MINIMAL REQUIREMENT

Cell signaling
- Basics of cell communication - 1
TOTAL-CONTENT:
1. The basics 1st lecture
2. Components of signaling pathways 1st lecture
3. Main signaling pathways 2nd lecture
4. Neural communication 3rd lecture
CONTENT - 1st lecture
1. Introduction
2. Multicellularity
3. Types of cell communication
4. Signal processing
5. Coordination of signaling
6. Other aspects of cell communication
7. Domains and modules

1. Introduction
Multicellular organisms consist of several cells that provide the development of the organism and
coherent functioning by communicating with each other. The cells divide, differentiate, live, undergo
apoptosis, move, maintain their genetic and biochemical mechanisms, etc. The point of being
multicellular is that the cells share their tasks; hence, they are able to solve more complicated
problems than a single-cell organism. Some cells specialize for contraction, respond to electric
signals, involved in detoxification, gas exchange, secretion of various substances, protection against
external effects, maintaining the conformation of the organism, etc. Cells send and receive signals in
order to change themselves and synchronize the behavior of neighboring cells or even separate from
each other. Considering cell signaling is large field of biology, instead of showing all of the details we
would like to present this topic on the whole.

1.1. Multicellularity
The difficulties of multicellularity There are signal transduction mechanisms within the cell of
unicellular organisms, too. These organisms receive signals from the outer environment, which are
processed, and finally they respond to them. These organisms also communicate with each other.
However, communication between cells in multicellular organisms became much more complicated
than in unicellular species. According to the fossil records, sophisticated multicellular organisms did
not appear on the Earth until unicellular organisms resembling present-day prokaryotes had already
been in existence for about 2.5 billion years (the first animals arose about 570 million years ago). The
long delay may reflect the difficulty of evolving the language systems of animals, plants, and fungal

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cells – the machinery that would enable cells sharing the same genome to collaborate and
coordinate their behavior, specializing in different ways and subordinating their individual chances of
survival to the interests of the multicellular organism as a whole. The main principles and
components behind the signaling mechanisms are essentially the same across the diverse range of
organisms, from bacteria, fungi, plants and animals. It is the fine detail of the component that gives
the specificity that is required for a particular cell.

The origin of multicellularity Three different theories attempt to explain the origin of multicellular life
forms.

(1) The Symbiotic Theory suggests that the first multicellular organisms occurred from cooperation of different
species of single celled organisms, each with different roles. Over time these organisms would become so
dependent on each other they would not be able to survive independently, eventually leading to their genomes
being incorporated into one, multicellular, organism. Each respective organism would become a separate
lineage of differentiated cells within the newly created species. However, the problem with this theory is that it
is still not known how each organism's DNA could be incorporated into one single genome to constitute them
as a single species. For instance, the two symbiotic organisms forming the composite lichen, while dependent
on each other for survival, have to separately reproduce and then re-form to create one individual organism
once more.

(2) The Cellularization (Syncytial) Theory states that a single unicellular organism could have developed
internal membrane partitions around each of its nuclei. Many protists such as the ciliates can have several
nuclei, lending support to this hypothesis. However, simple presence of multiple nuclei is not enough to
support the theory. Multiple nuclei of ciliates are dissimilar and have clear differentiated functions: the
macronucleus serves the organism's needs while the micronucleus is used for sexual-like reproduction with
exchange of genetic material. To be deemed valid, this theory needs a demonstrable example and mechanism
of generation of a multicellular organism from a pre-existing syncytium.

(3) The Colonial Theory claims that the symbiosis of many organisms of the same species (unlike the
symbiontic theory, which suggests the symbiosis of different species) led to a multicellular organism. At least
some, presumably land-evolved, multicellularity occurs by cells separating and then rejoining whereas for the
majority of multicellular types (those that evolved within aquatic environments), multicellularity occurs as a
consequence of cells failing to separate following division. The mechanism of this latter colony formation can
be as simple as incomplete cytokinesis, though multicellularity is also typically considered to involve cellular
differentiation. The advantage of this theory is that it has been seen to occur independently numerous times (in
16 different protoctistan phyla). For instance, during food shortages the amoeba Disctiostelium groups
together in a colony that moves as one to a new location. Some of these amoebas then slightly differentiate
from each other. Other example of colonial organization in protozoa is Volvox which consists of up to 500 —
50,000 cells (depending on the species), only a fraction of which reproduce (in one species 25 — 35 asexually
and around 15 — 25 sexually). However, it can often be hard to separate colonial protists from true
multicellular organisms, as the two concepts are not distinct. Most scientists accept that multicellular
organisms, from all phyla, evolved by the colonial mechanism.

