Alberts • Johnson • Lewis • Raff • Roberts • Walter

Molecular Biology of the Cell

Fifth Edition

Chapter 15
Mechanisms of Cell
Communication

Copyright © Garland Science 2008

 Communication between cells is mediated by extracellular
signals

Figure 15-1 Molecular Biology of the Cell (© Garland Science 2008)

 Cells respond to the extracellular environment: example:
Saccharomyces cerevisiae

Figure 15-2 Molecular Biology of the Cell (© Garland Science 2008)

Figure 15-3a Molecular Biology of the Cell (© Garland Science 2008)
Figure 15-3b Molecular Biology of the Cell (© Garland Science 2008)
Figure 15-4 Molecular Biology of the Cell (© Garland Science 2008)
 Endocrine signaling :
- slow
- Act at very low
concentration

Figure 15-5a Molecular Biology of the Cell (© Garland Science 2008)

 Synaptic signaling
- Fast and precise
- High local
concentration

Figure 15-5b Molecular Biology of the Cell (© Garland Science 2008)

 Extracellular signal can act slow or rapidly to change the
behavior of a target cell

Figure 15-6 Molecular Biology of the Cell (© Garland Science 2008)

 Gap junctions allow neighboring cells to share signaling
information

Allow small molecules to pass freely between cells, like

Calcium, Cyclic AMP (2nd messenger)

Figure 15-7 Molecular Biology of the Cell (© Garland Science 2008)

 Cells are programmed to respond to specific combinations of
extracellular signal molecules

Figure 15-8 Molecular Biology of the Cell (© Garland Science 2008)

Different types of cells usually respond differently to the same
extracellular signal molecules

Figure 15-9 Molecular Biology of the Cell (© Garland Science 2008)

The fate of some developing cells depends on their position in
Morphogen gradients

Figure 15-10 Molecular Biology of the Cell (© Garland Science 2008)

 The cell can alter the concentration of an intracellular
molecule quickly if the lifetime of the molecule is short

Figure 15-11 Molecular Biology of the Cell (© Garland Science 2008)

 Nitric oxide acts as a signaling molecule, it relaxes smooth
muscles

Nitroglycerides used on patients with

angina – reduces the work load of the
heart.
Figure 15-12b Molecular Biology of the Cell (© Garland Science 2008)
 Small hydrophobic molecules that diffuse directly across the
plasma membrane

These bind to intracellular receptors to regulate gene

expression
Figure 15-13 Molecular Biology of the Cell (© Garland Science 2008)
 THE NUCLEAR RECEPTORS SUPERFAMILY

Steroid hormones (cortisol) made

of cholesterol, cortisol is made in
the adrenal cortex, influences
metabolism.
Steroid sex hormones made by
testes and ovaries – reponsible for
secondary sex characteristics
Vitamin D – made in the skin,
regulates calcium metabolism.
* The nuclear receptor (with
ligand) then binds to DNA to
regulate transcription
Figure 15-14a Molecular Biology of the Cell (© Garland Science 2008)
 Ligand binding alters the conformation of the receptor

Figure 15-14b Molecular Biology of the Cell (© Garland Science 2008)

 Ligand binding alters the conformation of the receptor:
inhibitor dissociates and coactivator binds

* In some cases ligand binding inhibits transcription

Figure 15-14c Molecular Biology of the Cell (© Garland Science 2008)
 The transcription response takes place in multiple steps:
primary and secondary responses

Figure 15-15 Molecular Biology of the Cell (© Garland Science 2008)

THE THREE LARGEST CLASS OF CELL-SURFACE
RECEPTORS

Most extracellular signals do not enter the

cell like the hydrophobic ones, but they
bind to specific receptors at the plasma
membrane
Ion-channel-coupled
G-protein-coupled
Enzyme-coupled

