Komunikasi Antar Sel

(Cell Signalling)
Pertahanan hidup (survival) tergantung pada jaringan komunikasi
interselular yang mengkoordinasi pertumbuhan, diferensiasi dan
metabolisme
 Evolution of Cell Signaling
• Yeast cells
– Identify their mates by cell signaling
1 Exchange of  factor
mating factors. Receptor
Each cell type
secretes a
mating factor a 
that binds to
receptors on
the other cell
type. Yeast cell,  factor Yeast cell,
mating type a mating type 
2 Mating. Binding
of the factors to
receptors
induces changes a 
in the cells that
lead to their
fusion.
3 New a/ cell.
The nucleus of
the fused cell
includes all the
a/
genes from the
a and a cells.
 Methods used by Cells to
Communicate
• Cell-Cell communication
• Cell Signaling using chemical messengers
– Local signaling over short distances
• Cell-Cell Recognition
• Local regulators
– Paracrine (growth factors)
– Synaptic (neurotransmitters)
– Long distance signaling
• Hormones
 Cell-Cell Communication
• Animal and plant cells
– Have cell junctions that directly connect the
cytoplasm of adjacent cells
Plasma membranes

Gap junctions Plasmodesmata

between animal cells between plant cells
(a) Cell junctions. Both animals and plants have cell junctions that allow molecules
to pass readily between adjacent cells without crossing plasma membranes.
 Cell-Cell Communication

• Animal cells use gap junctions to send

signals
– Cells must be in direct contact
– Protein channels connecting two adjoining cells

Gap junctions
between animal cells
 Cell-Cell Communication

 Plant cells use plasmodesmata to send signals

 Cells must be in direct contact
 Gaps in the cell wall connecting the two

adjoining cells together

Plasmodesmata
between plant cells
 Local Signaling: Cell-Cell Recognition
• In local signaling, animal cells may communicate via direct
contact
• Membrane bound cell surface molecules
• Glycoproteins
• Glyolipids

(b) Cell-cell recognition. Two cells in an animal may communicate by interaction

between molecules protruding from their surfaces.
 Local Signaling: Local Regulators
• In other cases, animal cells
– Communicate using local regulators
– Only work over a short distance
Local signaling

Target cell Electrical signal

along nerve cell
triggers release of
neurotransmitter

Neurotransmitter
Secretory diffuses across
vesicle synapse

Local regulator
diffuses through Target cell
extracellular fluid is stimulated

(a) Paracrine signaling. A secreting cell acts
on nearby target cells by discharging
molecules of a local regulator (a growth
factor, for example) into the extracellular
fluid.
(b) Synaptic signaling. A nerve cell
releases neurotransmitter molecules
into a synapse, stimulating the
target cell.
 Long-distance Signaling: Hormones
• In long-distance signaling
– Both plants and animals use hormones
Long-distance signaling

Endocrine cell Blood

vessel

Hormone travels
in bloodstream
to target cells

Target
cell

(c) Hormonal signaling. Specialized

endocrine cells secrete hormones
into body fluids, often the blood.
Hormones may reach virtually all
body cells.
 Long-Distance Signaling
 Nervous System in Animals
 Electrical signals through neurons
 Endocrine System in Animals
 Uses hormones to transmit messages over long

distances
 Plants also use hormones
 Some transported through vascular system

 Others are released into the air

 Molekul sinyal
• Autokrin
– Sel mempunyai reseptor bagi
molekul sinyal yang disekresinya
• Parakrin
– Molekul sinyal terikat reseptor
pada sel-sel di sekitar sel yang
mensekresinya
• Endokrin
– Molekul sinyal terikat reseptor
pada sel-sel yang jauh dari sel yang
mensekresinya

13
Figure 15-4 Molecular Biology of the Cell (© Garland Science 2008)
 The Three Stages of Cell Signaling
• Earl W. Sutherland (1971)
– Discovered how the hormone epinephrine acts on cells
• Sutherland 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
 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
 Penerimaan (reception):
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

