand) binds to

the specific receptor protein.
 Stage Two: Transduction
EXTRACELLULAR CYTOPLASM
FLUID
Plasma membrane

1 Reception 2 Transduction
Receptor
2nd
Messenger
Relay molecules in a signal transduction pathway
!

Signaling
molecule

• a set off intracellular proteins ; second messengers carry the

original exterior signal to the interior of the cell
 Stage Three: Response
EXTRACELLULAR CYTOPLASM
FLUID
Plasma membrane

1 Reception 2 Transduction 3 Response

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

Signaling Can be activation of a gene,

molecule
triggering apoptosis,…etc

• The cell will respond to the signal (e.g. make a protein, enter mitosis,
apoptosis etc.)
 Signalling molecules
• Are released by signal-producing cells,
• reach and transfer biological signals to their target
cells
• to initiate specific cellular responses.
 Signalling molecules

• Proteins , Peptide hormones, (insulin, glucagon)

• Amino acids-epinephrine , histamine
• nucleotides
• Steroid hormones;(sex hormones,corticosteroids)
• thyroid hormone,
• vitamin D3,retinoic acid,
• fatty acid derivatives: prostaglandin,prostacyclins
• Gases- Nitric Oxide (NO,CO)

©2002 Lee Bardwell

 Types of Signaling molecules
1-Signal molecules that bind to cell-
surface receptors: (hydrophilic (charged,
polar) can't cross membrane can not enter the
cell
– Peptide hormones , i.e. insulin -
glucagon,
– Neurotransmitters (NT), i.e.
norepinephrine, histamine
– Growth factors (GF), i.e. NGF, EGF,
PDGF
– Fatty acid derivatives, i.e.
prostaglandins
 Types of Signaling molecules
2-Signal molecules that bind to intracellular receptors:
(lipid soluble hormones that diffuse across the plasma membrane
and interact with receptors in the cytosol or nucleus)
• steroids (Estrogen,Testosteron)
• thyroid hormone,
• retinoic acid,
• vitamin D3,
• gases ; nitric oxide NO,and CO
 Reception of the signal
(Receptors )
• Receptors for signal molecules can be either:
1-Specific membrane proteins ( membrane receptors)
2-intracellular proteins, (Intracellular receptors)
which are able
• to recognize and
• bind to signal molecules, (ligand)
• When activated by ligand ,
the receptor causes a change in the target cell
 Receptors
Cell surface receptors
Most signaling molecules are secreted
by one cell and bind to cell surface
receptors expressed by a target cell.

Intracellular receptors
The steroid hormones are small
hydrophobic molecules that diffuse
across the plasma membrane of
their target cells and bind to
intracellular receptors. (located in
cytosol or nuclei)
 Modes of Cell-cell signalling
1-Signalling by secreted signal molecules
In most cases, signal molecules are secreted
2- Signalling by membrane bound signal molecules
Signalling molecules remain bound to the surface of
the signalling cell. And influence only cells that
contact it.