These receptors act as signal transducers

 Involved in rapid synaptic signaling between nerve cells,
and nerve and muscle cells
Mediated by neurotransmitters that open / close the
channel
Most belong to a family of multipass transmembrane
proteins
Figure 15-16a Molecular Biology of the Cell (© Garland Science 2008)
 A trimeric G protein (GTP binding) mediates the
interaction between the activated receptor and this target
protein.
All belong to a family of multipass transmembrane
proteins
Figure 15-16b Molecular Biology of the Cell (© Garland Science 2008)
 Function as enzymes or associate with enzymes that they
activate.
Are usually single pass transmembrane proteins, ligand
binding site outside the cell and catalytic (enzyme-
binding) site inside the cell.
Majority are protein kinases or associate with protein
kinases.
Figure 15-16c Molecular Biology of the Cell (© Garland Science 2008)
 Most activated cell-surface receptors relay signals via small
molecules and a network of intracellular signaling proteins:
called second messengers

Examples of small messengers:

In cytosol:
-Cyclic AMP : cAMP
-Calcium ion

Fat soluble:
-Diacylglycerol

Large intracellular signaling proteins

Figure 15-17 Molecular Biology of the Cell (© Garland Science 2008)

Many intracellular signaling proteins function as switches that
are activated by phosphorylation or GTP binding

Ser/thre kinases are majority

Tyrosine kinases
Figure 15-18 Molecular Biology of the Cell (© Garland Science 2008)
 Small monomeric GTPases regulated by GTP/GDP binding

Figure 15-19 Molecular Biology of the Cell (© Garland Science 2008)

Signal integration: two pathways cause phosphorylation of one
target at different sites

Figure 15-20 Molecular Biology of the Cell (© Garland Science 2008)

TYPES OF INTRACELLULAR SIGNALING COMPLEXES

The scaffold holds signaling proteins in close proximity, the

components can interact at high local concentration and be
sequentially activated, efficiently and selectively
Figure 15-21a Molecular Biology of the Cell (© Garland Science 2008)
TYPES OF INTRACELLULAR SIGNALING COMPLEXES

Transient assembly of complexes, due to phosphorylation

(that is reversible)
Figure 15-21b Molecular Biology of the Cell (© Garland Science 2008)
TYPES OF INTRACELLULAR SIGNALING COMPLEXES

Receptor activation leads to the production of modified

phospholipids (phosphinositides), which recruit specific
intracellular signaling proteins.
Figure 15-21c Molecular Biology of the Cell (© Garland Science 2008)
 Induced proximity via interaction domains, used to relay
signals from protein to protein

Figure 15-22 Molecular Biology of the Cell (© Garland Science 2008)

 When a cell responds to extracellular signals, it can be a
smooth graded or a switch like response

Figure 15-23 Molecular Biology of the Cell (© Garland Science 2008)

 Looking at a whole population, the response may appear
smooth while each cell is having an all or non response

It is important to look at individual cells to detect all-or-

none responses
Figure 15-24b, c Molecular Biology of the Cell (© Garland Science 2008)
 Example:

Adrenaline binding to a G-protein-coupled cell-surface

receptor increases the intracellular concentration of cyclic
AMP which in turn activates enzymes that promote glycogen
breakdown and inhibit enzymes that promote glycogen
synthesis.

Figure 15-25 Molecular Biology of the Cell (© Garland Science 2008)

 Intracellular signaling incorporate feedback loops

Figure 15-26 Molecular Biology of the Cell (© Garland Science 2008)

 Positive feedback mechanism giving
switch-like behavior

Figure 15-27 Molecular Biology of the Cell (© Garland Science 2008)

 Positive feedback mechanism depends on the intensity of
the stimulus, that results in a signal that persists

Negative feedback mechanism counteracts the effect of a

stimulus making the system less sensitive
Figure 15-28 Molecular Biology of the Cell (© Garland Science 2008)
 Target cells can become adapted (desensitized) to an
extracellular signal molecule

Figure 15-29 Molecular Biology of the Cell (© Garland Science 2008)

 G-protein coupled receptors, the largest class of cell surface
receptors

- More than 700 GPCRs in humans

- Sigh, smell and taste use these receptors
- One signal can activate many GPCRs
Figure 15-30 Molecular Biology of the Cell (© Garland Science 2008)
Trimeric G-proteins relay signals
from GPCRs

