Cell signaling

Cell signaling (cell signalling in British English) is part of any communication process that governs basic activities of cells and
coordinates all cell actions. The ability of cells to perceive and correctly respond to their microenvironment is the basis of
development, tissue repair, and immunity, as well as normal tissue homeostasis. Errors in signaling interactions and cellular
information processing are responsible for diseases such as cancer, autoimmunity, and diabetes.[1][2][3] By understanding cell
signaling, diseases may be treated more effectively and, theoretically, artificial tissues may be created.[4]

Traditional work in biology has focused on studying individual parts of cell signaling pathways. Systems biology research helps us to
understand the underlying structure of cell signaling networks and how changes in these networks may affect the transmission and
flow of information (signal transduction). Such networks are complex systems in their organization and may exhibit a number of
emergent properties including bistability and ultrasensitivity. Analysis of cell signaling networks requires a combination of
experimental and theoretical approaches including the development and analysis of simulations and modeling.[5] Long-range
[6]
allostery is often a significant component of cell signaling events.

Contents
1 Signaling between cells of one organism and multiple organisms
2 Classification
3 Cell signaling in multicellular organisms
4 Receptors for cell motility and differentiation
5 Signaling pathways
6 Intraspecies and interspecies signaling
7 See also
8 References
9 External links

Signaling between cells of one organism and multiple organisms

Cell signaling has been most extensively studied in the context of human diseases
and signaling between cells of a single organism. However, cell signaling may also
occur between the cells of two different organisms. In many mammals, early embryo
cells exchange signals with cells of the uterus.[7] In the human gastrointestinal tract,
bacteria exchange signals with each other and with human epithelial and immune
system cells.[8] For the yeast Saccharomyces cerevisiae during mating, some cells
send a peptide signal (mating factor pheromones) into their environment. The mating
factor peptide may bind to a cell surface receptor on other yeast cells and induce
them to prepare for mating.[9]
Figure 1. Example of signaling
between bacteria. Salmonella
Classification enteritidis uses N-Acyl homoserine
Cell signaling can be classified to be mechanical and biochemical based on the type lactone for Quorum sensing (see:
Inter-Bacterial Communication)
of the signal. Mechanical signals are the forces exerted on the cell and the forces
[10]
produced by the cell. These forces can both be sensed and responded by the cells.
Biochemical signals are the biochemical molecules such as proteins, lipids, ions and gases. These signals can be categorized based on
the distance between signaling and responder cells. Signaling within, between, and amongst cells is subdivided into the following
classifications:

Intracrine signals are produced by the target cell that stay within the target cell.
Autocrine signals are produced by the target cell, are secreted, and af fect the target cell itself via receptors.
Sometimes autocrine cells can target cells close by if they are the same type of cell as the emitting cell. An example
of this are immune cells.
Juxtacrine signals target adjacent (touching) cells. These signals are transmitted along cell membranes via protein or
lipid components integral to the membrane and are capable of af fecting either the emitting cell or cells immediately
adjacent.
Paracrine signals target cells in the vicinity of the emitting cell.Neurotransmitters represent an example.
Endocrine signals target distant cells. Endocrine cells produce hormones that travel through the blood to reach all
parts of the body.
Cells communicate with each other via direct contact (juxtacrine signaling), over
short distances (paracrine signaling), or over large distances and/or scales (endocrine
signaling).

Some cellcell communication requires direct cellcell contact. Some cells can form
gap junctions that connect their cytoplasm to the cytoplasm of adjacent cells. In
cardiac muscle, gap junctions between adjacent cells allows for action potential
propagation from the cardiac pacemaker region of the heart to spread and
coordinately cause contraction of the heart.

