Cell Biology

Course No.: 7104102

2 CH.

Introduction to Cell Biology and Cell

Communication

1
Overview: Cellular Messaging

Cell communication is the process by which a

cell detects and responds to signals in its
environment.

Cell-to-cell
- communication is essential for both
-
en
0
multicellular and unicellular organisms

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Overview: Cellular Messaging
pheromones
5215
Unicellular organisms detecting by nose.

S how 20
can perceive changes in nutrient availability and
adapt their metabolism as needed.
may utilize environmental signals to locate a
suitable mate;
The cells of multicellular organisms must
communicate with one another to coordinate
the activities of the organism as a whole.

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Overview: Cellular Messaging
Biologists have discovered some universal
mechanisms of cellular regulation
Cells most often communicate with each other
via chemicalCsignals
For example, the fight-or-flight response is
-

triggered by a signaling molecule called

epinephrine

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 Signaling
Local Long-Distance
Direct contact hormones
Cell junctions
Cell-cell recognition receptor insulin

Local regulators targetall.

Paracrine signaling -
-

->
-

spraplingsare Synaptic signaling

↓
-

45
~

Sonal.
↑

d *
~ r

55jjy &

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Mechanisms of Local Signaling 190k
1. Local signaling by direct contact: two types:

a) Animal and plant cells have cell junctions that

directly connect the cytoplasm of adjacent cells

a) or cell-cell recognition: animal cells may

communicate via direct contact between
membrane-bound cell-surface molecules
especially important in embryonic
development and the immune response.
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&
connexors
 ⑥S
51555
cellulos
G detection.
↑
atime

system
-

cell cornicatio
#
cabolydal
2. Local signaling by local regulators: animal cells
communicate using local regulators, messenger
molecules that travel only short distances

-
⑮
 &
exocytosis

& agel
*
recaptors
 The Three Stages of Cell Signaling:
A Preview
Earl W. Sutherland discovered how the
-

<
hormone epinephrine acts on cells
55, Sutherland suggested that cells receiving
-

signals went through three processes

Reception -

Transduction - -
&

Response - ↑

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 ↓
↓
↓

I
-99 protein
71X
-
diffision.

·
 Concept 11.2: Reception: A signaling molecule
binds to a receptor protein, causing it to change
shape
The ability of a cell to respond to a signal depends
on whether or not it has a receptor specific to that
signal
The binding between a signal molecule (ligand)
and receptor is highly specific
A shape change in a receptor is often the initial
transduction of the signal
Most signal receptors are plasma membrane
proteins but others are located inside the cell

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Receptors in the Plasma Membrane
Most water-soluble signal molecules bind
to specific sites on receptor proteins that
span the plasma membrane
There are three main types of membrane
receptors
G protein-coupled receptors
Receptor tyrosine kinases
Ion channel receptors

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 G-protein-coupled receptor (GPCRs)
the largest family of cell-surface receptors
Many different signaling molecules use
GPCRs including:
yeast mating factors,
epinephrine (adrenaline), Glucagon and many
other hormones,
Neurotransmitters: for example serotonin on
serotonin receptors (5HTRs)

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Signaling molecule binding site A GPCR is a plasma
membrane receptor that
works with the help of a
G protein
G protein-coupled Plasma
receptor membrane
Segment that
interacts with
G proteins
⑳ So CYTOPLASM
GDP

G protein Enzyme
G protein-coupled receptor
d -> 6: Cinhibition
(inactive)
Monomeric Multimeric6sstimulations.
Rab ~

G proteins = Guanosine triphosphate dependent

regulatory proteins:
G protein
Why called G proteins? b.
1Active
2

because they binds guanine nucleotides (GTP and -

inactiveGDP) exchanging between (GDP/6T4)

=
 CT4

See SEF

Tuckerlich
Guanosine Exchange F

ga
Activating protein
654a12
hydrolysis S
·
C.S.,

gis
Achengere
-for
Imessenge

a
i-
firs GTP

re
in
Rop
Aud
A
ka
dep pro -
-
 Acatycholine

-)
-

cough
wopping
ults,

Iwihydiesar, th
-

i
 The G protein is the link a in the chain of
communication between the receptor and
other downstream enzymes
G protein acts as an on/off switch
In the inactive form of a G protein is bound to
GDP
Activation of G protein by the activated
receptor triggers replacement of GDP with
GTP (it is an exchange not a phosphorylation).