Signalling by direct cell to

cell contact
 Modes of cell Signalling

Signalling with secreted molecules

Signalling Target
cell cell

Signalling with molecules embedded in the membrane

Signalling
cell
Extracellular Signal Molecules Can Act Over Short or Long
Distances
AUTOCRİNE
 Contact-dependent signalling
Examples:
Molecules providing
• Cell-Cell and
Cell-matrix
interactions
• i.e.Cadherin,integrin
mediated signalling
• Signalling during
Embryonic development
(i.e.notch-delta signalling
pathway )and
• in immune responses.
 Modes of Cell-cell signalling:
• Signalling by secreted molecules divided into four
categories
• A- Endocrine signalling
• B-Paracrine signalling
• C-Autocrine signalling
• D- Synaptic signalling
AUTOCRİNE
1-Endocrine signaling
• Endocrine cells secrete
their signal molecules
(hormones), into the
bloodstream, which carries
the signal to target cells
distributed throughout the
body (at distant body sites )
• i.e estrogen is secreted
from ovaries and stimulates
development and
maintenance of female
reproductive system
• 50 different endocrine
hormones are produced by
(pituitary,Thyroid,
pancreas, adrenal glands,
gonads
 2-Paracrine signalling
• The secreted molecules may act
as local mediators, affecting
only cells in the environment of
the signaling cell.
• Paracrine signals affect only
their neighbouring target cells,
the secreted molecules are not
allowed to diffuse too far.
• they are rapidly taken up by
neighboring target cells,
destroyed by extracellular
enzymes, or immobilized by
the extracellular matrix.
 Autocrine signaling
• Cells may also produce signals to which they also respond.
• seen during development and
• rarely seen in adult tissues i.e.
• In immun system, certain types of T lymphocytes
synthesize a growth factor that stimulates their own
proliferation
• Cancer cells often produce extracellular signals that
stimulate their own survival and proliferation (abnormal
signalling uncontrolled division of cancer cells)
 Autocrine signaling
• Is seen during early development
• Differentiating cells produce signals to which they also respond.

• A group of differentiating cells produce and secrete the same

signal that results in a strong signal for differentiation
• “community effect”

A group of cells producing the same autocrine

Single cell weak signal
signal result in strong signal for
differentiation,Community effect
 Synaptic signaling
• For complex multicellular organism, short-
range signaling is not sufficient to
coordinate the behavior of its cells.
• Nerve cells extend long processes (axons)
that enable them to contact target cells
far away. The nerve terminals located
there secrete a chemical signal called
a neurotransmitter.
These signals are secreted at specialized cell
junctions called chemical synapses,
• Synapses transmit
the neurotransmitter to the postsynaptic
target cell
 Gap Junctions allow Signaling Information to Be
Shared by Neighboring Cells

• Cells connected by gap

junctions share small
molecules, including small
intracellular signaling
molecules
i.e.Ca+2,cyclic AMP,
and can therefore respond to
extracellular signals in a
coordinated way.
 An animal cell's dependence on multiple extracellular signals
• Each cell type displays a set of receptors that
enables it to respond to a set of signal
molecules
• These signal molecules work in
combinations to regulate the behavior of the
cell.
• An individual cell requires
– multiple signals to survive (blue arrows)
– additional signals to divide
– additional signals to differentiate (green
arrows).
• If deprived of appropriate survival signals, a
cell will undergo a form of cell suicide known
as programmed cell death, or apoptosis.
A single signal molecule often has different effects on
different target cells.
• Different cell types are specialized to respond to acetylcholine
(neurotransmitter) in different ways.

– For heart muscle and salivary gland cells,

acetylcholine binds to similar receptor proteins, but the
intracellular signalling pathways are different in cells specialized
for different functions. (reduction of heart rate, secretion)

– Skeletal muscle cell produces a distinct type of

receptor protein for acetylcholine, which generates different
intracellular signals and results in a different effect.
(contraction)
 Different Cells Can Respond Differently to the Same Extracellular
Signal Molecule
Response varies according to the receptor proteins of the cell,
It varies according to the intracellular pathway by which the cell interprets the
signals it receives.
 Simple Gas;
Nitric Oxide (NO)
Is an important paracrine signaling molecule
nitric oxide (NO) acts as a signal molecule in nervous,immune and
circulatory systems.
In 1998 by Prof. Dr. Louis J Ignarro
Nobel Prize in Medicine
N O More Heart Disease
“Molecule of the Year” 1992
Published in the Journal «Science»
In 1980 they first described EDRF; endothelium-
derived relaxing factor
In 1986 it has been shown that EDRF is nitric oxide .
 NO
• is an important signal molecule in
Nervous system
immun system and
circulatory system
NO can pass directly across the target-
cell plasma membrane by diffusion
• In many target cells, including endothelial cells,
• NO binds to the enzyme guanylyl cyclase,(binds to iron in
the active site of the enzyme)
• stimulating this enzyme to produce the small intracellular
mediator cyclic GMP,
 NO
• In mammals, it regulates smooth muscle contraction in blood
vessels.
• Acetylcholine is released by autonomic nerves in the walls of a
blood vessel, and it causes smooth muscle cells in the vessel wall
to relax.
• The acetylcholine acts indirectly by inducing the nearby
endothelial cells to make and release NO, Nitric oxide is
synthesized from arginin amino acid by the enzyme
• Nitric oxide sytnhase

