Chapter 15

CELL SIGNALING
Learning Objectives:
1. Cell signaling systems
2. The types of signal molecules, receptors,
molecular switches and effectors
3. The signal transduction pathways;
4. The convergence, divergence, and crosstalk
between different signaling pathways.
No Man Is An Island, by John Donne
No man is an island
Entire of itself
Every man is a piece of the continent
A part of the main
If a clod be washed away by the sea
Europe is the less
As well as if a promontory were
As well as if a manor of thy friend's
Or of thine own were
Any man's death diminishes me
Because I am involved in mankind
And therefore never send to know An English
For whom the bell tolls metaphysical
It tolls for thee poet in 17th-
century
 How many types of cell?
And how many cells are
there in human body?
Cells must
communicate with their
neighbors, monitor their
environment, and
respond appropriately to
different stimuli.
No Cell Cells carry out these
Is interactions by cell
Alone signaling, in which
messengers come in from
anywhere and relay
across the plasma
membrane to the cell
interior and often
transmitted to the
Overview of cell signaling systems
 Cell signaling means a cell responding to a
stimulus from its environment by relaying
information to its internal compartment.
 Signal transduction indicates that the stimulus
received by the cell surface receptor is
transformed into the cell interior in different forms.
 Signaling pathways consist of a series of distinct
proteins that mediate signal transduction.
 Essential steps of cell signaling

 Recognition of the stimulus at the outer surface of the

plasma membrane by a specific receptor embedded in
the membrane.
 Transfer of a signal across the plasma membrane to
its cytoplasmic surface.
 Transmission of the signal to specific effectors on the
inner surface of the membrane or within the cytoplasm
 The cell’s responses may involve a change in gene
expression, an alteration of the activity of metabolic
enzymes, and a reconfiguration of the cytoskeleton.
 Cessation of the response as a result of the destruction
or inactivation of the signaling molecules, combined with
a decrease in the level of the extracellular stimulus.
The basic elements of cell signaling

Extracellular messenger molecules

 A signaling molecule is a molecule involved in
transmitting information between cells of a living
multicellular organism, or between organisms of
the same or different species.
 Lipid-soluble hormones
 Water-soluble hormones
 Gases, Nitric oxide (NO) and carbon
monoxide(CO) as cellular messengers
At least three important classes of
signaling molecules are widely
recognized
 Hormones are the major signaling molecules
of the endocrine system. A classic example is
provided by the steroid hormone estrogen, which
is produced by the ovary and stimulates
development and maintenance of the female
reproductive system and secondary sex
characteristics.
 Neurotransmitters are signaling molecules of
the nervous system, also including neuropeptides
and neuromodulators. Neurotransmitters like the
catecholamines are also secreted by the endocrine
system into the systemic circulation.
 Local Mediators: For example, cytokines are
signaling molecules of the immune system, with a
primary paracrine or juxtacrine role, though they
can during significant immune responses have a
strong presence in the circulation, with systemic
effect (altering iron metabolism or body
temperature). Growth factors can be considered as
cytokines or a different class.
Action models of the extracellular signals
Autocrine Paracrine

Endocrine
Autocrine signaling is a form of cell signaling in which a
cell secretes a hormone or chemical messenger (called
the autocrine agent) that binds to autocrine receptors on
that same cell, leading to changes in the cell. This can be
contrasted with paracrine signaling, intracrine signaling,
or classical endocrine signaling.
Paracrine signaling is a
form of cell-cell
communication in which a
cell produces a signal to
induce changes in nearby
cells, altering the behavior
or differentiation of nearby
cells. Signaling molecules
known as paracrine factors
diffuse over a relatively
short distance (local
action), as opposed to
endocrine factors
(hormones which travel
considerably longer
distances via the 
circulatory system) and
juxtacrine interactions
The endocrine system is
the system of glands, each
of which secretes different
types of hormones directly
into the bloodstream
(some of which are
transported along nerve
tracts) to maintain
homeostasis. The
endocrine system is in
contrast to the exocrine
system, which secretes its
chemicals using ducts.
In the nervous system,
a synapse is a
structure that permits
a neuron (or nerve cell)
to pass an electrical or
chemical signal to
another cell.
Juxtacrine: A type of cell communication whereby a signal
molecule remains bound to the signaling cell surface, rather
than being released into the extracellular space, and influences
only cells that come into contact with it.

