Cell Signalling
BBS2042
Extensive summary of case studies integrated with lecture notes.
1
,Content
✓ Case 1: Theme 1: The cellular intra- and internet (connected to B-ILO1)
✓ Case 2: Theme 2: Listen very carefully, I will tell you this (more than) once (connected
to B-ILO2)
✓ Case 3: Theme 2: RNA as signalling molecule? (connected to B-ILO2)
✓ Case 4: Theme 3: From outside to inside without entering (connected to B-ILO3)
✓ Case 5: Theme 3: What happens when signals go nuclear? (connected to B-ILO3)
✓ Case 6: Theme 3: How to deal with foreign chemical exposures? (connected to B-ILO4)
✓ Case 7: Theme 4: Oxidative stress, the good, the bad, the ugly (connected to B-ILO5)
✓ Case 8: Theme 4: Incoming and outgoing signals (connected to B-ILO5)
✓ Case 9: Theme 5: The CRISP(Y) case (connected to B-ILO6)
✓ Lecture 7 & JC6: Explanatory lecture on cell signalling on a network level (connected
to B-ILO5 and case 8)
✓ Case 10: Theme 5: How to use the toolbox? (connected to B-ILO6)
✓ Case 12: Theme 6: From mutations to cancer (connected to B-ILO7)
2
,1.Cell junctions & Communication
LG1: Single-Cell Signalling (Intracrine vs. Autocrine)
o Themes: Internal vs. self-surface targeting, feedback loops.
o Keywords: Intracrine, autocrine, differences between the two.
LG2: Contact-Dependent & Juxtacrine Signalling
o Themes: Physical cell-to-cell/matrix adhesion, junctional transport, direct receptor cleavage.
o Keywords: Juxtacrine, desmosomes, cadherins, tight junctions, gap junctions, adherens, actin,
cell-to-cell, cell-to-matrix, homophilic, calcium, claudin, occludin, connexin, connexon, Notch
(ligand and receptor, cleavage, intracellular domain).
LG3: Short-Distance Signalling (Paracrine)
o Themes: Morphogen gradients, local tissue communication, pathway activation/inactivation
states.
o Keywords: Paracrine, Wnt (APC, GSK3, Frizzled, Dishevelled, TCF), Hedgehog (Drosophila:
SMO, FU, PKA; Vertebrates: Cos2, SUFU, iguana, Gli3), active and inactive pathways.
LG4: Long-Distance Signalling (Endocrine & Synaptic)
o Themes: Systemic blood transport vs. rapid, spatially targeted neural delivery.
o Keywords: Endocrine, hormones, bloodstream, synaptic, axons, neurotransmitters.
PART 1: Types of cell-cell and cell-ECM junctions
The key features of cell junctions and the extracellular matrix are best illustrated by considering two
broad categories:
1. Connective tissues (bone and tendon)
o Formed from an ECM produced by cells that are distributed sparsely in the matrix.
o It is the matrix—rather than the cells—that bears most of the mechanical stress to which the
tissue is subjected.
o Direct attachments between one cell and another are relatively rare, but the cells have
important attachments to the matrix.
o These cell–matrix junctions link the cytoskeleton to the matrix (allowing the cells to move
through the matrix and monitor changes in its mechanical properties).
2. Epithelial tissues (lining of the gut and epithelium of the skin)
o Cells are bound together by sheets of epithelia.
o ECM less pronounced, consisting mainly of a thin basal lamina (or basement membrane)
underlying the sheet.
o Within the epithelium, cells are attached to each other directly by cell–cell junctions, where
cytoskeletal filaments are anchored, transmitting stresses across the interiors of the cells,
from adhesion site to adhesion site.
3
,Each type of junction depends on transmembrane adhesion proteins. Adhesion proteins span the
plasma membrane, with one end linking to the cytoskeleton inside the cell and the other end linking
to other structures outside it. The external linkage may be:
o to other cells (cell–cell junctions, mediated typically by cadherins).
o ECM (cell–matrix junctions, mediated typically by integrins).
There is specialization within each family: some cadherins link to actin filaments and form adherens
junctions, while others link to intermediate filaments and form desmosomes. Some integrins link to
actin and form actin-linked cell–matrix junctions (focal adhesions), while others link to intermediate
filaments and form hemidesmosomes.
The main type of cell-cell and cell-matrix junctions found in the simple columnar epithelium.