1.2. Types of cell communication

The sources of signals Cells can receive signals from the outer environment (light, heat, sound,
chemical substances, etc.) or from other cells. We talk about cell communication in the later case.
Although unicellular organisms lead independent lives, they can communicate and influence one
another’s behavior. Many bacteria, for example, respond to chemical signals that are secreted by
their neighbors, which increase in concentration with increasing population density. This process
allows bacteria to coordinate their behavior, including their motility, antibiotic production, spore
formation, and sexual conjugation. Similarly, yeast cells communicate with each other in preparation
for mating. For example, the budding yeast (Saccharomyces cerevisiae) secretes a peptide mating
factor that signals cells of the opposite mating type to stop proliferating and prepare to mate. Cells in
multicellular animals communicate by means of hundreds of kinds of signal molecules, which include

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proteins, small peptides, amino acids, nucleotides, steroids, retinoids, fatty acid derivatives, dissolved
gases such as nitric oxide and carbon monoxide, and even non-coding RNAs. Most of these signal
molecules are released into the extracellular space by exocytosis from the signaling cells. Some,
however, are emitted by diffusion through the plasma membrane, whereas others are displayed on
the external surface of the cell and remain attached to it, providing a signal to other cells only when
they make contact. The target cell responds by means of a receptor, which specifically binds the
signal molecules and initiates a response. The extracellular signal molecules often act at very low
concentration, and the receptor usually bind them with high affinity. Many signal molecules remain
bound to the surface of the signaling cell and influence only cells that contact it. Such contact-
dependent signaling is especially important during development and immune responses. In most
cases, however, signaling cells secrete signal molecules into the extracellular fluid.

Communication between cells Not only the body's own cells communicate with each other, but also
the embryo’s cells with the mother's uterus (placental) cells and vice versa , and pathogenic bacteria
(and viruses, although they are not cells) with human cells. Cellular interactions in individuals can be
elicited by pheromones which mainly control the sexual behavior. Pheromones are transmitted by
individuals. Examples for non-chemical signals are audio/visual stimuli which become converted into
chemical signals along their signaling pathways.

Short-range signaling The secreted molecules may be carried far afield to act on distant target cells,
or they may act as local mediators, affecting only cells in the in the local environment of the signaling
cell. The latter process is called paracrine signaling. An example of such signaling is the immune
response, where a variety of white blood cells release cytokines and chemokines to modulate the
activity of other white blood cells, and other local cells in response to a pathogen attack. For
paracrine signals to act only locally, the secreted molecules must not be allowed to diffuse too far;
for this reason they are often rapidly taken up by neighboring cells, destroyed by extracellular
enzymes, or immobilized by the extracellular matrix. The antagonist molecules also affect the
distance over which a paracrine signal protein acts by binding to either the signal molecule itself or
its self-surface receptor. Usually, the signaling and target cells in paracrine signaling are different
cells, but cells may also produce signals that they themselves respond to: this is referred to as
autocrine signaling. During autocrine regulation, cells send a signal to adjacent cells but these signals
effect receptors on the signaling cells itself. This effect is usually negative. Therefore, the signaling
cell, if the signaling molecule in the environment is sufficient, inhibits its own secretion. A special
case of the paracrine effect is when the cells communicating with each other are in physical contact.
This group involves two cases: juxtacrine-effect is when ligand-receptor interaction is involved, and
gap-junction connection when the adjacent cells use the membrane ion channel to communicate.

Long-range signaling Large, complex, multicellular organisms need long-range signaling mechanisms
to coordinate the behavior of cells in remote parts of the body The endocrine communication
provides the remote connection i.e. the signaling cell is able to target cells far away in the body. The
endocrine glands release hormones into the blood stream that can only bind to cells containing the
appropriate receptors. The synaptic (= neurocrine) connections are difficult to classify into
categories such as near or distant since the signaling (pre-synaptic) and receiving (post-synaptic)
neurons are close to each other, but the neurons which receive the input signal usually have their
effect far away , think about some neurons can be as long as or even longer than 1m. Whereas
different endocrine cells must use different hormones to communicate specifically with their target
cells, different nerve cells can use the same neurotransmitter and still communicate in a highly
specific manner. Endocrine cells secrete hormones into the blood, and these act on those target cells
that carry the appropriate receptors. In synaptic signaling, by contrast, specificity arises from the
synaptic contacts between a nerve cell and the synaptic target cells it signal.