Notch-mediated juxtacrine
signal between adjacent cells
Step1, the release of a messenger molecule
by a cell;
Step2, receptors specifically recognize and
bind messenger molecule;
Step3, signal is relayed across the
membrane to the receptor’s cytoplasmic
domain;
Step4-5, 1) transmits a signal from its
cytoplasmic domain to a nearby enzyme,
which generates a second messenger; 2)
transmits a signal by transforming its
cytoplasmic domain into a recruiting station
for cellular signaling proteins.
Step6, a protein that is positioned at the top
of an intracellular signaling pathway is
activated;
Step7-9, each signaling pathway consists of
a series of distinct proteins that operate in
sequence ultimately reaching the target
proteins involved in basic cellular processes
Down-stream of a typical
signal transduction pathway
consisting of protein kinases
and protein phosphatases
whose catalytic actions change
the conformations, and thus
the activities, of the proteins
they modify.
Nitric Oxide is a major paracrine signaling molecule in
circulatory systems.
NO is able to diffuse directly across the
plasma membrane of its target cells. NO
alters the activity of intracellular target
enzymes, that operates cyclic GMP
production and leads to the dilation of
blood vessels.
 Based on their work on NO, three scientists— Robert F.
Furchgott, Louis J. Ignarro, and Ferid Murad — received
and shared the 1998 Nobel Prize for Physiology and
Medicine.

Robert F. Furchgott Louis J. Ignarro Ferid Murad

 Second messengers are defined as those signal
molecules relay signals from receptors on the cell surface
to target molecules inside the cell. They greatly amplify the
strength of the signal. Second messengers are a regular
component of signal transduction cascades.
Receptors
 Nuclear receptors

Nuclear receptors are a class of receptor

proteins found within cells that are responsible
for sensing steroid, retinoic acid, vitamin D
and thyroid hormones and other signal
molecules. These receptors work with other
proteins to regulate the expression of specific
genes, thereby controlling the development,
homeostasis, and metabolism of the organism.
Nuclear receptors have the ability to directly bind
to DNA and regulate the expression of adjacent
genes, hence these receptors are classified as
transcription factors.
 Nuclear receptors are modular in structure and contain the
following basic domains:
 N-terminal regulatory domain: Contains the activation
function 1 (AF-1) whose action is independent of the
presence of ligand.
 DNA-binding domain (DBD): Highly conserved domain
containing two zinc fingers that binds to specific sequences
of DNA called hormone response elemen
 Ligand binding domain (LBD): Moderately conserved in
sequence and highly conserved in structure between the
various nuclear receptors. The LBD also contains the
activation function 2 (AF-2) whose action is dependent
on the presence of bound ligand.
GPCR SIGNALING PATHWAYS
G protein coupled receptors (GPCRs) constitute
a large protein family of receptors that sense
molecules outside the cell and activate inside
signal transduction pathways and, ultimately,
cellular responses. They are also called seven-
transmembrane receptors, 7TM receptors,
because they pass through the cell membrane
seven times.
 GPCRs are found only in eukaryotes, nearly 800 different
human GPCRs genes (or ≈4% of the entire protein-coding
genome) have been predicted from genome sequence
analysis.
 GPCRs’ ligands include light-sensitive compounds, odors,
pheromones, hormones, and neurotransmitters, and vary in
size from small molecules to peptides to large proteins.
 GPCRs are involved in many diseases, and are also the
target of approximately 40% of all modern medicinal drugs.
 2012 Nobel prize in chemistry was awarded to Brian
Kobilka and Robert Lefkowitz for their work that was
"crucial for understanding how G-protein–coupled receptors
function.
GPCR signaling

G protein
cycle
Activation cycle of a G-protein (purple) by a G-protein-coupled receptor (light
blue) receiving a ligand (red).
Three types of GPCR Signaling Pathway