1. The tight junction occupies the most apical position, followed by the adherens junction
(adhesion belt) and then by a special parallel row of desmosomes; together these form a
structure called a junctional complex.
2. Gap junctions and additional desmosomes are less regularly organized. They link the
cytoplasm of adjacent cells.
3. Two additional types of anchoring junctions link the cytoskeleton of the epithelial cells to the
basal lamina: actin-linked cell–matrix junctions (focal adhesions) anchor actin filaments to
the matrix, while hemidesmosomes anchor intermediate filaments to it.
4
,1.1 Cell-Cell junctions (Cadherins)
o Function: Cell–cell anchoring junctions must also be dynamic and adaptable, so that they can
be altered or rearranged when tissues are remodelled or repaired, or when there are changes
in the forces acting on them to pull them apart.
o To note: Cadherins depend on Ca2+ ions: removing Ca2+ from the extracellular medium causes
adhesions mediated by cadherins to come apart.
Classical cadherins Non-classical cadherins
o E-cadherin is present on many Proteins with known adhesive function, such as the
types of epithelial cells; diverse protocadherin found in the brain, and the
o N-cadherin on nerve, muscle, desmocollins and desmogleins that form desmosome.
and lens cells;
o P-cadherin on cells in the
placenta and epidermis.
1.1.1 Cadherins mediate homophilic action
The binding between cadherins is symmetrical and homophilic (cadherin molecules of a specific
subtype on one cell bind to cadherin molecules of the same or closely related subtype on adjacent
cells).
o All members of the superfamily have an extracellular portion with several copies of the
extracellular cadherin (EC) domain.
o Homophilic binding occurs at the N-terminal tips of the cadherin molecules, which form a
knob and a pocket.
o Cadherin molecules from opposite cell membranes bind by insertion of one domain's knob into
the other's pocket.
1.1.2 Catenins Link Classical Cadherins to the Actin Cytoskeleton
o Cadherins' linkage to the cytoskeleton is indirect and dependent on adaptor proteins.
o At adherens junctions, β-catenin and p120-catenin bind to the cadherin tail. α-catenin
interacts with β-catenin and recruits other proteins for dynamic linkage to actin filaments.
o At desmosomes, cadherins are linked to intermediate filaments through other adaptor
proteins (plakoglobin, plakophilin, desmoplakin).
o On the cytoplasmic side, a network of catenins, actin regulators, and contractile actin bundles
holds the cluster of cadherins together and links it to the actin cytoskeleton.
The cadherins are coupled indirectly to actin filaments through an adaptor
protein complex containing p120-catenin, β-catenin, and α catenin. Other proteins, including vinculin,
associate with α-catenin and help provide the linkage to actin.
5
, Adherens Junctions: Tissue Remodelling
o Adherens junctions are cell-to-cell anchoring junctions that connect the actin filament bundle
of one cell to that in an adjacent cell.
o Their main role is to provide dynamic, adaptable connections that allow tissues to undergo
remodelling, repair, and withstand changing mechanical forces pulling them apart.
o Adherens junctions occur in multiple forms. In many nonepithelial tissues, they appear as
small punctate or linear attachments that connect the cortical actin filaments beneath the
plasma membranes of two interacting cells.
o In heart muscle, they anchor the actin bundles of the contractile apparatus and act in parallel
with desmosomes to link the contractile cells end-to-end.
Key Structural Components
o Transmembrane Adhesion Proteins: Mediated by classical
cadherins
o Extracellular Interaction: Binding is symmetrical and
homophilic, where the N-terminal tips (knob-and-pocket
structure) of identical cadherins from adjacent cell membranes
bind together in a Ca2+ -dependent manner.
o Cytoskeletal Attachment: Anchors internally to actin
filaments via intracellular adaptor proteins.
o Intracellular Adaptor Proteins: The cadherin tail links
indirectly to actin filaments via a complex containing 𝛽-catenin,
p120-catenin, 𝛼-catenin, and vinculin.
Assembly & Remodelling Mechanism: Step-by-Step
1. Initiation: Unattached precursor cells explore surroundings using actin-driven membrane
protrusions.
2. Initial Contact: Small clusters of cadherins and catenins form at contact sites and associate
with actin, activating the small GTPase Rac.
3. Expansion: Rac promotes local actin protrusions, expanding the contact zone and
recruiting more cadherins and catenins.
