Cellular Communication

A simple intracellular signaling pathway activated by an extracellular signal molecule

Extracellular signals can act slowly or rapidly to change the behavior of a target cell
The first cell communication to be discovered was
between two mating types of yeast cells.
Fig.1: Yeast cells respond to
mating factor

Fig.2: Signal transduction is the

process whereby one type of
signal is converted to another.
Fig.3: Animal cells can signal to one another in various ways.
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
Tab.1: Some examples of signal molecules
Hormones
Adrenalin increases blood pressure, heart rate,
and metabolism

Site of origin: adrenal gland

Derivative of the aminoacid

tyrosine
Local mediators
Epidermal growth factor (EGF) stimulates epidermal and many
other cell types to proliferate

Site of origin: various cells

Protein
Neurotransmitters
Acetylcholine excitatory neurotransmitter at
many nerve-muscle synapses and in central nervous
system

Site of origin: nerve terminals

Derivate of cholin
Contact-dependent signal molecules
Delta inhibits neighboring cells from
becomming specialized in a same way as the
signaling cell
 The receptor protein Notch is a latent gene regulatory protein

Lateral inhibition mediated by Notch and Delta during nerve cell development in Drosophila.
Signaling through the Notch receptor protein may be the most widely used signaling pathway
in animal development.
Figure 45.4 One chemical signal, different effects
Fig.6: An animal cell depends on multiple extracellular
signals.
Fig.7: Extracellular
signals alter the
activity of a variety of
cell proteins to change
the behavior of the cell.
Fig.8: Cellular
signaling cascades
can follow a complex
path.
 intra

Fig.9: Extracellular signal molecules

bind either to cell-surface receptors
or to intracellular enzymes or receptor. extra
Fig.10: Nitric oxide (NO) triggers
smooth muscle relaxation in a
blood-vessel wall.
Nitric oxide gas signals by binding directly to an enzyme inside the target cell
 testosteron

Fig.11: Some small hydrophobic hormones bind to

intracellular receptors that act as gene regulatory proteins.
Fig.12: The steroid hormone cortisol acts by activating a
gene regulatory protein.
Some signaling molecules that bind to nuclear receptors

Nuclear receptors are ligand-activated gene regulatory proteins

The nuclear receptor superfamily
Activation of nuclear hormone receptor leads to an early primary response and a
delayed secondary response
 Cyclic AMP induced responses could be rapid or slow. In skeletal muscle cells, PKA
induces a rapid response by phosphorylating enzymes involved in glycogen metabolism.
In an example of a slow response, cAMP activates transcription of a gene for a hormone,
such as somatostatin
Paracrine (para˘-krin) chemical signals are
released by cells and affect other cell
types locally without being transported in
the blood. For example, a peptide called
somatostatin is released by cells in the
pancreas and functions locally to inhibit
the secretion of insulin from other cells of
the pancreas
FIGURE 15.33 An example of
cross-talk between two major
signalingpathways.
Cyclic AMP acts in some
cells, by means of the cAMP
dependent kinase PKA, to
block the transmission of
signals from Ras to Raf,
which inhibits the activation
of the MAP kinase cascade.
In addition, both PKA and the
kinases of the MAP kinase
cascade phosphorylate
the transcription factor CREB
on the same serine residue,
activating the transcription
factor and allowing it to bind
to specificsites on the DNA
The three largest classes of cell-surface receptor proteins are ion-channel-linked,
G-protein-linked, and enzyme-linked receptors
Signaling through G-protein-coupled cell-surface receptors (GPCRs)
and small intracellular mediators
Trimeric G proteins disassemble to relay signals from G-protein-linked receptors
Activation of a G protein by an activated GPCR
 Some G-proteins regulate the production of cyclic AMP

A nerve cell in culture responding to the neurotransmitter serotonin, which acts through a
GPCR to cause a rapid rise in the intracellular concentration of cyclic AMP
 The synthesis and degradation of cyclic AMP

Many extracellular signals work by increasing cAMP concentration, and they do so by increasing the
activity of adenyl cyclase rather than decreasing the activity of phosphodiesterase. All receptors that
act via cAMP are coupled to a stimulatory G protein (Gs), which activates adenyl cyclase.
 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.
Some G proteins activate the inositol phospholipid signaling pathway by
activating phospholipase C-

The effects of IP3 can be mimicked by a Ca2+ ionophore (A23187 or ionomycin

and the effects of diacylglycerol can be mimicked by phorbol esters
The hydrolysis of PI(4,5)P2 by phospholipase C-
Fig.15: Many Intercellular signaling proteins act as
molecular switches
 Ca2+ functions as a ubiquitous intracellular messenger

Three main types of Ca2+ channels that mediate Ca2+ signaling:

• Voltage dependent Ca2+ channels in the plasma membrane

• IP3-gated Ca2+-release channels

• Ryanodine receptors
The concentration of Ca2+ in the cytosol is kept low in resting cells by several
mechanisms
Ca2+/ Calmodulin-dependent protein kinases (CaM-kinases)
mediate many of the actions of Ca2+ in animal cells

The structure of Ca2+/ Calmodulin

The stepwise activation of CaM-kinase II
CaM-kinase II as a frequency decoder of Ca2+ oscillations
Smell and vision depend on GPCRs that regulate cyclic-nucleotide-gated ion channels

Olfactory receptor neurons

GPCR desensitization depends on receptor phosphorylation
 Enzyme-coupled cell-surface receptors

1.
Receptor tyrosine kinases

2.
Tyrosine-kinase-associated receptors
3.
Receptor serine/threonine kinases
4.
Histidine-kinase-associated receptors
5.
Receptor guanylyl cyclases
6.
Receptorlike tyrosine phosphatases
Activated receptor tyrosine kinases (RTKs) phosphorylate themselves