The notch signaling mechanism is an example ofjuxtacrine signaling (also known as

Figure 2. Notch-mediated juxtacrine contact-dependent signaling) in which two adjacent cells must make physical contact
signal between adjacent cells. in order to communicate. This requirement for direct contact allows for very precise
control of cell differentiation during embryonic development. In the worm
Caenorhabditis elegans, two cells of the developing gonad each have an equal
chance of terminally differentiating or becoming a uterine precursor cell that continues to divide. The choice of which cell continues
to divide is controlled by competition of cell surface signals. One cell will happen to produce more of a cell surface protein that
activates the Notch receptor on the adjacent cell. This activates a feedback loop or system that reduces Notch expression in the cell
that will differentiate and that increases Notch onthe surface of the cell that continues as astem cell.[11]

Many cell signals are carried by molecules that are released by one cell and move to make contact with another cell. Endocrine
signals are called hormones. Hormones are produced by endocrine cells and they travel through the blood to reach all parts of the
body. Specificity of signaling can be controlled if only some cells can respond to a particular hormone. Paracrine signals such as
retinoic acid target only cells in the vicinity of the emitting cell.[12] Neurotransmitters represent another example of a paracrine
signal. Some signaling molecules can function as both a hormone and a neurotransmitter. For example, epinephrine and
norepinephrine can function as hormones when released from the adrenal gland and are transported to the heart by way of the blood
stream. Norepinephrine can also be produced by neurons to function as a neurotransmitter within the brain.[13] Estrogen can be
released by the ovary and function as a hormone or act locally via paracrine or autocrine signaling.[14] Active species of oxygen and
nitric oxide can also act as cellular messengers. This process is dubbedredox signaling.

Cell signaling in multicellular organisms

In a multicellular organism, signaling between cells occurs either through release into the extracellular space, divided in paracrine
signaling (over short distances) and endocrine signaling (over long distances), or by direct contact, known as juxtacrine signaling.[15]
Autocrine signaling is a special case of paracrine signaling where the secreting cell has the ability to respond to the secreted signaling
molecule.[16] Synaptic signaling is a special case of paracrine signaling (for chemical synapses) or juxtacrine signaling (for electrical
synapses) between neurons and target cells. Signaling molecules interact with a target cell as a ligand to cell surface receptors, and/or
by entering into the cell through its membrane or endocytosis for intracrine signaling. This generally results in the activation of
second messengers, leading to various physiological effects.
A particular molecule is generally used in diverse modes of signaling, and therefore a classification by mode of signaling is not
possible. At least three important classes of signaling molecules are widely recognized, although non-exhaustive and with imprecise
boundaries, as such membership is non-exclusive and depends on the context:

Hormones are the major signaling molecules of theendocrine system, though they often regulate each other's
secretion via local signaling (e.g.islet of Langerhans cells), and most are also expressed in tissues for local
purposes (e.g. angiotensin) or failing that, structurally related molecules are (e.g. PTHrP).
Neurotransmitters are signaling molecules of thenervous system, also including neuropeptides and
neuromodulators. Neurotransmitters like thecatecholamines are also secreted by the endocrine system into the
systemic circulation.
Cytokines are signaling molecules of theimmune system, with a primary paracrine or juxtacrine role, though they
can during significant immune responses have a strong presence in the circulation, with systemicfect ef (altering iron
metabolism or body temperature). Growth factors can be considered as cytokines or a different class.
Signaling molecules can belong to several chemical classes: lipids, phospholipids, amino acids, monoamines, proteins, glycoproteins,
or gases. Signaling molecules binding surface receptors are generally large and hydrophilic (e.g. TRH, Vasopressin, Acetylcholine),
while those entering the cell are generally small and hydrophobic (e.g. glucocorticoids, thyroid hormones, cholecalciferol, retinoic
acid), but important exceptions to both are numerous, and a same molecule can act both via surface receptor or in an intracrine
manner to different effects.[16] In intracrine signaling, once inside the cell, a signaling molecule can bind to intracellular receptors,
other elements, or stimulateenzyme activity (e.g. gasses). The intracrine action ofpeptide hormones remains a subject of debate.[17]

