Signal

transduc.on -1

Cells are alert detectors, sensing and interpreting information constantly to adjust
to the environment and coordinate activities with surrounding cells
Signals can inform about
T, light, pH, Ionic force, pressure
availability of O2, nutrients, proliferative and anti-proliferative factors
presence of competitors,mating partners,predators or preys, infectious agents
genome status
A cell can respond to signals by
changing the genes that it transcribes
altering the cell surface
modifying proteins and enzyme activities
moving materials between compartments
remodelling its cytoskeleton
migrating
dying
Cell-to-cell communication is essential for multicellular organisms
Cell junction
Cell-cell recognition
Cell signalling

Cell junctions and contact-dependent signaling

Animal and plant cells have cell junctions that directly connect the cytoplasm of adjacent
cells
Gap junctions
between animal cells

Plasmodesmata
between plant cells

(a) Cell junctions

In local signaling, animal cells may communicate by direct contact

Cell-cell recognition

Cell to cell communication by Signaling

Local- paracrine, synaptic signaling
Long-distance- hormonal signaling (endocrine)
Autocrine
Local signaling

Long-distance signaling

Target cell

Secreting
cell

Local regulator
diffuses through
extracellular fluid
Paracrine signaling

Electrical signal
along nerve cell
triggers release of
neurotransmitter

Endocrine cell

Neurotransmitter
diffuses across
synapse

Secretory
vesicle

Target cell
is stimulated

Blood
vessel

Hormone travels
in bloodstream
to target cells

Target
cell

Synaptic signaling

Hormonal signaling

The Three Stages of Cell Signaling

Reception
Transduction
Response

Reception
Enormous variety of chemicals function as signaling molecules:
proteins, aminoacid or lipid derivatives, nucleotides, steroids, retinoids, dissolved gasses

The binding between a signal molecule (ligand) and receptor is highly

specific
A conformational change in a receptor is often the initial transduction of
the signal
Most signal receptors are plasma membrane proteins
EXTRACELLULAR
FLUID
Reception

CYTOPLASM
Plasma membrane
Transduction

Receptor

Stimulus

Signal
molecule
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First messenger

Transduction
Usually involves multiple steps
alteration of the activity, by conformational changes, or localization of
intracellular signal proteins (enzymes and adaptors proteins)
production of second messengers
Multistep pathways can amplify a signal
EXTRACELLULAR
FLUID
Reception

CYTOPLASM
Plasma membrane
Transduction

Receptor

Relay molecules in a signal transduction

pathway
Signal
molecule

Signal transduction pathways: the diverse sequences of events between receptor

activation and cellular responses.

Response
Signal transduction pathways lead to regulation of one or more cellular activities

EXTRACELLULAR
FLUID
Reception

change the permeability, transport properties, or electrical state of cell

cell metabolism
cell secretory activity
cell rate of proliferation and differentiation
cell contractile activity
cell migration
cell death
CYTOPLASM
Plasma membrane
Transduction

Response

Receptor
Activation
of cellular
response
Relay molecules in a signal transduction
pathway
Signal
molecule

Two major types of responses exist:

1) changes in the activity or function of specific pre-existing proteins
2) changes in the amounts of specific proteins, as result of alteration of gene expression

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

Each cell can responde to specific combination of extracellular signal molecules

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

Some signal molecules induce different responses

in different cells of a same organism

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

A same response in a cell can be induced by

different signal molecules, or different ligand/receptor
complexes, if a common intracellular signaling circuit is
activated
i.e. epinefrin, glucagon and ACTH promote glicogen demolition in the liver cells
by interacting with different receptors that lead all to an increase in the
intracellular level of a signal molecule, cAMP.

The specific response of a single cell or tissue

to a specific external stimulus depend by
specific receptors-pattern endowed
specific intracellular trasducing machinery endowed
Signal trasduction mechanisms are well conserved

La velocit con cui una cellula risponde alla rimozione del segnale dipende da
velocit di distruzione o turnover delle molecole influenzate dal segnale.
E tale velocit di turnover determina anche la prontezza della risposta quando
arriva un nuovo segnale.