The cAMP signal pathway

The phosphatidylinositol signal pathway
G protein-gated ion channels
 GPCR GPCR
Effector

G protein G protein

Secondary messenger, cAMP

The cAMP
dependent
signal pathway
PKA, protein kinase A
PKA, protein kinase A
 The inactive form of PKA complex consists of two
regulatory (R) and two catalytic (C) subunits.
 Cyclic AMP binds to the R subunits of PKA, leading to
their dissociation from the C subunits.
 The free C subunits of PKA are then activated and able
to phosphorylate serine residues on their many target
proteins located in cytoplasm.
 In nucleus, free C phosphorylates the CREB, in turn
binds to the CRE, a regulatory sequence called the
cAMP response element (CRE), and promotes the
expression of the target genes.
The free C subunit of PKA
translocates to the nucleus
and phosphorylates the
transcription factor CREB
(CRE-binding protein),
leading to expression of
cAMP-inducible genes.
The phosphatidylinositol signal pathway
 Lipid-derived second
messengers:
phospholipid-based
second messengers
 Generation of second
messengers by PLC
 IP3 signaling and Calcium flux
 IP3 molecules formed at the membrane
diffuse into the cytosol and bind to a
specific IP3 receptor located at the surface of
the smooth endoplasmic reticulum .
 The IP3 receptor does more than bind a
ligand; it is also a tetrameric Ca2+ channel.
Binding of IP3 opens the channel, allowing
Ca2+ ions to diffuse into the cytoplasm .
 Calcium ions can also be considered as
intracellular messengers because they bind
to various target molecules, triggering
specific responses. 37
 IP3-Ca2+ pathway and DG-PKC pathway

 SignalsGPCR GP PLC

IP3 and DAG (twin signals).
 IP3 IP3 receptor(Ca2+
channel, located at the
surface of sER)  Elevation
of cytosolic Ca2+;
 DAG activates PKC to
phosphoralate Ser and Thr
on target proteins.
 Calcium binds to calcium-
binding proteins(CaM) which
affects other proteins.

Elevation of cytosolic Ca2+ via the

IP signaling pathway
Calmodulin

39
Structure of calmodulin, a cytosolic protein of 148 amino
acids that bind Ca2+ ions Ca2+/CaM dep. protein kinase (CaM-
kinase) mediate many of the actions of
Ca2+ in animal cells.

The functions of increase the

levels of cytosolic calcium-
CaM : start-up embryo
development after the
fecundation. excitating
contract of muscle cells; 
excitating secretion of
endocrine and nerve cells.
Regulating calcium concentrations in plant cells
Cytosolic calcium changes in response to several stimuli,
including light, pressure, gravity, and hormones.
Calcium signaling aids in decreasing turgor pressure in
guard cells.
Receptor tyrosine kinase(RTK) and RTK-
Ras signaling pathway

 Signaling ligands to RTKs:

Nerve growth factor (NGF)
Platelet-derived growth factor (PDGF)
Fibroblast growth factor (FGF)
Epidermal growth factor (EGF)
Insulin and insulin-like GF(IGF-1)
Ephrins(Eph)
Vascular endothelial factor(VEGF)
 Ligand binding leads to RTK autophosphorylation
RTK activity stimulated by cross-phosphorylation.

Phsphorylated
Tyrosine Serve as
docking sites for
protein with SH2
domains (Src homology
region).
Other protein modules
such as SH3 binds to
proline-rich motifs in
dimerization
intracellular proteins.
RTK-Ras signaling pathway
 The target cells can become desensitized to a signal
molecule by five ways.

Sequestration; down-regulation; inactivation; inactivation; inhibitory

protein
Three general ways of the desensitization:
1. Receptor inactivation by alteration;
2. Receptor sequestration by internalization;
3. Receptor down-regulation by destroying in Ls.
Convergence, divergence, and crosstalk
among different signaling pathway

A. Convergence:
Signals from a variety
of unrelated receptors
can converge to
activate a common
effecter.
B. Divergence: Signals from the same ligand can
diverge to activate a variety of different effectors.
C. Crosstalk: Signals can be passed back
and forth between different pathways
In actual fact, signaling pathways in
the cell are much more complex.