CELL

COMMUNICATION
Dr. Gwenny Ichsan Prabowo, dr., M.Kes
Departemen Biokimia FKUA
2019
 INTRODUCTION
A multi cellular organism consist of a great
number of cells, each with its own location,
function and activity

To insure the survival of the organism, the

activity of each cell must be well coordinated,
integrated and synchronized

To achieve this objective, there must be a way

for cells to signal each other i.e. to
communicate with each other
*Multicellular organisms need to
coordinate cellular functions in
different tissues

*Cell-to-cell communication is also used

by single cell organisms to signal to

other organisms

*Biologists have discovered several

universal mechanisms of cellular
regulation
• Cell-to-cell communication is
essential for multicellular organisms

• 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
Cell to Cell Communication
 Cells communicate with each other
through signaling molecules

Hello!

signaling cell target cell

 Cells that produce the signaling molecule are

referred to as signaling cells
 Cells that receive the signal are target cells
Cell Communication
 Types of Chemical
Signaling

Chemical signaling
between cells is one of the
most important ways that
activities of tissues and
.organs are coordinated
The nervous system is the
other major coordinating
system in animals, but
even here chemical
signaling is used between
.adjacent neurons
 Modes of cell-cell signaling

1. Direct cell-cell or cell-matrix

2. Indirect secreted molecules.
A. Endocrine signaling. The signaling molecules are hormones
secreted by endocrine cells and carried through the
circulation system to act on target cells at distant body
sites.
B. Paracrine signaling. The signaling molecules released by
one cell act on neighboring target cells.

C. Autocrine signaling. Cells respond to signaling molecules

that they themselves produce.
A simple intracellular signaling pathway activated by an extracellular signal molecule
RECEPTORS :

1. CYTOSOLIC / INTRACELLULAR
For hydrophobic signaling molecules

2. TRANS MEMBRANE / CELL SURFACE

For hydrophilic signaling molecules
 Extracellular signal molecules bind to specific receptors

Regardless of the nature of the signal, the target cell responds

by means of a receptor protein, which specifically binds
the signal molecule and initiates a response
Example:
 Receptor types

There are 3 subclasses of transmembrane

receptor
The three largest classes of cell-surface receptor proteins are ion-channel-linked,
G-protein-linked, and enzyme-linked receptors
 Signaling molecules could be
proteins, small peptides, amino
acids, nucleotides, steroids,
retinoids, fatty acid derivatives,
nitric oxide, carbon monoxide

 The signaling molecule could either

be secreted from the signaling cell
or it could stay tightly bound to
the cell surface of the signaling
cell
 Four forms of intercellular signaling

Extracellular signal molecules can act over either short or long distances
The Three Stages of Cell Signaling
• Earl W. Sutherland (1971)  suggested that
cells receiving signals went through three
processes
– Reception
– Transduction
– Response
• Called Signal transduction pathways
– Convert signals on a cell’s surface into
cellular responses
– Are similar in microbes and mammals,
suggesting an early origin
General mechanism of cellular signaling

1.Reception of signal
2.Transduction of signal
3.Cellular response
 Signaling cascades perform 5 crucial functions

Transduce signal into

molecular form that can
stimulate response
• Relay signal from point
of reception to point of
action in the cell
• Amplify the received
signal
• Distribute the signal to
influence several
responses in parallel
• Each step is open to
modulation by other
signals
 Receptors relay signals via intracellular
signaling pathways
• Individualcells respond
to a limited set of signals
for which they have
receptors
• A single cell may have 10
to 100,000 different
receptors
• Many signals acting
together can elicit
different cellular
responses - a complex
network
A signaling molecule may induce different responses in
different cell types
 Overview of cell signaling

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
 Three Stages of Cell Signaling
EXTRACELLULAR CYTOPLASM
FLUID
Plasma membrane

1 Reception
Receptor The receptor and signaling molecules
fit together (lock and key model,
induced fit model, just like enzymes!)

Signaling
molecule

 Signaling molecule binds to the receptor

protein
AP Biology
1. Reception
• A signal molecule, a ligand, binds to a receptor
protein in a lock and key model, induced fit model
causing the receptor to change shape.

 Most receptor
proteins are in the
cell membrane but
some are inside the
cell.

 The G-protein is a
common membrane
receptor.
 Three Stages of Cell Signaling
EXTRACELLULAR CYTOPLASM
FLUID
Plasma membrane

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

Signaling
molecule

The signal is converted into a form that can

produce a cellular response
AP Biology
2. Transduction
• Transduction: Cascades of molecular
interactions relay signals from receptors to
target molecules in the cell
• Multistep pathways
– Can amplify a signal (Amplifies the signal by
activating multiple copies of the next
component in the pathway)
– Provide more opportunities for coordination
and regulation
• At each step in a pathway, the signal is
transduced into a different form, commonly a
conformational change in a protein.
Fig. 11-9