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 33 X
-

L
Discl

⑳ -

phospho
lipaa
azge
g) cond
Cybusul ⑪ S
messenger

Fo
I(
channel
&
S

⑧ &

⑧
La

endopl a smi c
Reticular riphosphate.
ca-calmodulin. Seeado
⑧-

-,
 air cill
Tayrosine

G protein hydrolysis GTP to GDP rapidly

(has an GTPase activity)
This causes:
inactivation of the G protein,
its dissociation from the enzyme,
thus the actions of the G protein GTP
complex are short-lived

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 Malfunctions of the associated G proteins
themselves are involved in many human
diseases, including bacterial infections.
The bacteria that cause cholera, pertussis
(whooping cough), and botulism, among
others cause illness by producing toxins that
interfere with G protein function.

Up to 60% of all medicines used today exert

their effects by influencing G protein
pathways.
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 Receptor tyrosine kinases (RTKs)
membrane receptors that when activated attach
phosphates to tyrosines on themselves
A RTK can trigger multiple signal transduction
pathways at once (compare to GPCRs which
trigger a single pathway)
Abnormal functioning of RTKs (example:
continuous activation in the absence of signaling
molecules) is associated with many types of
cancers

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Rassignalliyah
Signaling
molecule (ligand)
is jus
Ligand-binding site

helix in the Signaling

membrane molecule

Tyr Tyr Tyr Tyr Tyr

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

CYTOPLASM Receptor tyrosine Dimer

kinase proteins
1 (inactive monomers) 2

Activated relay
proteins

Cellular
P Tyr Tyr P
Tyr Tyr P Tyr Tyr P response 1
Tyr Tyr P Tyr Tyr P P Tyr Tyr P
Tyr Tyr P Tyr Tyr P P Tyr Tyr P Cellular
6 ATP 6 ADP
response 2
Activated tyrosine Fully activated Are
kinase regions receptor tyrosine -

3
(unphosphorylated
dimer)
kinase
(phosphorylated
4
chos
I
retir Inactive
relay proteins
dimer) I
y ~
+
 Cancer and RTKs:
Abnormal functioning of RTKs is associated with many types
of cancers.
Example: breast cancer patients have a poor prognosis if
their tumor cells harbor excessive levels of an RTK called
HER2.
Using molecular biological techniques, researchers have
developed a protein (monoclonal antibody) called
Trastuzumab (Herceptin®) that binds to HER2
receptors on cells, prevent their dimerization and inhibits
cell division, thus preventing further tumor development.
treatment with Trastuzumab improved patient survival
rates by more than one-third. Ipatients
->

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 multisubmi ↓
Ligand-gated ion channel -
-
S

a membrane receptor containing a region that

-

acts as a gate when the receptor changes

shape
When a signal molecule binds as a ligand to
the receptor, the gate allows specific ions,
such as Na+ or Ca2+, through the channel in
the receptor
Ligand-gated ion channels are very important in the nervous
system.

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 1 2 3

Signaling 0 Gate
closed Ions Gate
open
Gate closed
-
molecule
(ligand) 0

ligand
crys
formatio
8
Cellular
response

in

x5 : 9.5
i
system
nervous
~

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 Ligand-gated
ion channels
are very
important in
the nervous

en
system.

eric
much,
are
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Receptors in the Plasma Membrane:
cell surface receptors
cell-surface receptors represent 30% of all
human proteins but determining their structures
has proved challenging:
only 1% of cell-surface receptors structures have
been determined
Receptor (hydrophilic
unders
integral m.
or
intracellular hydrophobic in
cyl
t -

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Intracellular Receptors
Intracellular receptor proteins are found in the
cytosol or nucleus of target cells
Small or hydrophobic chemical messengers
can readily cross the membrane and activate
receptors
Examples of hydrophobic messengers are the
steroid and thyroid hormones of animals and
Nitric Oxide gas

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How the intracellular Receptors work?
1. The hormone has entered a cell,
2. Binds to the intracellular receptor in the
cytoplasm or the nucleus.
3. The binding changes the receptor into a
hormone-receptor complex that is able to cause
a response
in many cases, the turning on or off of
particular genes.