Some subfamilies of receptor tyrosine kinases

Activation and inactivation of RTKs by dimerization
Docking of intracellular signaling proteins on phosphotyrosines on an activated RTK
Phosphorylated tyrosines serve as docking sites for proteins with
SH2 domains (for Src homology region) or, less commonly,
PTB domains (for phosphotyrosine-binding)
The SH2 domain

Binding site for

phosphotyrosine
Ras belongs to a large superfamily of monomeric GTPases
Ras activates a MAP Kinase signaling module

(genes encoding G1 cyclins)

A major intracellular signaling pathway leading to cell growth involves PI 3-kinase

PI 3-kinase produces inositol phospholipid docking sites in the plasma membrane

Docking site for

signaling proteins
with PH domains
One way in which signaling through PI 3-kinase promotes cell survival
The downstream signaling pathways activated by RTKs and GPCRs overlap
 Cytokine receptors activate the Jak-STAT signaling pathway

Interferons –

cytokines secreted by cells in response to viral infection

Cytokine receptors –
composed of two or more polypeptide chains

JAKs –


Janus kinases - cytoplasmic tyrosine kinases

STATs –

signal transducers and activators of transcription

(latent gene regulatory proteins
The JAK-STAT signaling pathway activated by cytokines
Signal proteins of the TGF superfamily act through
Receptor Serine/Threonine kinases and Smads
Bacterial chemotaxis depends on a two-component signaling pathway
activated by Histidine-kinase-associated receptors
Counterclockwise
- smooth swimming

Clockwise
- tumbling
The two-component signaling pathway that enables chemotaxis receptors to
control the flagellar motors during bacterial chemotaxis
 Signaling pathways that depend on regulated proteolysis
of latent gene regulatory proteins

1. The Notch receptor

2. The Wnt/ -catenin pathway

3. The Hedgehog proteins

4. NF B proteins
 The receptor protein Notch is a latent gene regulatory protein

Lateral inhibition mediated by Notch and Delta during nerve cell development in Drosophila.
Signaling through the Notch receptor protein may be the most widely used signaling pathway
in animal development.
 The processing and activation of Notch by proteolytic cleavage

Both Notch and Delta are single-pass transmembrane proteins, and both require proteolytic
processing to function. Notch signaling is also regulated by glycosylation. The Fringe
family of glycosyltransferases adds extra sugars to the O-linked oligosaccharide on
Notch, which alters the specificity of Notch for its ligands.
Fig.15: Many Intercellular signaling proteins act as
molecular switches
Communication can occur through junctions
through which chemical signals that are
dissolved in the cytosol can move.

Cells can recognize

each other through
cell surface molecules
Some chemicals signal nearby target cells. This is know
as paracrine signaling or synaptic signaling.
 Local regulators affect neighboring target cells.

Growth factors are peptides and proteins that

stimulate cell proliferation

Nitric oxide functions as a neurotransmitter

Secreted by white blood cells it kills bacteria and certain cancer cells

Released by endothelial cells it relaxes smooth muscles in

blood vessel walls causing dilation

Prostaglandins (PGs)
Help induce childbirth, fever and inflammation
Hormones are used in plants and animals
for long distance signaling.

In animals, this is
called endocine
signaling.
The three stage of cellular signaling: Reception,
Transduction, and Response.
Signal Transduction Pathway

• The process by which a signal

(ligand) received on its receptor is
converted into particular cellular
response.
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.
There are three most common types of
membrane receptor proteins.

• G-protein coupled receptors

• Receptor tyrosine-kinases
• Ion channel receptors
G-Protein Coupled Receptors are often involved
in diseases such as bacterial infections.
Receptor Tyrosine kinases catalyze the transfer
of phosphate groups to initiate cell response.
Ligand-Gated Ion Channel
Receptors contain a region
that can act as a “gate” when
the receptor changes shape.

Ligand gated channels are very

important in the nervous
system- neurotransmitters.

Voltage-gated ion channels are

crucial to functioning of nervous
system.
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.
The transduction stage of signaling is often a
multistep process that amplifies the signal.

About 2% of
our genes
are thought
to code for
kinases.
Small molecules and ions act as secondary
messengers.
Response- cell signaling leads to regulation of
transcription or cytoplasmic activities.
Apoptosis, programmed cell death, integrates
multiple cell-signaling pathways.

• Paw development and digit

development requires apoptosis.
 Invertebrates have a variety of hormones for
signaling

Regulation of water balance

In hydra- regulation of growth and budding

Specialized neurons control egg laying in

mollusks and reduce feeding and locomotion

Arthropod molting is hormonally controlled by an

enzyme called ecdysone

In insects, control is by brain hormone (BH):

Juvenile hormone (JH) controls BH and ecdysone
Hormonal regulation of insect development
Two systems control all physiological processes

1. Nervous System –

neurosecretory glands in

endocrine tissues secrete hormones.

2. Endocrine System
Human Endocrine System
Major Vertebrate Endocrine Glands Their Hormones
(Hypothalamus–Parathyroid glands)
Two regulatory systems of humans work together

Nervous system

Endocrine system
Neurosecretory cells in endocrine organs and
tissues secrete hormones. These hormones are
excreted into the circulatory system.
Stress and the Adrenal Gland
Testicular Feminization Syndrome (Androgen Insensitive
Syndrome; 44 + XY)
Fig.17: G proteins
dissociate into two
signaling proteins when
activated.

Fig.16: All G-protein-linked

receptors possess a
similar structure.
Fig.18: The G-protein submit
switches itself off by hydrolizing
its bound GTP.