• Proses pendeteksian molekul sinyal yang datang dari luar sel

• Molekul sinyal berikatan dengan reseptor
• Berdasarkan sifat molekul sinyal, penerimaan dapat dilakukan
oleh protein reseptor yang terdapat di: membran plasma
(Contoh: reseptor hormon epinefrin), atau Sitoplasma (reseptor
intraseluler). Contoh: reseptor hormon steroid
 Transduksi: (pengolahan sinyal)
EXTRACELLULAR CYTOPLASM
FLUID
Plasma membrane

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

Signaling
molecule

 Merupakan urutan perubahan dalam sederetan molekul yg berbeda, dan

disebut jalur transduksi sinyal
 Pada tahap ini terjadi perubahan sinyal menjadi suatu bentuk yang dapat
menimbulkan respon seluler spesifik
 Respon
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 catalysis, activation of a gene,

molecule
triggering apoptosis, almost anything!
Produksi respon seluler spesifik --- Aktivitas seluler seperti:
 Reaksi enzimatik
 Penyusunan ulang sitoskeleton
 Pengaktifan gen spesifik dalam nukleus
 Macam-macam Reseptor Sinyal
1. Reseptor Terkait-Protein G (G protein-coupled
reseptor/GPCR)
– Berupa protein membran yg bekerja bersamaan dgn protein G dan
protein lain (biasanya enzim)
– Pendeteksian sinyal berupa cahaya, bau, dan deteksi hormon serta
neurotransmiter tertentu
– Jalur ini bisa mengaktivasi atau menginhibisi tgt protein G yg terikat
pada reseptor
• Protein G yang menstimulasi (Gs): protein menstimulasi
effector enzyme
• Protein G yang menginhibisi (Gi): protein menginhibisi effector
enzyme
– Aktivasi enzim (Contoh: adenylil cyclase) akan menghasilkan
sejumlah second messenger yang menentukan respon seluler
terhadap sinyal yang datang
Ligan berikatan Aktivasi Aktivasi/ Respon
dgn reseptor protein G seluler
Inhibisi
shg teraktivasi
enzim
 Reseptor Terkait-Protein G

Struktur GPCR
adenylyl cyclase (AC)
2. Reseptor Tirosin-Kinase
– Reseptor membran yang memiliki bagian protein di sisi sitoplasmik
yang berperan sbg enzim (tirosin kinase)
– Fungsi: mengkatalisis transfer gugus fosfat (fosforilasi) dari ATP ke
asam amino tirosin pd protein substrat
– Tahapan proses transduksi sinyal yang terjadi:
• Pengikatan ligan menyebabkan 2 polipeptida reseptor membentuk
dimer
• Dengan menggunakan gugus fosfat dari ATP, daerah tirosin kinase
setiap polipeptida memfosforilasi tirosin pada peptida lain (dimer
merupakan substrat sekaligus enzim) → protein reseptor
teraktivasi
• Aktivasi reseptor menyebabkan reseptor dapat berikatan dengan
protein intraseluler dan mengaktifkannya melalui fosforilasi
– Contoh: faktor pertumbuhan, yg merangsang sel untuk tumbuh dan
bereproduksi.
Reseptor Tirosin-Kinase
3. Reseptor Saluran Ion
– Protein membran berupa ion-channel protein yang membuka
ketika berikatan dengan ligan dan menutup ketika ligan terlepas
dari reseptor
– Pengikatan ligan menyebabkan terbukanya saluran ion sehingga
ion-ion dari cairan ekstraseluler dapat masuk ke dalam sitosol sel
target
– Perubahan konsentrasi menyebabkan perubahan potensial
elektrik membran plasma
– Contoh:
• Pada sel saraf: Saluran ion Na+ dan K+ pada sel saraf terbuka
ketika hormon asetilkolin berikatan dengan reseptornya
• Pada sel otot: pengikatan asetilkolin mengakibatkan
masuknya ion Ca2+ dan menghasilkan kontraksi otot
Reseptor Saluran Ion
4. Reseptor Inti
– Berupa reseptor yg terletak di
sitoplasma atau nukleus sel
target.
– Sinyal kimiawi masuk ke dalam
sel melewati membran plasma
– Molekul sinyal berukuran cukup
kecil shg bisa melewati
- fosfolipid membran atau
molekul sinyal berupa lipid shg
terlarut dalam membran.
– Contoh:
• Hormon steroid dan
hormon tiroid (lipid), mis:
testosteron
• Molekul gas oksida nitrat
(NO)
 1. Reception
• A signal molecule, a ligand, binds to a receptor
protein in a lock and key fashion, 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.
 G-Protein Receptors G-Protein Coupled Receptors are
often involved in diseases such as
bacterial infections.
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
• 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)
Ion Channel Receptors 1
Gate
closed Ions
Signaling
molecule
• Very important in the (ligand)