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Example: Aldosterone
1. secreted by cells of the adrenal gland
2. Aldosterone then travels through the blood
and enters cells all over the body. (response
occurs mainly in kidney cells)
3. In these cells, the hormone binds to the
receptor protein, activating it.
4. the active form of the receptor protein then
enters the nucleus and turns on specific
genes intracetat
-1
helps Receptor licon

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blogarity 1S transcrip
fastor
Example: Aldosterone (cont.)
5. The genes control water and sodium flow in
kidney cells, ultimately affecting blood
volume
When the aldosterone receptor is
activated, it acts as a transcription
factor that turns on specific genes.
Transcription factors: are special
proteins control which genes are turned
on; that is, which genes are transcribed
into mRNA in a particular cell at a
particular time
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 al

transcript
Concept 11.3: Transduction: Cascades
of molecular interactions relay signals
from receptors to target molecules in
the cell
Signal transduction pathway usually involves
multiple steps (plasma membrane receptors)
3
-
Multistep pathways can amplify a signal: A few
molecules can produce a large cellular response
Multistep pathways provide more opportunities
for coordination and regulation of the cellular
response
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Signal Transduction Pathways
The molecules that relay a signal from receptor
to response are mostly proteins
Like falling dominoes, the receptor activates
another protein, which activates another, and so
on, until the protein producing the response is
activated
At each step, the signal is transduced into a
different form, usually a shape change in a
protein (Very often, shape change is brought
about by phosphorylation)
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 Protein Phosphorylation and
Dephosphorylation
In many pathways, the signal is transmitted by a
cascade of protein phosphorylations
Protein kinases transfer phosphates from ATP
to protein, a process called phosphorylation

Protein kinase
(enzyme)
Protein Protein-P
(Substrate-1) (Product-2)
ATP ADP
(Substrate-2) (Product-2)
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 Protein phosphatases remove the phosphates
from proteins, a process called dephosphorylation

Protein
Phosphatase
Protein-P (enzyme) Protein
(Substrate) (Product-1)
Shake
PO hisp
(Product-2) P
↑
phospholabel
This phosphorylation and dephosphorylation
system acts as a molecular switch, turning
activities on and off or up or down, as required
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Figure 11.10

Signaling molecule

Receptor
Activated relay
molecule

Inactive
protein kinase
1 Active
protein
kinase
1

Inactive
protein kinase ATP
2 ADP P
Active
protein
PP kinase
Pi 2

Inactive
protein kinase ATP
3 ADP P
Active
protein
PP kinase
Pi 3
Inactive
protein ATP
ADP P
Active Cellular
PP
protein response
Pi
Small Molecules and Ions as Second
Messengers
The extracellular signal molecule (ligand)

first messenger
Second messengers are small, nonprotein,
water-soluble molecules or ions that spread
throughout a cell by diffusion

ge
e
↳ second massager
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Small Molecules and Ions as Second
Messengers
Second messengers participate in pathways
initiated by GPCRs and RTKs
Cyclic AMP and calcium ions are common
second messengers
G-protein

"gratal,
L

OTP-RNA- 2
GDP D. I
nucleic acid
-

ATP DNA

-
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Cyclic AMP
Cyclic AMP (cAMP) is one of the most widely
used second messengers

Adenylyl cyclase, an enzyme in the plasma

membrane, converts ATP to cAMP in response
to an extracellular signal

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Figure 11.11

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Figure 11.11a

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Figure 11.11b

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 Many signal molecules trigger formation of
cAMP
Other components of cAMP pathways are G
proteins, G protein-coupled receptors, and
protein kinases
cAMP usually activates protein kinase A, which
phosphorylates various other proteins
Further regulation of cell metabolism is provided
by G-protein systems that inhibit adenylyl
cyclase
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 First messenger
(signaling molecule
such as epinephrine)
Adenylyl
G protein cyclase