Hydrogen sulfide is produced in small amounts by some cells of the human body and has a number of biological signaling functions.
Only two other such gases are currently known to act as signaling molecules in the human body: nitric oxide and carbon
monoxide.[18]

Receptors for cell motility and differentiation

Cells receive information from their neighbors through a class of proteins known as receptors. Notch is a cell surface protein that
functions as a receptor. Animals have a small set of genes that code for signaling proteins that interact specifically with Notch
receptors and stimulate a response in cells that express Notch on their surface. Molecules that activate (or, in some cases, inhibit)
receptors can be classified as hormones, neurotransmitters, cytokines, and growth factors, in general called receptor ligands. Ligand
receptor interactions such as that of the Notch receptor interaction, are known to be the main interactions responsible for cell
signaling mechanisms and communication.[19]

As shown in Figure 2 (above; left), notch acts as a receptor for ligands that are expressed on adjacent cells. While some receptors are
cell surface proteins, others are found inside cells. For example, estrogen is a hydrophobic molecule that can pass through the lipid
bilayer of the membranes. As part of the endocrine system, intracellular estrogen receptors from a variety of cell types can be
activated by estrogen produced in theovaries.

A number of transmembrane receptors[20][21] for small molecules and peptide hormones[22] , as well as intracellular receptors for
steroid hormones exist, giving cells the ability to respond to a great number of hormonal and pharmacological stimuli. In diseases,
[23]
often, proteins that interact with receptors are aberrantly activated, resulting in constitutively activated downstream signals.

For several types of intercellular signaling molecules that are unable to permeate the hydrophobic cell membrane due to their
hydrophilic nature, the target receptor is expressed on the membrane. When such a signaling molecule activates its receptor, the
cAMP.[24][25]
signal is carried into the cell usually by means of a second messenger such as

Signaling pathways
In some cases, receptor activation caused by ligand binding to a receptor is directly coupled to the cell's response to the ligand. For
example, the neurotransmitter GABA can activate a cell surface receptor that is part of an ion channel. GABA binding to a GABAA
receptor on a neuron opens a chloride-selective ion channel that is part of the receptor. GABAA receptor activation allows negatively
charged chloride ions to move into the neuron, which inhibits the ability of the neuron to produce action potentials. However, for
many cell surface receptors, ligand-receptor interactions are not directly linked to the cell's response. The activated receptor must first
interact with other proteins
inside the cell before the
ultimate physiological effect of
the ligand on the cell's
behavior is produced. Often,
the behavior of a chain of
several interacting cell
proteins is altered following
receptor activation. The entire
set of cell changes induced by
receptor activation is called a
signal transduction mechanism
or pathway.[26]

In the case of Notch-mediated

signaling, the signal
transduction mechanism can
be relatively simple. As shown
in Figure 2, activation of
Overview of signal transduction pathways
Notch can cause the Notch
protein to be altered by a
protease. Part of the Notch protein is released from the cell surface membrane and takes part in gene regulation. Cell signaling
research involves studying the spatial and temporal dynamics of both receptors and the components of signaling pathways that are
activated by receptors in various cell types.

A more complex signal transduction pathway is shown in Figure 3. This pathway involves changes of proteinprotein interactions
inside the cell, induced by an external signal. Many growth factors bind to receptors at the cell surface and stimulate cells to progress
through the cell cycle and divide. Several of these receptors are kinases that start to phosphorylate themselves and other proteins
when binding to a ligand. This phosphorylation can generate a binding site for a different protein and thus induce proteinprotein
interaction. In Figure 3, the ligand (called epidermal growth factor (EGF)) binds to the receptor (called EGFR). This activates the
receptor to phosphorylate itself. The phosphorylated receptor binds to an adaptor protein (GRB2), which couples the signal to further
downstream signaling processes. For example, one of the signal transduction pathways that are activated is called the mitogen-
activated protein kinase (MAPK) pathway. The signal transduction component labeled as "MAPK" in the pathway was originally
called "ERK," so the pathway is called the MAPK/ERK pathway. The MAPK protein is an enzyme, a protein kinase that can attach
phosphate to target proteins such as the transcription factor MYC and, thus, alter gene transcription and, ultimately, cell cycle
progression. Many cellular proteins are activated downstream of the growth factor receptors (such as EGFR) that initiate this signal
transduction pathway.