-Various types of G-proteins, each one

specific for a particular set of GPCRs,
and particular set of target proteins in
the membrane
- They all have similar structures and
operate similarly.
- Gproteins have three subunits: alpha,
beta and gamma.
-Alpha-GDP unstimulated
-Alpha-GTP stimulated
(has intrinsic GTPase); also regulators
of G-protein signaling act as GTPases

Figure 15-32 Molecular Biology of the Cell (© Garland Science 2008)

 Some G-proteins regulate the production of Cyclic AMP
Cyclic AMP acts as a second messenger

Figure 15-33 Molecular Biology of the Cell (© Garland Science 2008)

 Cyclic AMP is synthesized from ATP by a plasma
membrane bound enzyme adenylyl cyclase and is quickly
destroyed by cAMP phosphodiesterase
Different G-proteins cause different
effect of cAMP:
-Stimulatory G-protein (Gs) activates
adenylyl cyclase
- Inhibitory G-protein (Gi) inhibits
adenylyl cyclase

Ex: cholera toxin is an enzyme that catalyzes

transfer of ADP ribose from NAD+ to Gs.
Now Gs can no longer hydrolyze the GTP and
is always ON, making adenylyl cyclase active
always, more cAMP causes more Cl- to be in
the gut (and hence more water)

Figure 15-34 Molecular Biology of the Cell (© Garland Science 2008)

Individuals with genetic defects in Gs alpha show decrease
response to some hormones (so they have metabolic
abnormalities, abnormal bone development and are mentally
retarded).
Table 15-1 Molecular Biology of the Cell (© Garland Science 2008)
Cyclic AMP dependent protein kinase (PKA) mediates most
of the effects of cyclic AMP

PKA is a Ser/Thre Kinase

Figure 15-35 Molecular Biology of the Cell (© Garland Science 2008)

 A rise in cyclic AMP can alter gene
transcription

Figure 15-36 Molecular Biology of the Cell (© Garland Science 2008)

 Many GPCRs exert their effects mainly via G proteins that
activate the plasma membrane - bound enzyme phospholipase C-
β (PLCβ)

Table 15-2 Molecular Biology of the Cell (© Garland Science 2008)

 Phospholipase C-β (PLCβ) works on PIP2 to make DAG and IP3

Figure 15-38 Molecular Biology of the Cell (© Garland Science 2008)

 IP3 diffuses in the cytoplasm and binds to the ER causing Calcium
release in the cytosol

Figure 15-39 Molecular Biology of the Cell (© Garland Science 2008)

 Calcium functions as an intracellular mediator, for example during
fertilization it initiates embryonic development

Figure 15-40 Molecular Biology of the Cell (© Garland Science 2008)

 In a resting cell, several mechanisms ensure that calcium
concentration remains low

Figure 15-41a Molecular Biology of the Cell (© Garland Science 2008)

 In a resting cell, several mechanisms ensure that calcium
concentration remains low

Figure 15-41b Molecular Biology of the Cell (© Garland Science 2008)

 Various Ca2+-binding proteins help to relay the cytosolic Ca2+
signal: Calmodulin, when bound to Calcium changes conformation

Figure 15-43 Molecular Biology of the Cell (© Garland Science 2008)

 Activated Calmodulin binds and activates other proteins: CAM Kinase

Figure 15-44 Molecular Biology of the Cell (© Garland Science 2008)

Table 15-3 Molecular Biology of the Cell (© Garland Science 2008)
 GPCR Kinases and arrestins in GPCR desesitization

Figure 15-51 Molecular Biology of the Cell (© Garland Science 2008)

 Receptor Tyrosine kinases

Figure 15-52 Molecular Biology of the Cell (© Garland Science 2008)

Table 15-4 Molecular Biology of the Cell (© Garland Science 2008)
Figure 15-53a Molecular Biology of the Cell (© Garland Science 2008)
Figure 15-53b Molecular Biology of the Cell (© Garland Science 2008)
Figure 15-54 Molecular Biology of the Cell (© Garland Science 2008)
Figure 15-55a Molecular Biology of the Cell (© Garland Science 2008)
Table 15-5 Molecular Biology of the Cell (© Garland Science 2008)
Figure 15-66 Molecular Biology of the Cell (© Garland Science 2008)