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1.3. The main steps of cell signaling

The main underlying event for many cell signaling mechanisms is the arrival at the cell of something
that requires the cell to respond. This might be the arrival of light photons, as in the case of cells in
the eyes of humans. Likewise, the arrival may be a chemical released from another organism (such as
pheromones), or from another cell in the same organism. Most signals are perceived at the plasma
membrane (except intracellular receptors). The scenario of cell signaling in most cases is as follows.

 Perception of the signal by receptors

 Transmission of the signal by the receptors into the cell
 Passing on of the message to a series of cell signaling components, often referred to as a cell
signaling cascade
 The arrival of the message at the destination in the cell
 A response by the cell, an action carried out so that the outcome is appropriate to the
original signal

1.4. Processing of the signals

Transduction The information affecting cells comes in the form of a chemical molecule. As a first
step, this information is converted by receptor by changing in its conformation (G-protein-coupled
receptors) or by becoming phosphorylated (tyrosine kinase receptors) upon binding the ligand. The
production of second messengers is considered as the transformation of the signal.

Transferring the signal (relay) is the process, when the intracellular signaling molecules pass the
incoming signal by activating each other. In many pathways small molecules (second messengers) are
generated and transferring the original signal. The components of various signaling pathways are
usually physically linked either binding to an adaptor protein prier the arrival of primary signal
(ligand) or by binding directly to a receptor after being induced by the ligand.

The signal amplification is the process in which the number of activated molecules increases with
each step. The signal amplification within the cell allows detecting even very weak signals. In the
route of cAMP, one adenylate cyclase molecule produces a lot of cAMP; one protein kinase molecule
activates many other kinases, each of which can activate several other kinase enzymes.

The signal divergence means that one signal affects more than one types of effector molecules,
which then can give rise to independent effects on the cell or can participate in the same cellular
function.

Convergence of signals is the opposite of divergence. Two or more pathways affect the same signal
molecule.

During signal modulation the signaling pathway is influenced by certain protein molecules, which
usually has a negative effect on the signaling pathway.

Separation of signaling pathways Given the complexity of signal-response systems, which often
involve multiple interacting relay chains of signaling proteins, how does an individual cell manage to
make specific responses to so many combinations of extracellular signals? In other words, how is it
possible to achieve specificity and avoid cross-talks? (1) One strategy makes use of scaffold proteins,
which bind together groups of interacting signaling proteins into signaling complexes, often before a
signal has been received. Because the scaffold holds the signaling proteins in close proximity, the
components can interact at high local concentrations and be sequentially activated speedily,
efficiently, and selectively in response to an appropriate extracellular signal, avoiding unwanted
cross-talk with other signaling pathways. (2) In other cases, signaling complexes form only transiently

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in response to an extracellular signal and rapidly disassemble when the signal is gone. Such transient
complexes often assemble around a receptor after an extracellular signal has activated it. In many
cases the cytoplasmic tail of the activated receptor is phosphorylated during the activation process,
and the phosphorylated amino acids then serve as docking sites for the assembly of other signaling
proteins. (3) In yet other cases, receptor activation leads to the production of modified phospholipid
molecules in the adjacent plasma membrane (lipid rafts), which then recruit specific intracellular
signaling proteins to this region of membrane, where they are activated.

1.5. COORDINATION OF SIGNALING

Interaction between the components of signaling pathways Essential characteristic of the signal
pathways is the interaction: the first existing (upstream) component affects the next component
(downstream). However, there are also a number of points in each signal pathway when a
component which usually operates later (downward component) in the chain reacts with a
component that appears earlier (upstream component) in the signal pathway. If the reaction is
getting stronger, it is called positive feedback, if it is inhibiting, it is called negative feedback. The
signaling pathways can communicate with each other (called cross-talk) modulate each other’s effect
positively or negatively. The different signal pathways may also be linked to each other by a sharing
on or more components.