Signaling molecule

Transduction:
Receptor
Activated relay
molecule

Inactive
protein kinase
A Phosphorylation
1 Active
protein Cascade
kinase

Ph
1

os
ph
Inactive

or
ATP

yla
protein kinase
ADP Active P

ti o
2
protein

n
ca
PP kinase

sc
Pi 2

ad
e
Inactive
protein kinase ATP
ADP Active P
3
protein
PP kinase
Pi 3
Inactive
protein ATP
ADP P
Active Cellular
protein response
PP
Pi
Protein Phosphorylation & Dephosphorylation

• Many signal pathways

– Include phosphorylation cascades

– In this process, a series of protein kinases

add a phosphate to the next one in line,
activating it
– Phosphatase enzymes then remove the
phosphates
 Protein phosphorylation

 Protein activity
regulation
 Adding phosphate from
ATP to a protein
(activates proteins)
 Enzyme: protein kinases
(1% of all our genes)
 Example: cell
reproduction
 Reversal enzyme:
protein phosphatases
 A phosphorylation cascade
Signal molecule

Receptor Activated relay 1 A relay molecule

molecule activates protein kinase 1.

Inactive
protein kinase 2 Active protein kinase 1
1 Active transfers a phosphate from ATP
protein to an inactive molecule of
kinase protein kinase 2, thus activating

Ph
1 this second kinase.

os
ph
Inactive

ory
protein kinase ATP

lat
2 ADP Active P 3 Active protein kinase 2

ion
protein then catalyzes the phos-

c
kinase phorylation (and activation) of

as
PP
Pi

ca
2 protein kinase 3.

de
Inactive
protein kinase ATP
3 ADP Active P 4 Finally, active protein
protein kinase 3 phosphorylates a
5 Enzymes called protein kinase protein (pink) that brings
phosphatases (PP) PP
Pi 3 about the cell’s response to
catalyze the removal of
the phosphate groups Inactive the signal.
from the proteins, protein ATP
ADP P
making them inactive
Active Cellular
and available for reuse.
protein response
PP
P i
 Three Stages of Cell Signaling
EXTRACELLULAR CYTOPLASM
FLUID
Plasma membrane

1 Reception 2 Transduction 3 Response

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

Can be catalysis, activation of a gene,

Signaling
molecule triggering apoptosis, almost anything!

The transduced signal triggers a cellular

response
AP Biology
 Growth factor

3. Response Receptor Reception

 Many possible
outcomes Phosphorylation
cascade Transduction

 This example
CYTOPLASM

shows a
transcription Inactive
transcription
Active

response
transcription
factor factor Response
P

DNA
Gene

NUCLEUS
mRNA
AP Biology
 Signaling
molecule

 Specificity of the Receptor

signal
 The same signal
molecule can
trigger Relay
different molecules

responses

 Many responses Response 1 Response 2 Response 3

can come from Cell A. Pathway leads Cell B. Pathway branches,

one signal! to a single response. leading to two responses.

AP Biology
 The signal can
also trigger
an activator
or inhibitor

 The signal can

also trigger Activation
multiple or inhibition
receptors and
different
responses
Response 4 Response 5

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

between two pathways. leads to a different response.

AP Biology
Response- cell signaling leads to regulation of transcription
(turn genes on or off) or cytoplasmic activities.
Cellular responses to signals

 Cytoplasmic activity
regulation

 Cell metabolism
regulation

 Nuclear transcription
regulation
 G-Protein Receptors
Inactive
Plasma
G protein-coupled enzyme
membrane Activated Signaling molecule
receptor
receptor

Enzyme

GDP
1 2
GDP
GTP
CYTOPLASM G protein
(inactive)

Activated
enzyme

GTP
GDP

P
3 4
Cellular response

AP Biology
Some G proteins activate the inositol phospholipid signaling pathway by
activating phospholipase C-b
Activation of a G protein by an activated GPCR
Enzyme-coupled cell-surface receptors

1. Receptor tyrosine kinases

2. Tyrosine-kinase-associated receptor

3. Receptor serine/threonine kinases

4. Histidine-kinase-associated receptors

5. Receptor guanylyl cyclases

6. Receptorlike tyrosine phosphatases

 Receptor tyrosine kinases
Signal Signal-binding site
molecule
Signal
Helix in the molecule
Membrane

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

Receptor tyrosine
CYTOPLASM kinase proteins Dimer
(inactive monomers)

Activated
relay proteins

Cellular
Tyr Tyr P Tyr Tyr P P Tyr Tyr P
Tyr P
response 1
Tyr Tyr P Tyr Tyr P P Tyr
Tyr Tyr P Tyr Tyr P P Tyr Tyr P Cellular
6 ATP 6 ADP
response 2
Activated tyrosine- Fully activated receptor
kinase regions tyrosine-kinase Inactive
(unphosphorylated (phosphorylated relay proteins
dimer) dimer)
The downstream signaling pathways activated by RTKs and GPCRs overlap
 Ion Channel Receptors
Gate
1 closed Ions
Signaling
molecule
(ligand)
 Very important in
the nervous system Ligand-gated
ion channel receptor
Plasma
membrane

 Signal triggers the 2

opening of an ion
Gate open

channel
 Depolarization Cellular
response
 Triggered by

neurotransmitters 3 Gate closed

AP Biology
The transduction stage of signaling is often a multistep
process that amplifies the signal.