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Reception

Intracellular receptors
Receptors in the plasma membrane

14

Intracellular Receptors

Some receptor proteins

are intracellular, found in
the cytosol or nucleus of
target cells

Hormone
(testosterone)

EXTRACELLULAR
FLUID

Plasma
membrane

Receptor
protein

Hormonereceptor
complex

Small or hydrophobic
chemical messengers
(steroids, retinoids, thyroid
hormones, vitamin D) can
readily cross the
membrane and activate
receptors
An activated hormonereceptor complex can act
as a transcription factor,
turning on specific genes

Testosterone binds
to a receptor protein
in the cytoplasm,
activating it.

The hormonereceptor complex

enters the nucleus
and binds to specific
genes.
DNA
The bound protein
stimulates the
transcription of
the gene into mRNA.

mRNA

The steroid
hormone testosterone
passes through the
plasma membrane.

NUCLEUS

New protein
The mRNA is
translated into a
specific protein.

CYTOPLASM

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EXCURSUS
Transcription factors
are regulatory proteins that influence gene transcription.

help RNA polymerase bind to the promoter region on DNA.

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

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

Receptors in the Plasma Membrane

Most water-soluble signal molecules (eg. epinephrine, insulin, growth hormones)

bind to specific sites on receptor proteins in the plasma membrane

There are three main types of membrane receptors:

Ion channel-linked
receptors

Enzyme-linked
receptors

G-protein-linked
receptors
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Hypothetical intracellular
signaling pathway
activated by a plasmamembrane receptor

Extracellular signals (1 messengers)

Receptors
Intracellular transducing protein/enzyme
Intracellular small molecules (2 messengers)

The nomenclature of signaling

pathways is quite arbitrary!

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

Four features of Signal transducing systems

Molecular switches in signal transduction

Figure 15-18 Molecular Biology of the Cell ( Garland Science 2008)

Receptors
can be activated by
binding to a signalling molecule (ligand)
changes in the concentration of a metabolite (as oxygen,
nutrients)
physical stimuli (as light, touch, heat)

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Binding of a signalling molecule (ligand) to the receptor

Identified by mutational studies

Growth hormone
(ligand)

Growth hormone
receptor
Ligand/Receptor complex

Receptor dimerization

Binding depends on
weak, non covalent forces
(i.e. ionic, van der Waals, hydrophobic interactions)
and
molecular complementarity
between the interacting surface of a receptor and ligand

24

Binding of a signalling molecule (ligand) to the receptor

The maximal physiological response to many

external signals occurs when only a fraction of
the receptor molecules are occupied by ligand.

Kd=koff/Kon

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Examples

Synthetic analogs of natural hormones

can be divided in:

Agonists
Mimic the function of a natural hormone
by binding its receptor and inducing response

Antagonists
Bind to the receptor but induce no response

Beta-blocker

EP promotes relaxation of bronchial smooth muscle

IP binds EP receptors tenfold more strongly

(used in treating bronchial asthma, etc..)

decontrazione

EP increases contraction rate of bronchial smooth muscle

AP binds EP receptors with high affinity

(used in treating cardiac arhythmias etc..)

contrazione

To note:
different effect of EP
on different type of
cells target
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Receptors

27

Receptors
rarely are uniformly distributed on the cell surface of cell target
(es. Epinephrine receptors in adipose cells)
commonly are clusterized with other signalling proteins in a particular region of the cell
surface
(es. Neurotrasmitters receptors in postsynaptic cell)

Clustering of membrane proteins

mediated by cytosolic adapter proteins
containing multiple protein binding
domains, as PDZ-domain.

PDZ-domains bind
to the sequence Ser/Thr-X-F or F-X-F

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Lipids Rafts

(Caveolae in mammalian cells)

Microdomains or Aggregates of certain lipids (cholesterol and sphingolipids) in the

plasma membrane
containing several different receptors and other signaling proteins
marked by the presence of caveolina
Signal proteins may be recruited
to such membrane domains
- by scaffold proteins
-by insertion of lipid anchors
- by pleckstrin homology or other lipid-binding domains

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