6
BBS2042
Extensive summary of case studies integrated with lecture notes.
1
,Content
✓ Case 1: Theme 1: The cellular intra- and internet (connected to B-ILO1)
✓ Case 2: Theme 2: Listen very carefully, I will tell you this (more than) once (connected
to B-ILO2)
✓ Case 3: Theme 2: RNA as signalling molecule? (connected to B-ILO2)
✓ Case 4: Theme 3: From outside to inside without entering (connected to B-ILO3)
✓ Case 5: Theme 3: What happens when signals go nuclear? (connected to B-ILO3)
✓ Case 6: Theme 3: How to deal with foreign chemical exposures? (connected to B-ILO4)
✓ Case 7: Theme 4: Oxidative stress, the good, the bad, the ugly (connected to B-ILO5)
✓ Case 8: Theme 4: Incoming and outgoing signals (connected to B-ILO5)
✓ Case 9: Theme 5: The CRISP(Y) case (connected to B-ILO6)
✓ Lecture 7 & JC6: Explanatory lecture on cell signalling on a network level (connected
to B-ILO5 and case 8)
✓ Case 10: Theme 5: How to use the toolbox? (connected to B-ILO6)
✓ Case 12: Theme 6: From mutations to cancer (connected to B-ILO7)
2
,1.Cell junctions & Communication
LG1: Single-Cell Signalling (Intracrine vs. Autocrine)
o Themes: Internal vs. self-surface targeting, feedback loops.
o Keywords: Intracrine, autocrine, differences between the two.
LG2: Contact-Dependent & Juxtacrine Signalling
o Themes: Physical cell-to-cell/matrix adhesion, junctional transport, direct receptor cleavage.
o Keywords: Juxtacrine, desmosomes, cadherins, tight junctions, gap junctions, adherens, actin,
cell-to-cell, cell-to-matrix, homophilic, calcium, claudin, occludin, connexin, connexon, Notch
(ligand and receptor, cleavage, intracellular domain).
LG3: Short-Distance Signalling (Paracrine)
o Themes: Morphogen gradients, local tissue communication, pathway activation/inactivation
states.
o Keywords: Paracrine, Wnt (APC, GSK3, Frizzled, Dishevelled, TCF), Hedgehog (Drosophila:
SMO, FU, PKA; Vertebrates: Cos2, SUFU, iguana, Gli3), active and inactive pathways.
LG4: Long-Distance Signalling (Endocrine & Synaptic)
o Themes: Systemic blood transport vs. rapid, spatially targeted neural delivery.
o Keywords: Endocrine, hormones, bloodstream, synaptic, axons, neurotransmitters.
PART 1: Types of cell-cell and cell-ECM junctions
The key features of cell junctions and the extracellular matrix are best illustrated by considering two
broad categories:
1. Connective tissues (bone and tendon)
o Formed from an ECM produced by cells that are distributed sparsely in the matrix.
o It is the matrix—rather than the cells—that bears most of the mechanical stress to which the
tissue is subjected.
o Direct attachments between one cell and another are relatively rare, but the cells have
important attachments to the matrix.
o These cell–matrix junctions link the cytoskeleton to the matrix (allowing the cells to move
through the matrix and monitor changes in its mechanical properties).
2. Epithelial tissues (lining of the gut and epithelium of the skin)
o Cells are bound together by sheets of epithelia.
o ECM less pronounced, consisting mainly of a thin basal lamina (or basement membrane)
underlying the sheet.
o Within the epithelium, cells are attached to each other directly by cell–cell junctions, where
cytoskeletal filaments are anchored, transmitting stresses across the interiors of the cells,
from adhesion site to adhesion site.
3
,Each type of junction depends on transmembrane adhesion proteins. Adhesion proteins span the
plasma membrane, with one end linking to the cytoskeleton inside the cell and the other end linking
to other structures outside it. The external linkage may be:
o to other cells (cell–cell junctions, mediated typically by cadherins).
o ECM (cell–matrix junctions, mediated typically by integrins).
There is specialization within each family: some cadherins link to actin filaments and form adherens
junctions, while others link to intermediate filaments and form desmosomes. Some integrins link to
actin and form actin-linked cell–matrix junctions (focal adhesions), while others link to intermediate
filaments and form hemidesmosomes.
The main type of cell-cell and cell-matrix junctions found in the simple columnar epithelium.