G protein-coupled GTP
receptor

ATP
Second
cAMP messenger

Protein
kinase A

Cellular responses
The ability of a hormone or neurotransmitter to stimulate or
inhibit AC depends on the type of G protein that is linked to
the receptor.
One type, designated Gs, stimulates AC,
whereas another type, designated Gi, inhibits the enzyme
Cholera toxin
an enzyme that chemically modifies a G protein
involved in regulating salt and water secretion.
Because the modified G protein is unable to
hydrolyze GTP to GDP, it remains stuck in its
active form, continuously stimulating adenylyl
cyclase to make cAMP.

Viagra (sildenafil)
A compound that inhibits the hydrolysis of
cGMP to GMP (Phosphodiesterase inhibitor)
a treatment for erectile dysfunction in human males.
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Calcium Ions and Inositol Triphosphate
(IP3)
Calcium ions (Ca2+) act as a second messenger
in many pathways
Calcium is an important second messenger
because cells can regulate its concentration

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EXTRACELLULAR Plasma
FLUID membrane

Ca2
ATP pump
Mitochondrion

Nucleus

CYTOSOL

Ca2
pump
Endoplasmic
Ca2 reticulum
ATP pump (ER)

Key High [Ca2 ] Low [Ca2 ]

 A signal relayed by a signal transduction
pathway may trigger an increase in calcium in
the cytosol
Pathways leading to the release of calcium
involve inositol triphosphate (IP3) and
diacylglycerol (DAG) as additional second
messengers
Example: -adrenergic receptor in liver
cells

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Figure 11.14-1

EXTRA-
Signaling molecule Example: -adrenergic
CELLULAR
FLUID (first messenger) receptor in liver cells
G protein

DAG
GTP
G protein-coupled PIP2
Phospholipase C
receptor
IP3
(second messenger)

IP3-gated
calcium channel

Endoplasmic Ca2
reticulum (ER)

CYTOSOL
Figure 11.14-2

EXTRA-
Signaling molecule Example: -adrenergic
CELLULAR
FLUID (first messenger) receptor in liver cells
G protein

DAG
GTP
G protein-coupled PIP2
Phospholipase C
receptor
IP3
(second messenger)

IP3-gated
calcium channel

Endoplasmic Ca2
reticulum (ER)
Ca2
(second
CYTOSOL messenger)
Figure 11.14-3

EXTRA-
Signaling molecule Example: -adrenergic
CELLULAR
FLUID (first messenger) receptor in liver cells
G protein

DAG
GTP
G protein-coupled PIP2
Phospholipase C
receptor
IP3
(second messenger)

IP3-gated
calcium channel

Various Cellular
Endoplasmic Ca2 proteins
reticulum (ER) responses
activated
Ca2
(second
CYTOSOL messenger)
Concept 11.4: Response: Cell signaling
leads to regulation of transcription or
cytoplasmic activities

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Nuclear and Cytoplasmic Responses
Ultimately, a signal transduction pathway leads
to regulation of one or more cellular activities
The response may occur in the cytoplasm or in
the nucleus
Many signaling pathways regulate the
synthesis of enzymes or other proteins,
usually by turning genes on or off in the
nucleus
The final activated molecule in the signaling
pathway may function as a transcription factor

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 Growth factor
Nuclear responses to a Reception
Receptor
signal: the activation
of a specific gene by a
growth factor Phosphorylation
cascade
Transduction

CYTOPLASM

Inactive Active
transcription transcription
factor factor Response
P

DNA

Gene

NUCLEUS mRNA
 Sometimes signaling pathways regulate the
activity of enzymes rather than their synthesis
Epinephrine signal on liver cells for example
ultimately leads to glycogen degradation by the
activation of glycogen phosphorylase enzyme
Other signals may cause the opening or closing
of an ion channel in the plasma membrane or a
change in cell metabolism
Signaling pathways can also affect the overall
behavior of a cell, for example, changes in cell
shape
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 First messenger
(signaling molecule
such as epinephrine)
Adenylyl
G protein cyclase