nervous system Ligand-gated Plasma

ion channel receptor membrane
• Signal triggers the 2
opening of an ion Gate open

channel
– depolarization Cellular
response
– Triggered by
neurotransmitters 3 Gate closed
 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.
 • Transduksi
sinyal
– Proses dimana
informasi yang
dibawa
molekul sinyal
dari luar sel
menyebabkan
perubahan di
dalam sel

35
Figure 15-1 Molecular Biology of the Cell (© Garland Science 2008)
 Fig. 11-9

Signaling molecule

Receptor
Activated relay
molecule Transduction:
Inactive
protein kinase
A Phosphorylation
1 Active
protein
Cascade
kinase
1
Inactive
protein kinase ATP
ADP Active P
2
protein
PP kinase
Pi 2
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 and
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
• A phosphorylation cascade
Signal molecule

Receptor Activated relay A1relay 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
1 this second kinase.
Inactive
protein kinase ATP
2 ADP Active P 3 Active protein kinase 2
protein then catalyzes the phos-
PP kinase phorylation (and activation) of
Pi 2 protein kinase 3.
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
Pi
 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.

http://media.pearsoncmg.com/bc
/bc_campbell_biology_7/media/in
teractivemedia/activities/load.ht
ml?11&C
Small Molecules and Ions as Second
Messengers
 Molekul sinyal kedua
(second messenger)
• Ligan yang terikat reseptor = molekul sinyal pertama
• Akibat aktivasi reseptor, akan dihasilkan molekul
sinyal lain yang dapat berdifusi di dalam sel seperti:

 Ca2+ – Diasil gliserol (DAG)

 Fosfoinositida – cGMP
 Inositol trifosfat – cAMP
– NO (Nitric oxide)

41
 Molekul sinyal kedua
(second messenger)
• Second messenger berfungsi memperjelas/menguatkan
sinyal ekstraseluler
• 1 molekul epinephrine berikatan dg 1 GPCR – menghasilkan
sintesis beberapa molekul cAMP yg dapat mengaktifkan dan
memperkuat beberapa molekul PKAs
• Konsentrasi epinefrin dalam darah sebesar 10-10M dapat
meningkatkan kadar glukosa hingga 50%

42
 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
 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
– HO P O CH2
O P O P O 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
 First messenger

Adenylyl
G protein cyclase

G protein-coupled GTP
receptor

ATP
Second
cAMP messenger

Transduction in a Protein
kinase A
G-protein pathway

Cellular responses
 Calcium ions and Inositol Triphosphate
(IP3)
• Calcium, when released into the cytosol of a cell acts as a second
messenger in many different pathways
EXTRACELLULAR Plasma
FLUID membrane
Ca2+
Calcium is an important second
ATP pump messenger because cells are able to
Mitochondrion regulate its concentration in the
cytosol
Nucleus

CYTOSOL

Ca2+
pump
Endoplasmic
ATP Ca2+ reticulum (ER)
pump Other second messengers such as
inositol triphosphate and
Key High [Ca2+] Low [Ca2+]
diacylglycerol can trigger an
increase in calcium in the cytosol
– Ion Kalsium
• Dihasilkan melalui pembukaan saluran kalsium pd
membran plasma RE, melepaskan kalsium
• Peningkatan ion Ca+ dalam sel β menyebabkan
sekresi insulin
• Peningkatan ion Ca+ intraseluler juga
menyebabkan kontraksi sel otot
• Melalui bantuan calmodulin, protein pengikat
Ca+, ion Ca+ mengaktifkan atau menginaktifkan
protein transduksi secara langsung
 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
Cellular
reticulum (ER) Ca2+ 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.
 Growth factor

