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BBS2042 - Cell signaling - Summary of all cases
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All cases from BBS2042 - Cell signaling, including notes from the lectures
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General principles of cell communication
The extracellular signal molecule (in low concentration)
usually binds to a receptor protein (with high affinity)
that is embedded in the plasma membrane of the target
cell and activates one or more intracellular signalling
pathways mediated by a series of signalling proteins.
Finally, one or more of the intracellular signalling
proteins alters the activity of effector proteins and
thereby the behaviour of the cell.
Signal molecules include proteins, small peptides, amino
acids, nucleotides, steroids, retinoids, fatty acid
derivatives, and even dissolved gases such as nitric oxide
and carbon monoxide.
Regardless of the nature of the signal, the target cell responds by means of a receptor, which
specifically binds the signal molecule and then initiates a response in the target cell.
● In most cases, the receptors are transmembrane proteins on the target cell surface. When
these proteins bind an extracellular signal molecule (a ligand), they become activated and
generate various intracellular signals that alter the behaviour of the cell.
● In other cases, the receptor proteins are inside the target cell, and the signal molecule has to
enter the cell to bind to them: this requires that the signal molecule be sufficiently small and
hydrophobic to diffuse across the target cell's plasma membrane.
Cell Signalling
There are four forms of intercellular signalling
1. Contact-dependent signalling requires cells to
be in
direct membrane-membrane contact
2. Paracrine signalling depends on signals that are
released into the extracellular space and act
locally on neighbouring cells
3. Synaptic signalling is performed by neurons that
transmit signals electrically along their axons and
release neurotransmitters at synapses, which are
often located far away from the neuronal cell
body.
4. Endocrine signalling depends on endocrine cells,
which secrete hormones into the bloodstream for distribution throughout the body.
1
,Many of the same types of signalling molecules are used in paracrine, synaptic, and endocrine
signalling; the crucial difference lies in the speed and selectivity with which the signals are
delivered to their targets.
Contact-dependent Signalling
Juxtacrine Signalling
Juxtacrine signalling is a type of intercellular communication that is transmitted by oligosaccharide,
lipid or protein components of a cell membrane. Many juxtacrine signals affect the emitting cell or
the adjacent cells nearby. A juxtacrine signal occurs between neighbouring cells that have extensive
patches of closely opposed plasma membranes linked by transmembrane channels known as
connexons. Unlike other types of cell signalling, like paracrine and endocrine, juxtacrine signalling
requires physical contact between the two cells involved.
There are three types of signalling modes of juxtacrine interactions:
● The Notch Pathway
● The Extracellular matrix
● Gap Junctions
The Notch Pathway
Notch signalling promotes proliferative signalling during neurogenesis, and its activity is inhibited by
Numb to promote neural differentiation. Notch plays
a major role in the regulation of embryonic
development and neurulation.
● Notch is a juxtacrine pathway
Notch proteins are activated by cells that express the
Delta, Jagged or Serrate proteins (ligands) in their cell
membranes and is present in most multicellular
organisms. A Notch protein extends through the cell
membrane and has an external compartment
exposed to the outsides, which is where it contacts
Delta, Jagged or Serrate proteins that are protruding
out from an adjacent cell. When attached to one of
these ligands, plasma-membrane-bound protease
(gamma-secretase) cleaves off the cytoplasmic tail of
Notch receptor. The intracellular tail translocates to
the nucleus and regulates gene
expression/transcription by activating the CSL
transcription factors. Once the transcription is over,
Notch is degraded by the proteasomal complex.
● samen met P300
2
,Short-Distance Signalling
Paracrine/Autocrine signalling
Paracrine and autocrine signal molecules act as local mediators, affecting only cells in the local
environment of the signalling cell. With autocrine, the signal and target cell are of the same cell type,
thereby activating themselves. Regarding paracrine signalling, the signalling cells secrete signal
molecules into the extracellular fluid, affecting target cells of a different type in the local
environment of the signalling cell.
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 neighbouring target cells, destroyed by
extracellular enzymes, or immobilized by the extracellular matrix.
● Heparan sulfate proteoglycans (secreted protein antagonist), either in the extracellular
matrix or attached to cell surfaces, often play a part in localizing the action of secreted signal
proteins. They contain long polysaccharide side chains that bind the signal proteins and
immobilize them. They may also control the stability of these proteins, their transport
through the extracellular space, or their interaction with cell-surface receptors.