G protein-coupled GTP
receptor

ATP
Second
cAMP messenger

Protein
kinase A

Activation of Glycogen phosphorylase

which degrades glycogen
Regulation of the Response
-
the extent and specificity of the response
are regulated in multiple ways.
Amplifying the signal (and thus the response)
Specificity of the response
Overall efficiency of response, enhanced by
scaffolding proteins
Termination of the signal

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Signal Amplification

At each step, the number of activated products is

much greater than in the preceding step

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 The Specificity of Cell Signaling and
Coordination of the Response
Different kinds of cells have different collections
of proteins (different sets of genes are on)
These different proteins allow cells to detect and
respond to different signals
Even the same signal can have different effects in
cells with different proteins and pathways
Pathway branching and - further help
the cell coordinate incoming signals
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 The Specificity of Cell Signaling and
Coordination of the Response
Signaling
molecule

Receptor

Relay
Activation
molecules
or inhibition

Response 1 Response 2 Response 3 Response 4 Response 5

Cell A. Pathway leads Cell B. Pathway branches, Cell C. Cross-talk occurs Cell D. Different receptor
to a single response. leading to two responses. between two pathways. leads to a different
response.
Signaling
molecule

Receptor

Relay
molecules

Response 1 Response 2 Response 3

Cell A. Pathway leads Cell B. Pathway branches,

to a single response. leading to two responses.
(RTKs and 2nd messengers)
 Activation
or inhibition

Response 4 Response 5

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

between two pathways. leads to a different
(concept 11.5) response.
Signaling Efficiency: Scaffolding
Proteins and Signaling Complexes
Scaffolding proteins are large relay proteins to
which other relay proteins are attached
Scaffolding proteins can increase the signal
transduction efficiency by grouping together
different proteins involved in the same pathway
In some cases, scaffolding proteins may also
help activate some of the relay proteins

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 Signaling Plasma
molecule membrane

Receptor

Three
different
protein
kinases
Scaffolding
protein

One scaffolding protein isolated from mouse brain cells holds three
protein kinases and carries these kinases with it when it binds to an
appropriately activated membrane receptor; it thus facilitates a specific
phosphorylation cascade (The above Figure).
 Wiskott-Aldrich syndrome (WAS)
a primary human immunodeficiency
X-linked recessive inherited disorder
absence of a single relay protein (WASp) leads to
diverse effects
abnormal bleeding (due to thrombocytopenia),
eczema, a predisposition to infections,
autoimmunity and leukemia.
symptoms are thought to arise primarily from
the absence of the protein in cells of the
immune system.

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 Wiskott-Aldrich syndrome (WAS)
WAS protein is located just beneath the immune
cell surface and interacts both with:
microfilaments of the cytoskeleton
and with several different components of
signaling pathways that relay information
from the cell surface, including pathways
regulating immune cell proliferation.
When the WAS protein is absent, the
cytoskeleton is not properly organized and
signaling pathways are disrupted, leading to the
WAS symptoms.
© 2011 Pearson Education, Inc.
 Termination of the Signal
Inactivation mechanisms are an essential
aspect of cell signaling
It prepares the cell to respond to a fresh signal.
Abnormal signaling often seen in tumor cells is
proof that the termination of a signal at the
appropriate time can be just as important as the
initiation of a signal.
Remember the cholera toxin and G protein

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 Receptor inactivation : -
1. If ligand concentration falls, fewer receptors
will be bound (the binding of the ligand to the
receptor is reversible)
2. Unbound receptors revert to an inactive state
3. The cellular response occurs only when the
concentration of receptors with bound signaling
molecules is above a certain threshold. When
the number of active receptors falls below that
threshold, the cellular response ceases.