3. Response Receptor Reception

• Many possible
Phosphorylation
outcomes cascade Transduction

• This example
CYTOPLASM
shows a
transcription
response Inactive
transcription
Active
transcription
factor factor Response
P

DNA
Gene

NUCLEUS
mRNA
 Signaling
molecule

• Specificity of the Receptor

signal
– The same signal
molecule can
trigger different Relay
responses molecules

– Many responses
can come from one
signal! Response 1 Response 2 Response 3

Cell A. Pathway leads Cell B. Pathway branches,

to a single response. leading to two responses.
• The signal can
also trigger an
activator or
inhibitor
• The signal can
also trigger
multiple Activation
receptors and or inhibition
different
responses
Response 4 Response 5

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

between two pathways. leads to a different response.
• Jalur transduksi mengarah ke pengaturan aktivitas seluler
yang dapat berupa:
– Penyusunan ulang sitoskeleton
– Pembukaan atau penutupan saluran ion dalam
membran plasma
– Aktivitas metabolisme sel
– Sintesis protein
• Jalur pensinyalan yang rumit memiliki manfaat penting:
– Menguatkan sinyal.
Pada setiap langkah katalitik pada kaskade fosforilasi
jalur transduksi sinyal, jumlah produk yang teraktivasi
jauh lebih besar dari pada langkah sebelumnya
– Penentuan respon.
Respon suatu sel terhadap sinyal bergantung pada
variasi sinyal, reseptor, molekul relay, dan protein
yang dibutuhkan untuk melaksanakan respon.
Suatu respon seluler dapat dihasilkan
melalui aktivasi jalur yang berbeda

 StimulasiGPCRs atau RTKs

menghasilkan sejumlah second
messengers, dan kedua jenis
reseptor mengaktifkan dan
menginhibisi sekresi sejumlah
second messenger yang sama
 RTKs dapat meningkatkan
signal transduction cascade yg
seringkali bekerja pada target
yg sama dgn GPCR
 Suatu respon seluler dapat
diinduksi oleh beberapa jalur
pensinyalan sel yang
berbeda
 Interaksi jalur pensinyalan yg
berbeda memungkinkan
aktivitas seluler berjalan dg baik
 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.
Figure 11.6 CYTOPLASM
 Signaling Efficiency: Scaffolding Proteins
and Signaling Complexes
• Scaffolding proteins
– Can increase the signal transduction efficiency

Signal
molecule Plasma
membrane

Receptor

Three
different
protein
Scaffolding kinases
protein

Figure 11.16
 Terminasi sinyal
• Molekul sinyal didegradasi oleh enzim ektraseluler
• Reseptor bersama ligannya didegradasi
• Reseptor terpisah dari ligan di dalam endosom
– Reseptor kembali ke permukaan sel
– Ligan didegradasi

57
 REVIEW: Signal-transduction pathway
• Definition: Signal on a cell’s surface is converted into a specific
cellular response

• Local signaling (short distance): √

Paracrine (growth factors) √
Synaptic (neurotransmitters)
• Long distance: hormones
 Stages of cell signaling

• Sutherland (‘71)
• Glycogen depolymerization by epinephrine
• 3 steps:
•Reception: target cell detection
•Transduction: single-step or series of changes
•Response: triggering of a specific cellular response
• G-protein-linked receptors
Signal-binding site

Segment that
interacts with
G proteins

G-protein-linked Activated Inctivate

Plasma Membrane Signal molecule
Receptor Receptor enzyme

GDP
G-protein GDP GTP
CYTOPLASM (inactive) Enzyme

Activated
enzyme

GTP
GDP
Pi

Cellular response
Figure 11.7
 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
 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)
 Cellular responses to signals

• Cytoplasmic activity
regulation
• Cell metabolism
regulation
• Nuclear transcription
regulation