• It enters the underlying smooth muscle cells then

signals them to relax.
NITRIC OXIDE SIGNALS BY BINDING DIRECTLY TO AN ENZYME
INSIDE THE TARGET CELL IN MANY TARGET CELLS,
INCLUDING ENDOTHELIAL CELLS, NO BINDS TO IRON
ATOM( İN HEME GROUP) IN THE ACTIVE SITE OF THE
ENZYME GUANYLYL CYCLASE, STIMULATING THIS
ENZYME TO PRODUCE THE SMALL INTRACELLULAR
MEDIATOR CYCLIC GMP,
IT ACTS ONLY LOCALLY BECAUSE IT HAS A SHORT
HALF-LIFE—ABOUT 5–10 SECONDS—IN THE
EXTRACELLULAR SPACE BEFORE IT IS CONVERTED
TO NITRATES AND NITRITES BY OXYGEN AND WATER.
 Signalling pathway that stimulates dilation of blood
vessels
Acetylcholine is released by autonomic nerves in the walls
of a blood vessel(indirect effect)

induces the nearby endothelial cells to make and release
NO,

NO enters the underlying smooth muscle cells.

NO binds to the enzyme guanylyl cyclase and

Activates cGMP synthesis then signals smooth muscle
cells to relax
 Effect of NO on blood vessels
• This effect of NO on blood vessels provides an
explanation for the mechanism of action of
nitroglycerine, (sublingual tablet)
• which has been used for about 100 years to treat
patients with angina pectoris(pain resulting from
inadequate blood flow to the heart muscle).
Myocardial ischemia
• nitroglycerine, has coronary vasodilatory effect
• The nitroglycerine is converted to NO, which relaxes
blood vessels. Increase the blood circulation as a
consequence, it reduces the oxygen requirement of
the heart muscle and the pain is relieved
In immun system

• Active macrophagesNO

• Active neutrophiles NO To kill the

microorganisms
• Carbon monoxide (CO) is another gas that is used as an
intercellular signal. It can act in the same way as NO, by
stimulating guanylyl cyclase.

• These gases are not the only signal molecules that can pass
directly across the target-cell plasma membrane.
• A group of small, hydrophobic, nongaseous hormones and local
mediators enter target cells in this way.
• But instead of binding to enzymes, they bind to
intracellular receptor proteins that directly regulate gene
transcription.
Part II: Signal transmission with cell
surface receptors and intracellular
receptors
 Receptors

Two types of Receptors :

1-Cell surface receptors

2- Intracellular receptors
• Most extracellular signals are hydrophilic molecules
that bind to receptors on the surface of the target
cell
• But some signal molecules are hydrophobic and
small enough to pass across the target-cell plasma
membrane.
• Once inside, they directly regulate the activity of a
specific intracellular receptor protein
THE İNTRACELLULAR RECEPTORS:
THE NUCLEAR RECEPTOR
SUPERFAMİLY
 Signal molecules that can pass across the plasma
membrane
– Steroid hormones
– corticosteroids: (glucocorticoids,mineralocorticoids)is produced in the
adrenal gland and influences the metabolism of many types of cells.
– steroid sex hormones (Testosteron,estrogen, progesteron)are made in the
testes and ovaries.
– Not steroids ( but hydrophobic):
– vitamin D3 (in vertebrates): is synthesized in the skin in response to
sunlight; it regulates Ca2+ metabolism (many other functions),
– The thyroid hormones: act to increase the metabolic rate in a wide
variety of cell types
– the retinoids: (i.e. retinoic acid) are made from vitamin A and have
important roles in vertebrate development
• all made from cholesterol.
• for transport in the bloodstream they are made
soluble by binding to specific carrier proteins,