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Termination of the Signal
Relay molecules inactivation: differs
according to the molecule
The GTPase activity intrinsic to a G protein
hydrolyzes its bound GTP
the enzyme phosphodiesterase converts
cAMP to AMP;
protein phosphatases inactivate
phosphorylated kinases and other proteins;

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Concept 11.5: Apoptosis integrates
multiple cell-signaling pathways
Apoptosis is programmed or controlled cell
suicide
from Greek apo

Cells that are infected, damaged, or have

reached the end of their functional life span
programmed cell death

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Concept 11.5: Apoptosis integrates
multiple cell-signaling pathways
Components of the cell are chopped up and
packaged into vesicles that are digested by
scavenger cells

Apoptosis prevents enzymes from leaking out

of a dying cell and damaging neighboring cells

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Figure 11.20

2 m

Apoptosis of a human white blood cell. On the left is a

normal white blood cell, while on the right is a white
blood cell undergoing apoptosis. The apoptotic cell is
shrinking and forming lobes
are shed as membrane-bounded cell fragments (colorized
SEMs).
Signals for Apoptosis
The signal that triggers apoptosis can come from
either outside or inside the cell.
Outside the cell, signaling molecules released
from other cells can initiate a signal transduction
pathway that activates the genes and proteins
responsible for carrying out cell death.
Within a cell whose DNA has been irretrievably
damaged, a series of protein-protein interactions
can pass along a signal that similarly triggers cell
death.
© 2011 Pearson Education, Inc.
Apoptotic Pathways and the Signals
That Trigger Them 65
$
x

- >
j
->
⑧
exte

infect
cell
© 2011 Pearson Education, Inc.
 BC =

1 Family

->
L
pro-apoptotic anti-apoptotic.

->
cybc + Apa* 1 + Procaspase

damages?DNA
d Caspagc3
caspase s
-
Example: Apoptosis in the Soil Worm
⑮

Caenorhabditis elegans
Etymology: 'Caeno' and 'rhabditis' derived from
Greek, means 'recent' and 'rod-like' respectively.
'Elegans' is derived from Latin, means 'elegant'
due to the elegant sinusoidal movement of this
nematode (WIKIBOOKS)

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Apoptosis in the Soil Worm Caenorhabditis
elegans

Apoptosis is important in shaping an organism

-

during embryonic development

-

The role of apoptosis in embryonic development

was studied in C. elegans
In C. elegans, apoptosis results when proteins

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Apoptosis in the Soil Worm Caenorhabditis
elegans -
S

When there is no death

- &lig signal: apopto

E
As long as Ced-9, located in the outer
↓

mitochondrial membrane, is active, apoptosis is

inhibited, and the cell remains alive.
-

↓Y.
protein
I
-
small
&
-S
gen

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 Ced-9
protein (active)
inhibits Ced-4
activity

Mitochondrion

Ced-4 Ced-3
Receptor
for death- Inactive proteins
signaling
molecule
(a) No death signal
 When a cell receives a death signal:

Ced-9 is inactivated, relieving its inhibition of

Ced-3 and Ced-4.
Active Ced-3, a protease, triggers a cascade of
reactions leading to activation of nucleases and
other proteases.
The action of these enzymes causes the changes
seen in apoptotic cells and eventual cell death.

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 Ced-9 Cell
(inactive) forms
blebs
Death-
signaling
molecule

Active Active Other

Ced-4 Ced-3 proteases

Activation Nucleases
cascade

(b) Death signal

Apoptotic Pathways and the Signals
That Trigger Them
Caspases are the main proteases (enzymes that cut
up proteins) that carry out apoptosis
Apoptosis can be triggered by
An extracellular death-signaling ligand
DNA damage in the nucleus
Protein misfolding in the endoplasmic
reticulum

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 Apoptosis is essential for the development
-

and maintenance of all animals

-
- -

C
In vertebrates, apoptosis is essential for
normal development of the nervous system,
-
for normal operation of the immune system,
i t
and for normal morphogenesis of hands and
-

feet in humans and paws in other mammals

-

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⑧

ener
 Apoptosis may be involved in some diseases
- => -

Central nervous system

~Dys-p
In disease, an accumulation
of aggregated proteins in neuronal cellsStimulation
activates an enzyme that - triggers
apoptosis, resulting in the loss of brain
-
function seen in these patients.

proteins dismerlinin

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 Interference with apoptosis may contribute
to some cancers
S
-
j' /

- -

-
cancer can result from a failure of cell
apoptosis
suicide; some cases of human melanoma,
I
->

for example, have been linked to faulty

forms of the human version of the C.
elegans Ced-4 protein.
I .

⑤
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