PRINCIPLES OF CELL SIGNALLING
Principles of cell signalling
The principle of cell signalling is hinged on the fact that cellular communication frequently involves
converting signals that carry information from one form to another.
During cell communication, the signalling cell releases a particular signalling molecule that is then
detected by the target cell.
Most animal cells send and receive signals and as such act as both signalling and target cells. Animal
cells can communicate through direct contact or by secreting local regulators such as growth
factors or neurotransmitters.
There are three stages of cell signalling:
• Reception – where the target cell detects a signalling molecule present in the exogenous
environment.
• Transduction – the conversion of the signal to a form that can bring about a specific cellular
response.
• Response – the specific cellular effect brought about by the signalling molecule.
Reception: a signal molecule (ligand) binds to a receptor protein (receptor), causing it to change shape.
The interaction between a ligand and receptor is highly specific. A conformational change in a receptor
is often the initial stage in the transduction of a signal. Receptors are found in two places;
Intracellular proteins are found inside the plasma membrane in the cytoplasm or nucleus. The
signalling molecule must cross the plasma membrane and therefore must be hydrophobic
(for instance the steroid hormone testosterone), or very small (Nitric Oxide).
Cell-surface proteins are embedded in the plasma membrane, and these receptors bind to water-
soluble ligands.
Transduction: cascades of molecular interactions relay signals from receptors to target molecule in the
cell. Signal transduction pathways often involve a phosphorylation cascade. Because the pathway is
usually a multistep one, the possibility of greatly amplifying the signal exists. At each step, enzymes
called protein kinases phosphorylate and thereby activate many proteins at the next level. This cascade
of phosphorylation greatly enhances the signal, allowing for a large cellular response. Not all
components of signal transduction pathways are proteins, some are small non-protein water-soluble ions
called second messengers, for example cyclic AMP.
Response: cell signalling leads to the regulation of transcription or cytoplasmic activities. Many
signalling pathways ultimately affect protein synthesis, usually by turning specific genes on or off within
the nucleus. Often, the final activated molecule in a signalling pathway functions as a transcription
factor. In the cytoplasm, signalling pathways often regulate the activity of proteins rather than their
synthesis. For example, the final step in the signalling pathway may affect the activity of enzymes or
cause cytoskeleton rearrangement.
FORMS / TYPES OF SIGNALS
In multicellular organisms, cells use numerous kinds of extracellular molecules to send signals and
communicate with one another. These means of cell signalling are grouped into four types:
Endocrine
Paracrine
Neuronal/ Synaptic
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Juxtacrine dept. of pharmacology
jspc pulikkal
Endocrine: This is the most common type of cell signaling and involves sending a signal throughout
the whole body by secreting hormones into the bloodstream of animals or the sap in plants. The cells
that produce hormones in animals are called endocrine cells. For example, the pancreas is an endocrine
gland and produces the hormone insulin, which regulates the uptake of glucose in cells all over the
body. Examples of hormones that function in an endocrine manner include testosterone, progesterone
and gonadotropins.
Endocrine signalling. Endocrine cells release hormones (green) Paracrine signalling. Paracrine cells release signalling
into the blood stream where they are able to travel and bind to molecules (green) into the immediate surrounding area, targeting
target cells located downstream. The binding of these nearby cells.
hormones to target cells may lead to cellular responses such as
the release of a second hormone (blue).
Paracrine: Signalling molecules are released from paracrine cells and diffuse locally through the
extracellular fluid, targeting cells that are nearby, thus acting as local mediators. Many of the cells that
are involved in inflammation during infection, or that regulate cell proliferation utilise this type of
signalling. For example cancer cells sometimes enhance their own survival or proliferation in this way.
Examples of signalling molecules that often function in a paracrine manner include transforming growth
factor-β (TGF-β) and fibroblast growth factors (FGFs).
Neuronal/ Synaptic: Nerve cells (neurons) are specialised cells with a unique structure that can send
signals very quickly, over long distances and to specific target cells. A signal is detected by receptors
present on dendrites and then carried along the axon to a presynaptic terminal. When the signal reaches
the presynaptic terminal, vesicles containing signalling molecules (neurotransmitters) fuse with the
membrane, releasing the contents into the synaptic space (Figure 4). These neurotransmitters are
detected by receptors on the postsynaptic membrane i.e. the cell membrane of the target cell, which may
be another neuron or an effector cell. Examples of neurotransmitters include acetylcholine, serotonin
and histamine.