The integration of signals occurs when an effector molecule receives inputs from two different
pathways, and the effect of these different pathways determines the effector effect. Integration can
also occur when one component of the effector molecule (e.g. subunit) is produced by one pathway,
and the other component is produced by another pathway. The slide shows the real interactions and
integration of signaling pathways. These are not all addressed in this presentation (e.g. Wnt,
Hedgehog, extracellular matrix).

1.6. OTHER ASPECTS OF SIGNALING

Desensitization In response to many types of stimuli, cells (and organisms) are able to detect the
same percentage of change in a signal over a very wide range of stimulus strength. The target cells
accomplish this through a reversible process of adaptation, or desensitization, whereby a prolonged
exposure to a stimulus decreases the cell’s response to that level of stimulus (there are exceptions,
e.g. in memory formation where a prolonged exposure to signals results in increased sensitivity
toward this signal). Desensitization to a signal molecule can occur in various ways:
(1) receptor sequestration
(2) receptor down-regulation
(3) receptor inactivation
(4) inactivation of signaling protein
(5) production of inhibitory protein

One ligand affects more receptors The number of receptors is much numerous than the number of
the ligands. It means that one ligand can affect more receptor molecules. The same ligand-receptors
interaction may have different effects on different cells. Acetyl-choline (ACH) is an example. The
figure shows that the Ach causes relaxation in smooth and cardiac muscles (but contraction in
skeletal muscles), causes secretion in the salivary gland and the pancreas, (stimulates the secretion of
digestive enzymes and insulin), and stimulates the nerve cells to fire (the most common
neurotransmitter).

Interaction domains The assembly of signaling complexes depends on various highly conserved,
small interaction domains, which are found in many intracellular signaling proteins. Each of these

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compact protein modules binds to a particular structural motif in another protein (or lipid) molecule.
The recognized motif can be a short peptide sequence, a covalent modification (such as a
phosphorylated amino acid), or another protein domain. There are many interaction domains in

A cell's fate depends on the incoming signal combinations The cells have to receive different signals
(survival factors) in order to stay alive. For cell division and differentiation other factors in addition to
survival factors are required, these are growth and differentiation factors. If cells do not receive
survival factors, or receive death signals, programmed cell death (apoptosis) will be the
consequence. Apoptosis without any external factors can also take place due to the effect of
internal signals

Cells adopt different fates depending on their position in a morphogen gradient The same signal
acting on the same cell can have qualitatively different effect depending on the signal’s
concentration. This process is especially important in animal development, where the signal molecule
is called a morphogen. In the simplest case, the morphogen diffuses out from a localized cellular
source (a signaling center), generating a signal concentration gradient. The responding cells adopt
different cell fates in accordance with their position in the gradient. This is because the different
levels of receptor activation lead to differences in the concentration or activity of one or more gene
regulatory proteins (transcription factors) in the nucleus of each cell, which in turn results in different
gene expression.

Response to gradually increasing concentration of extracellular signal

(1) Smoothly graded signaling response Some cells response to extracellular signals are smoothly
graded according to the concentration of the signal molecule.
(2) Switchlike signaling response In other cases, the relationship between signal and response can be
discontinuous or all-or-none, with abrupt switch from one type of outcome to another as the signal
concentration increases beyond a certain value.

No figure: Signal withdrawal During development, transient extracellular signals often produce
lasting effect: they can trigger a change in the cell’s development that persists indefinitely through
cell memory mechanisms. In most cases in adult tissues, however, the response fades when a signal
ceases (except in some types of neurons and immune cells). Often the effect is transient because the
signal exerts its effect by altering the concentrations of intracellular molecules that are short lived
(unstable), undergoing continual turnover. Thus, once the extracellular signal is gone, the
replacement of the old molecules by new ones wipes out all traces of the signal’s actions.

Fast and slow pathways The signal speed of the process is dependent on the number of components
involved. However, each of the components of the activation process is very fast, so there is no
significant difference between a longer and a shorter pathway. The slow pathway involves a step,
which affects the activation of gene expression. Traditionally, the signal, which does not change the
activity of DNA, is called the fast pathways, and which contains the step of formation of new proteins
is called slow pathway.

Interaction domains SRC homology 2 (SH2) domains and phosphotyrosine-binding (PTB) domains, for
example, bind to phosphorylated tyrosines in a particular peptide sequence on activated receptors or
intracellular signaling proteins. SH3 domains bind to short proline-rich amino acid sequences. Some
PH domains bind to the charged head groups of specific modified phospholipids.

Cell Signaling – 1. Introduction