These antagonists bind to either the signal molecule itself or its cell-surface receptor and block its
activity
The Wnt pathway
The Wnt signalling pathways are a group of signal transduction pathways which begin with the Wnt
(glyco)proteins that pass signals into a cell through cell surface receptors. The Wnt pathways are
involved in the control of gene expression, cell behaviour, cell adhesion, and cell polarity. They also
control tissue regeneration in adult bone marrow, skin, and intestine
● Wnt signalling acts in a paracrine and autocrine fashion for the proliferation and embryonic
development
Canonical (β-Catenin-Dependent) Wnt Signalling Pathway:
In this pathway, Wnt signalling inhibits the degradation of β-catenin, which can regulate the
transcription of a number of genes.
● This causes an accumulation of β-catenin in the cytoplasm
● The β-catenin eventually translocate into the nucleus to act as a transcriptional coactivator
of transcription factors (that being to the TCF/LEF family).
First, Wnt signalling is activated via ligation of Wnt proteins to LRP5/6 and frizzled proteins, which
are the respective dimeric cell surface receptors
● This binding inactivates the “destruction complex”: because Wnt translocates Axin, and
therefore the destruction complex, to the plasma membrane. AND other proteins in the
destruction complex phosphorylate Axin to the cytoplasmic tail of LRP5/6. Therefore, the
Axin becomes de-phosphorylated and its stability and level decrease?????
Second, upon ligation to their receptors, the cytoplasmic protein dishevelled (Dsh) is activated via
phosphorylation.
3
, ● Activation of Dsh induces the dissociation of GSK-3β from Axin and leads to the inhibition of
GSK-3β.
Third, the phosphorylation and degradation of β-catenin are inhibited as a result of the inactivation
of the "destruction complex".
● The destruction complex consists of axin, APC (adenomatosis polyposis coli), PP2A (protein
phosphatase 2A), GSK3 (glycogen synthase kinase 3), and CK1a (Casein kinase 1a)
● The destruction complex degrades β-catenin by targeting it for ubiquitination.
Fourth, the inhibition of GSK3, and overall inactivation of the destruction complex, allows β-catenin
to accumulate and localize to the nucleus and induce a cellular response via gene transduction.
Sonic Hedgehog pathway
A sonic hedgehog protein- a member of the Hedgehog family- spreads out from its source, forming a
morphogen gradient that controls the characters of the cells along with the limbs, and activates
transcription.
Simplified depiction of Hedgehog (Hh) signalling. Without Hh, the membrane protein Patched (Ptc)
represses the membrane protein Smoothened (Smo) and the Hh cytoplasmic complex in conjunction
with the kinases, Protein Kinase A (PKA), Casein kinase I (CKI) and GSK3 which phosphorylate Cubitus
interruptus (Ci)(asterisks), lead to the formation of the repressor form (CiR). Hh binds to Ptc and its
4
,co-receptor Ihog(interference hedgehog) (and Boi(brother of iHog, not shown) to relieve the
inhibition of Smo by Ptc. This prevents the proteolysis of Ci which translocates to the nucleus and,
with the transcriptional co-activator CREB, activates transcription. Smo is phosphorylated (asterisks)
in the process.
The Shh pathway works in a paracrine way for the proliferation of stem cells
Long-distance cell signalling
Synaptic signalling
Nerve cells, or neurons, extend long branching processes (axons) that enable them to contact target
cells far away, where the processes terminate at the specialized sites of signal transmission known at
chemical synapses. --> a long-range signalling mechanism to coordinate the behaviour of cells in
remote parts of the body.
When activated by stimuli from the environment or from other nerve cells, the neuron sends
electrical impulses (action potentials) rapidly along its axon; when such an impulse reaches the
synapse at the end of the axon, it triggers the secretion of a chemical signal that acts as a
neurotransmitter.
Endocrine signalling
Endocrine cells secrete hormones into the bloodstream, which carries the molecules far and wide,
allowing them to act on target cells that may lie anywhere in the body.
Major endocrine glands are the pineal gland, pituitary gland, pancreas, ovaries, testes, thyroid and
parathyroid gland, and the adrenal gland. The neural control centre for the endocrine system is the
hypothalamus.
5
,Synaptic vs Endocrine
● Because endocrine signalling relies on diffusion and blood flow, it is relatively slow. Synaptic
signalling, by contrast, is much faster, as well as more precise. Nerve cells can transmit
information over long distances by electrical impulses that travel at speeds of up to 100
meters per second; once released from a nerve terminal, a neurotransmitter has to diffuse
less than 100 nm to the target cell, a process that takes less than a millisecond.