Juxtacrine: This is often referred to as a contact-dependent signalling.
This does not involve the release of secreted molecules and only occurs over short distances. The cells
make direct physical contact through signal molecules found in the plasma membrane of the signalling
cells and receptor proteins present in the plasma membrane of the target cell. This type of signalling is
extremely important during embryonic development and cell-fate determination (when similar cells that
are close to each other specialise to form a specific cell type). The Notch pathway mediates juxtacrine
signalling between adjacent cells (Figure 5). Notch receptors are single transmembrane proteins and they
bind to specific ligands (e.g. Delta and Serrate ligands) on adjacent cells. Ligand binding results in
proteolytic cleavage of the Notch receptor which releases an intracellular domain that is translocated to
the nucleus where it regulates gene expression.
Ligands and Receptors
Sending cell: this cell secretes a ligand.
Target cell: this cell has a receptor that can bind the ligand and trigger intracellular cascade.
Nontarget cell: this cell does not have a receptor for the ligand – no response
Signaling molecules are often called ligands, a general term for molecules that bind specifically to other
molecules (such as receptors).
The message carried by a ligand is often relayed through a chain of chemical messengers inside the cell.
Ultimately, it leads to a change in the cell, such as alteration in the activity of a gene or even the
induction of a whole process, such as cell division. Thus, the original intercellular (between-cells)
signal is converted into an intracellular (within-cell) signal that triggers a response.
INTRACELLULAR SIGNAL TRANSDUCTION PATHWAYS
Binding initiates a signaling pathway
• When a ligand binds to a cell-surface receptor, the receptor’s intracellular domain (part inside the
cell) changes in some way. Generally, it takes on a new shape, which may make it active as an
enzyme or let it bind other molecules.
• The change in the receptor sets off a series of signaling events. For instance, the receptor may turn
on another signaling molecule inside of the cell, which in turn activates its own target.
• Many signal transduction pathways amplify the initial signal, so that one molecule of ligand can
lead to the activation of many molecules of a downstream target.
• Intracellular signal transduction by
1. Phosphorylation
2. Second messenger pathways (Ca2+, cAMP, IP3, Diacyl glycerol etc)
Phosphorylation example: MAPK signaling cascade
• To get a better sense of how phosphorylation works, let’s examine a real-life example of a signaling
pathway that uses this technique: growth factor signaling. Specifically, we'll look at part of the
epidermal growth factor (EGF) pathway that acts through a series of kinases to produce a cellular
response.
• This diagram shows part of the epidermal growth factor signaling pathway:
• MAPK – mitogen activated protein kinase
• MAP2K – mitogen activated protein kinase kinase, MAPKK
(MEK)
• MAP3K – mitogen activated protein kinase kinase kinase,
MAPKKK
• MAPKAPK – MAPK-activated protein kinase
• GF – growth factors
• Ras – Ras family of small G protein Ras superfamily
• Rho – Rho family of small G protein Ras superfamily
• Traf – TNF associated factor protein family
• RTK – receptor tyrosine kinase
• GPCR – G-protein coupled receptors
Phosphorylation (marked as a P) is important at many stages of
this pathway.
Second messengers
Although proteins are important in signal transduction pathways, other types of molecules can
participate as well. Many pathways involve second messengers, small, non-protein molecules that pass
along a signal initiated by the binding of a ligand (the “first messenger”) to its receptor.
DAG (diacyl glycerol)
PIP2 ( phosphatidylinositols)
Cyclic AMP (cAMP)
Another second messenger used in many different cell types is cyclic adenosine
monophosphate (cyclic AMP or cAMP), a small molecule made from ATP. In response to signals, an
enzyme called adenylyl cyclase converts ATP into cAMP, removing two phosphates and linking the
remaining phosphate to the sugar in a ring shape.
Once generated, cAMP can activate an enzyme called protein kinase A (PKA), enabling it to
phosphorylate its targets and pass along the signal.
raashkpharma@[Link]
dept. of pharmacology
jspc pulikkal