About 1%
of our genes
are thought
to code for
kinases.
2 messenger
nd
 c-AMP, c-GMP
Second messengers

 Non-protein signaling
pathway
 Example: cyclic AMP
(cAMP)
 Ex: Glycogen breakdown
with epinephrine
 Enzyme: adenylyl cyclase
 G-protein-linked receptor
in membrane (guanosine
di- or tri- phosphate)
Small Molecules and Ions as Second Messengers
• Secondary messengers are small, nonprotein, water-soluble
molecules or ions that act as secondary messengers.
Cyclic AMP
• Many G-proteins trigger the formation of
cAMP, which then acts as a second
messenger in cellular pathways.
First messenger
(signal molecule
such as epinephrine) Adenylyl
G protein cyclase

G-protein-linked GTP
receptor
ATP
cAMP

Protein
kinase A

Cellular responses
Figure 11.10
Cyclic AMP
• Cyclic AMP (cAMP)
– Is made from ATP

NH2 NH2 NH2

N N N
N N N
O O N N N N O N N
O
Adenylyl cyclase Phoshodiesterase
O P O P O P O Ch2
–
HO P O CH2
CH2
O O O O O O O O O
Pyrophosphate P H2O
P Pi O 
O
OH OH OH OH OH
ATP Cyclic AMP AMP
 Cyclic-AMP-dependent protein kinase (PKA) mediates most of
the effects of cyclic AMP

Mammalian cells have at least two types of PKAs: type I is mainly in the cytosol, whereas
type II is bound via its regulatory subunit and special anchoring proteins to the plasma
membrane, nuclear membrane, mitochondrial outer membrane, and microtubules.
Calcium ions and Inositol Triphosphate (IP3)
• Calcium, when released into the cytosol of a cell acts as
a second messenger in many different pathways

Calcium is an important
EXTRACELLULAR
FLUID
Plasma
membrane
second messenger
Ca2+ because cells are able to
ATP
regulate its
pump
Mitochondrion

concentration in the
Nucleus cytosol
CYTOSOL
Other second
messengers such as
inositol triphosphate
Ca2+
pump
Endoplasmic
ATP Ca2+ reticulum (ER) and diacylglycerol can
pump
trigger an increase in
calcium in the cytosol
Key High [Ca2+] Low [Ca2+]
 1 A signal molecule binds 2 Phospholipase C cleaves a 3 DAG functions as
to a receptor, leading to plasma membrane phospholipid a second messenger
activation of phospholipase C. called PIP2 into DAG and IP3. in other pathways.

EXTRA-
Signal molecule
CELLULAR
(first messenger)
FLUID
G protein

DAG
GTP

G-protein-linked PIP2
receptor Phospholipase C
IP3
(second messenger)

IP3-gated
calcium channel

Endoplasmic Various
reticulum (ER) Cellular
Ca 2+ proteins
response
activated
Ca2+
(second
messenger)

4 IP3 quickly diffuses through 5 Calcium ions flow out of 6 The calcium ions
the cytosol and binds to an IP3– the ER (down their con- activate the next
gated calcium channel in the ER centration gradient), raising protein in one or more
membrane, causing it to open. the Ca2+ level in the cytosol. signaling pathways.
 Communication Hormones
– Involved in
• Growth
• Development
• Metabolism
• Reproduction
– Act by
1. Altering rates of enzyme mediated reactions
2. Control the movement of molecules across
the plasma membrane
3. Regulating the rate of gene expression (&
therefore protein production)
Some signaling molecules that bind to nuclear receptors

Nuclear receptors are ligand-activated gene regulatory proteins

The nuclear receptor superfamily
Long-distance Signaling
Intracellular signaling includes hormones that are
hydrophobic and can cross the cell membrane.

Once inside the cell, the

hormone attaches to a
protein that takes it into
the nucleus where
transcription can be
stimulated.

Testosterone acts as a
transcription factor.
Steroid hormones  bind to intracellular receptors

Hormone EXTRACELLULAR
(testosterone) FLUID 1 The steroid
hormone testosterone
passes through the
plasma membrane.
Plasma
Receptor membrane
2 Testosterone binds
protein to a receptor protein
Hormone- in the cytoplasm,
receptor activating it.
complex

3 The hormone-
receptor complex
enters the nucleus
and binds to specific
DNA genes.
mRNA 4 The bound protein
stimulates the
transcription of
NUCLEUS New protein the gene into mRNA.

5 The mRNA is
translated into a
specific protein.
CYTOPLASM
Figure 45.10 Glucose homeostasis maintained by insulin and glucagon
Termination of the Signal

• Signal response is terminated quickly

– By the reversal of ligand binding
 Signal Termination

protein tyrosine phosphatase (PTP).

Extracellular signals can act slowly or rapidly to change the behavior of a target cell
Cell to matrix interaction

Adhesion protein, eg:

• Integrin
• Cadherin
• Selectin