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BBS2042 Cell Signaling
Case 1: The cellular intra- and internet
Cell-cell contact
Anchoring junctions
Cell-cell connections are essential for multiple purposes such as providing a barrier function
to epithelial cells as well as movement and strength to muscle cells. No cell-cell contact
results in no life being possible.
- Occluding junction: tight junction seals gap between epithelial cells.
- Cell-cell anchoring junctions: adherens junction connects actin filament bundle in
one cell with that in the next cell. Desmosome
connects intermediate filaments in one cell to
those in the next cell.
- Channel-forming junctions: gap junction
allows the passage of small water-soluble
molecules from the cell to cell.
- Cell-matrix anchoring junctions: (focal
adhesions) actin-linked cell-matrix adhesion
anchors actin filaments in cell to extracellular
matrix. Hemidesmosome anchors
intermediate filaments in a cell to extracellular
matrix.
General composition of anchoring junctions
- Transmembrane adhesion proteins.
- Intracellular adaptor proteins, connecting the intracellular
filaments with the adhesion proteins.
Composition of adherens junctions
- Connects actin filaments in one cell with that in the
neighbor cell.
- Composed of classical cadherins (E,P,N), catenin and actin.
- Ca2+ essential for extracellular cadherin domain
interactions.
Composition of desmosomes
- Connects intermediate filaments in one cell with that I the
neighbor.
- Composed of non-classical cadherins (desmoglein,
desmocolin) as TM proteins adaptor proteins: plakoglobin,
plakophilin and desmoplakin.
Composition of hemidesmosomes
- Anchors intermediate filaments in a cell to the ECM.
- Composed of integrin 64, collagen XVII as TM proteins.
Adaptor proteins: plectin and dystonin.
,Composition of focal adhesions
- Anchors actin filaments in the cell to extracellular matrix.
- Involved in down-stream signaling events.
- Adaptor proteins: Talin, FAK, tensin and vinculin.
Composition of tight junctions
- Composed of claudins as major TM protein (essential for TJ
formation).
- Supported by occludins and junction adhesion molecules
(JAM’s).
- Connected by ZO proteins (adaptor protein) to actin
filaments.
Functions of the tight junctions:
- Hold cells together.
- Forms a tight barrier.
- Help to maintain the polarity of cells by preventing lateral diffusion of integral
membrane proteins between apical and basolateral surfaces.
- Prevents passage of molecules and ions through the space between plasma
membranes of adjacent cells.
Acantholysis: affects desmosomes which leads to the loss of desmosomes, and it causes
epidermal cells to float away.
Mutation in claudin-14: affects tight junctions and results in deafness.
Composition of gap junctions
Connexons are composed primarily of connexin proteins. 1
connexon is made up of 6 connexin proteins. 1 gap junction is
composed of 2 attaching connexons.
- Functions: transfer of inorganic ions and small water-
soluble molecules between neighboring cells (need to
be less than 5 KDa).
- Gap junctions can switch between open/closed states in seconds.
- By closing gap junctions healthy cells can be protected from damaged neighboring
cells.
Autocrine signaling (diffusion)
An autocrine signal is a chemical signal that acts on the cell that
secreted it. A form of autocrine signaling is purinergic signaling,
which involves purine derivative. A cell secretes ATP which can
change to ADP and AMP and these forms can then influence the
same cell that secreted the ATP.
Intracrine signaling
Intracrine refers to a compound (hormone) that acts inside a cell,
regulating intracellular events. Usually the compound is produced in
the cell itself.
,Juxtracrine signaling (non-diffusion)
Juxtracrine signaling involves direct cell-to-cell communication
where the signaling molecules remains attached to the cell
membrane of the signaling cell and interacts with receptors on the
membrane of the target cell. An example of juxtacrine signalig is
Notch signaling:
- The differentiation of the stem cells into the other cells
occurs through Delta-Notch signaling. So, you have the Notch receptors and you have
Notch ligands for example Delta, and when the Delta binds to the Notch receptors the
intracellular part of the Notch receptor will be cut off and will move to the nucleus,
where it will activate the transcription program (HES).
This activation leads to the cell not making Delta
anymore. This simple step already ensures
differentiation because the cell on the left does not make
any Delta, but only makes Notch receptors and the cell
on the right does not make HES since it hasn’t received a
Delta signal and will therefore continue making Delta.
- Applications of notch signaling: embryonic development, angiogenesis, bone
development and immune system.
Paracrine signaling (diffusion)
Target cells in close proximity to the paracrine cell. In contrast to
juxtracrine signaling, with paracrine signaling secreted molecules
diffuse through extracellular fluid. There are four main pathways
that are involved in paracrine signaling (ligand-receptor mode):
- Fibroblast growth factor pathway (RTK)
- Tumor growth factor- pathway (RTK)
- Wnt pathway
- Hedgehog pathway
Canonical Wnt Signaling Pathway:
• In the canonical Wnt pathway, the key mediator is β-catenin, which plays a central role in
regulating gene transcription.
• In the absence of Wnt ligands, a destruction complex comprising Axin, adenomatous
polyposis coli (APC), glycogen synthase kinase 3β (GSK3β), and casein kinase 1α (CK1α)
phosphorylates β-catenin, marking it for ubiquitin-mediated degradation.
, • When Wnt ligands bind to their receptors, which consist of Frizzled (Fz) proteins and low-
density lipoprotein receptor-related
proteins (LRP5/6), the destruction
complex is inhibited. This leads to the
stabilization and accumulation of β-
catenin in the cytoplasm.
• Accumulated β-catenin translocates into
the nucleus, where it interacts with T-cell
factor/lymphoid enhancer factor
(TCF/LEF) transcription factors to activate
the transcription of Wnt target genes
involved in cell proliferation, survival, and
stem cell maintenance.
Sonic Hedgehog signaling (SHH)
Absence of SHH: Patched inhibits Smoothened, what you have is that
Gli 2/3 is phosphorylated and truncated in proteasome to Gli2/3R.
Gli2/3R translocated to nucleus to inhibit gene expression.
Presence of SHH: SHH binds to Patched, which inhibits Patched, and
this leads to Patched no longer inhibiting Smoothened. As a result,
smoothened translocated to the plasma membrane. Gli2/3 is not
phosphorylated and truncated, and it will translocate to the nucleus
to stimulate gene expression.
Endocrine signaling (diffusion)
The endocrine system communicates by using hormones, chemical
signals that are secreted into the blood and distributed all over the
body by circulation. Only those cells with receptors for the hormone
are target cells.
Neurocrine signaling
The nervous system uses a combination of chemical signals
and electrical signals. An electrical signal travels along a nerve
cell (neuron) until it reaches the end of the cell, where it is
translated into a chemical signal (neurocrine) secreted by the
neuron. If a neurocrine molecule diffuses from the neuron across an extracellular space to a
target cell and has a rapid effect, it is called a neurotransmitter. If a neurocrine acts more
slowly, it is called a neuromodulator. If a neurocrine released by a neuron diffuses into the
blood for distribution, it is called a neurohormone.
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