Some signaling transduction pathways respond differently, depending on the amount of signaling received by the cell. For instance,
the hedgehog protein activates different genes, depending on the amount of hedgehog protein present.

Complex multi-component signal transduction pathways provide opportunities for feedback, signal amplification, and interactions
inside one cell between multiple signals and signaling pathways.

Intraspecies and interspecies signaling

Molecular signaling can occur between different organisms, whether unicellular or multicellular. The emitting organism produces the
signaling molecule, secretes it into the environment, where it diffuses, and it is sensed or internalized by the receiving organism. In
some cases of interspecies signaling, the emitting or
ganism can actually be ahost of the receiving organism, or vice versa.
Intraspecies signaling occurs especially in bacteria, yeast, social insects, but also
many vertebrates. The signaling molecules used by multicellular organisms are often
called pheromones. They can have such purposes as alerting against danger,
indicating food supply, or assisting in reproduction.[27] In unicellular organisms such
as bacteria, signaling can be used to 'activate' peers from a dormant state, enhance
virulence, defend against bacteriophages, etc.[28] In quorum sensing, which is also
found in social insects, the multiplicity of individual signals has the potentiality to
create a positive feedback loop, generating coordinated response. In this context, the
signaling molecules are called autoinducers.[29][30][31] This signaling mechanism
may have been involved in evolution from unicellular to multicellular
organisms.[29][32] Bacteria also use contact-dependent signaling, notably to limit
their growth.[33]

Molecular signaling can also occur between individuals of dif

ferent species. This has
been particularly studied in bacteria.[34][35][36] Different bacterial species can
coordinate to colonize a host and participate in common quorum sensing.[37]
Therapeutic strategies to disrupt this phenomenon are being investigated.[38][39]
Interactions mediated through signaling molecules are also thought to occur between
the gut flora and their host, as part of their commensal or symbiotic
relationship.[39][40] Gram negative microbes deploy bacterial outer membrane
vesicles for intra- and inter-species signaling in natural environments and at thehost-
pathogen interface.

Additionally, interspecies signaling occurs between multicellular organisms. In

Vespa mandarinia, individuals release a scent that directs the colony to a food
source.[41]

See also
Biosemiotics Cell Signaling Technology, an
Molecular cellular cognition antibody development and
production company
Cellular communication
(biology) ESIGNET Project, a project to
investigate CSNs in silico,
Crosstalk (biology)
funded by the EU under FP6.
Bacterial outer membrane
Netpath A curated resource of
vesicles Figure 3. Key components of a signal
signal transduction pathways in
Membrane vesicle trafficking humans transduction pathway (MAPK/ERK
Host-pathogen interface Nanoscale networking pathway shown)
MAPK signaling pathway leveraging biological signaling to
Wnt signaling pathway construct ad hoc in vivo
communication networks
Hedgehog signaling pathway
International q-bio Conference
Retinoic acid on Cellular Information
TGF beta signaling pathway Processing
JAK-STAT signaling pathway Literature-curated human
cAMP-dependent pathway signaling network, the largest
Protein dynamics human signaling network
database
Signal transduction
Soliton model in neuroscience
Systems biology Physical communication via
Lipid signaling sound waves in membranes
Redox signaling

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External links
Signaling Gateway Free summaries of recent research and theMolecule Pages database.
Protein signaling domains
NCI-Nature Pathway Interaction Database: authoritative information about signaling pathways in human cells.
Intercellular Signaling Peptides and Proteinsat the US National Library of MedicineMedical Subject Headings
(MeSH)
Cell Communication at the US National Library of MedicineMedical Subject Headings(MeSH)

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