1. The tight junction occupies the most apical position, followed by the adherens junction
(adhesion belt) and then by a special parallel row of desmosomes; together these form a
structure called a junctional complex.
2. Gap junctions and additional desmosomes are less regularly organized. They link the
cytoplasm of adjacent cells.
3. Two additional types of anchoring junctions link the cytoskeleton of the epithelial cells to the
basal lamina: actin-linked cell–matrix junctions (focal adhesions) anchor actin filaments to
the matrix, while hemidesmosomes anchor intermediate filaments to it.
4
,1.1 Cell-Cell junctions (Cadherins)
o Function: Cell–cell anchoring junctions must also be dynamic and adaptable, so that they can
be altered or rearranged when tissues are remodelled or repaired, or when there are changes
in the forces acting on them to pull them apart.
o To note: Cadherins depend on Ca2+ ions: removing Ca2+ from the extracellular medium causes
adhesions mediated by cadherins to come apart.
Classical cadherins Non-classical cadherins
o E-cadherin is present on many Proteins with known adhesive function, such as the
types of epithelial cells; diverse protocadherin found in the brain, and the
o N-cadherin on nerve, muscle, desmocollins and desmogleins that form desmosome.
and lens cells;
o P-cadherin on cells in the
placenta and epidermis.
1.1.1 Cadherins mediate homophilic action
The binding between cadherins is symmetrical and homophilic (cadherin molecules of a specific
subtype on one cell bind to cadherin molecules of the same or closely related subtype on adjacent
cells).
o All members of the superfamily have an extracellular portion with several copies of the
extracellular cadherin (EC) domain.
o Homophilic binding occurs at the N-terminal tips of the cadherin molecules, which form a
knob and a pocket.
o Cadherin molecules from opposite cell membranes bind by insertion of one domain's knob into
the other's pocket.
1.1.2 Catenins Link Classical Cadherins to the Actin Cytoskeleton
o Cadherins' linkage to the cytoskeleton is indirect and dependent on adaptor proteins.
o At adherens junctions, β-catenin and p120-catenin bind to the cadherin tail. α-catenin
interacts with β-catenin and recruits other proteins for dynamic linkage to actin filaments.
o At desmosomes, cadherins are linked to intermediate filaments through other adaptor
proteins (plakoglobin, plakophilin, desmoplakin).
o On the cytoplasmic side, a network of catenins, actin regulators, and contractile actin bundles
holds the cluster of cadherins together and links it to the actin cytoskeleton.
The cadherins are coupled indirectly to actin filaments through an adaptor
protein complex containing p120-catenin, β-catenin, and α catenin. Other proteins, including vinculin,
associate with α-catenin and help provide the linkage to actin.
5
, Adherens Junctions: Tissue Remodelling
o Adherens junctions are cell-to-cell anchoring junctions that connect the actin filament bundle
of one cell to that in an adjacent cell.
o Their main role is to provide dynamic, adaptable connections that allow tissues to undergo
remodelling, repair, and withstand changing mechanical forces pulling them apart.
o Adherens junctions occur in multiple forms. In many nonepithelial tissues, they appear as
small punctate or linear attachments that connect the cortical actin filaments beneath the
plasma membranes of two interacting cells.
o In heart muscle, they anchor the actin bundles of the contractile apparatus and act in parallel
with desmosomes to link the contractile cells end-to-end.
Key Structural Components
o Transmembrane Adhesion Proteins: Mediated by classical
cadherins
o Extracellular Interaction: Binding is symmetrical and
homophilic, where the N-terminal tips (knob-and-pocket
structure) of identical cadherins from adjacent cell membranes
bind together in a Ca2+ -dependent manner.
o Cytoskeletal Attachment: Anchors internally to actin
filaments via intracellular adaptor proteins.
o Intracellular Adaptor Proteins: The cadherin tail links
indirectly to actin filaments via a complex containing 𝛽-catenin,
p120-catenin, 𝛼-catenin, and vinculin.
Assembly & Remodelling Mechanism: Step-by-Step
1. Initiation: Unattached precursor cells explore surroundings using actin-driven membrane
protrusions.
2. Initial Contact: Small clusters of cadherins and catenins form at contact sites and associate
with actin, activating the small GTPase Rac.
3. Expansion: Rac promotes local actin protrusions, expanding the contact zone and
recruiting more cadherins and catenins.
6