● Another difference between endocrine and synaptic signalling is that, whereas hormones are
greatly diluted in the bloodstream and interstitial fluid and therefore must be able to act at
very low concentrations (typically < 10–8 M) with high-affinity receptors, neurotransmitters
are diluted much less and can achieve high local concentrations with low-affinity receptors.
● Moreover, after its release from a nerve terminal, a neurotransmitter is quickly removed
from the synaptic cleft, either by specific hydrolytic enzymes that destroy it or by specific
membrane transport proteins that pump it back into either the nerve terminal or
neighbouring glial cells. Thus synaptic signalling is much more precise than endocrine
signalling, both in time and in space.
When there is no signal
For most of the cells in animal tissues, even the decision to continue living depends on the correct
interpretation of a specific combination of signals required for survival. When deprived of these
signals (in a culture dish, for example), the cell activates a suicide program and kills itself—usually by
apoptosis, a form of programmed cell death. Because different types of cells require different
combinations of survival signals, each cell type is restricted to a specific set of environments in the
body.
Junctions
The junctions between cells create pathways for communication, allowing the cells to exchange the
signals that coordinate their behaviour and regulate their patterns of gene expression.
Animal tissues fall into one or other of two broad categories, representing two architectural
extremes.
1. Connective tissues, such as bone or tendon; the extracellular matrix is plentiful, and cells are
sparsely distributed within it. The matrix is rich in fibrous polymers, especially collagen, and
it is the matrix- rather than the cells- that bears most of the mechanical stress to which the
tissue is subjected. Direct attachments between one cell and another are relatively rare, but
the cells have important attachments to the matrix, allowing them to pull on it and to be
pulled by it.
6
, 2. Epithelial tissues, e.g. the lining of the gut or the epidermal covering of the skin, cells are
closely bound together into sheets called epithelia. The extracellular matrix is scant,
consisting mainly of a thin mat called the basal lamina, underlying one face of the sheet.
Within the epithelium, the cells are attached to each other directly by cell-cell adhesions,
where cytoskeletal filaments are anchored, transmitting stresses across the interior of each
cell, from adhesion site to adhesion site.
Silverthorn) Stronger cell junctions can be grouped into three broad categories by function:
communicating junctions, occluding junctions {occludere, to close up}, and anchoring junctions
In animals, the communicating junctions are gap junctions. The occluding junctions of vertebrates
are tight junctions that limit movement of materials between cells. Animals have three major types
of junctions, described below.
1. Gap junctions are the simplest cell-cell junctions. They allow direct and rapid cell-to-cell
communication through cytoplasmic bridges between adjoining cells. Cylindrical proteins
called connexins interlock to create passageways that look like hollow rivets with narrow
channels through their centres. The channels are able to open and close, regulating the
exchange of inorganic ions and other small water-soluble molecules from cell to cell, but not
of macromolecules such as proteins or nucleic acids. Amino acids, ATP, cAMP diffuse directly
between cytoplasms of connected cells. Gap junctions allow both chemical and electrical
signals to pass rapidly from one cell to the next. They were once thought to occur only in
certain muscle and nerve cells, but we now know they are important in cell-to-cell
communication in many tissues, including the liver, pancreas, ovary, and thyroid gland.
2. Tight junctions are occluding
junctions that restrict the movement
of material between the cells they
link. In tight junctions, the cell
membranes of adjacent cells partly
fuse together with the help of
proteins called claudins, tricellulin
and occludins (They determine the
tight junction permeability), thereby
making a barrier. As in many
physiological processes, the barrier
properties of tight junctions are
dynamic and can be altered
depending on the body’s needs. Tight
junctions may have varying degrees of “leakiness.” Tight junctions in the intestinal tract and
kidney prevent most substances from moving freely between the external and internal
environments. In this way, they enable cells to regulate what enters and leaves the body.
Tight junctions also create the so-called blood-brain barrier that prevents many potentially
harmful substances in the blood from reaching the extracellular fluid of the brain.
3. Anchoring junctions attach cells to each other (cell-cell anchoring junctions) or to the
extracellular matrix (cell-matrix anchoring junctions). Regarding vertebrates, cell-cell
anchoring junctions are created by CAMs called cadherins, which connect with one another
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