L14: Cell adhesion Flashcards
different types of cell-cell contacts?
Occluding (Tight) Junctions
* Provide tight seals in epithelial sheets (and endothelial cells) and control passage of solutes from the lumen and foreign bodies.
- Anchoring adhesions.
- Attach cells to each other and to the extracellular matrix
- Cell-cell junctions (Adherens and Desmosomes) form junctional complex.
- Cell-matrix junctions (Focal adhesions and Hemi-desmosomes) in epithelial cells attached to basal lamina.
- Channel forming and signal-relaying junctions
- chemical and electrical signals between cells
- GAP junctions
- Chemical synapses
- Immunological synapses
And epithelial and endothelial cells
cadherins?
Homophilic binding: Each cadherin receptor binds to an identical cadherin on a neighboring cell.
Structure: Mostly made of cadherin domains (extracellular repeats).
Calcium-dependent: Cadherins require Ca²⁺ to maintain their structure and function.
Maintain cell-cell adhesion
* Cadherins – homotypic adhesion of extracellular domains
- Classical and most characterised AJ family member is E-cadherin (epithelial cadherin)
* Cadherins in AJ linked to actin via anchor proteins (catenins,
alpha-actinin and vinculin) which bind to the cytoplasmic tail.
tight junctions?
Functions of Tight Junctions:
✅ Permeability barrier: Regulate paracellular transport (movement of molecules between cells).
✅ Cell polarity: Separate the apical and basolateral surfaces, helping cells maintain function.
✅ Macromolecular restriction: Prevent unwanted passage of proteins, ions, and pathogens.
Key Components:
Claudins (main structural proteins)
Homophilic interactions form the tight seal.
Different claudins determine selective permeability.
Interact with cytosolic scaffolding proteins (ZO-1, ZO-2, MAGI).
Occludins
Help stabilize the junction.
Contribute to regulation of tight junction permeability.
Junctional Adhesion Molecules (JAMs)
Interact with cingulin, which links to the actin cytoskeleton.
Important in cell signaling and immune response.
found mainly in epithelia and endothelial cells.
anchoring adhesions?
- Cell-cell Junctions: through 1 integrin
– Adherens Junctions (Actin)
– Desmosomes (Intermediate filaments)
– Main receptors are cadherins - Cell-matrix Junctions: connect ecm through integrins to actin cytoskeleton
– Focal Adhesions (Actin)
– Hemi-desmosomes (Intermediate filaments)
– Main receptors are integrins
Cell-cell adhesion receptors: classical cadherins
Provide calcium-dependent cell-cell adhesion
Highly conserved and different family members are widely expressed
extracellular domains: EC1, EC2, EC3, DC5, EC5
+ cytoplasmic tail: juxta-membrane domain + cateninin binding site.
Cadherins are calcium-dependent adhesion molecules. Without Ca²⁺, cadherins become unstable and lose their adhesive function.
When Ca²⁺ is present, cadherins undergo a conformational change and cluster at the plasma membrane, forming adherens junctions.
Once adherens junctions form, they help recruit and stabilize tight junctions.
α-Catenin & Actin Cytoskeleton
α-Catenin links cadherins to the actin cytoskeleton.
It binds to F-actin and helps regulate the mechanical strength of junctions.
catenins and their functions?
beta-cateninin and gamma catenin/plakoglobin: bind to cadherin tail and alpha catenin. neccessary for cadherin adhesion.
p120^ctn + delta?-catenin: bind to juxtamembrane domain, psoitive and negative effects on adhesion, regulate cadhderin turnover, binds to juxtamembrane domain, mostly neuronal, has negative effects on epithelial adhesion.
- all of these are armadillo family members
alpha catenin: bind to beta-cat or plaoglobin, actin binding and bundling, essential for cadherin adhesion. this is of homology to vincullin.
knockouts of cadherin and phenotype?
E-cadherin: stage E4: phenotype: pre-implantation lethality
N-cadherin: E10, mycoytes dissociate, severe cardiovascular defect.
P-cadherin: V,F. precocious differentiation of mammary gland.
VE-cadherin: E10: vascular defects.
alpha catenin: E4- Pre-implantation lethality
beta catenin: E8. Epiblast dissociates, no mesoderm formation.
gamma catenin (plakoglobin): E12-17. Cardiac rupture, desmosomal defects, epidermal blistering.
desmosomes?
E.g: intercalated discs between cardiomyocytes.
Maintain cell-cell adhesion (strong
mechanical linkers)
* Main components are desmosomal
cadherin family members (desmoglein and
desmocollin)
* Cadherins are bound to plakophilin and
plakoglobin, that in turn bind desmoplakin
(and then to intermediate filament
cytoskeleton)
He explains image
focal adhesions?
Key Points About Cell-Matrix Anchoring Junctions
Integrins Are the Main Receptors
Heterodimeric transmembrane receptors made of α and β subunits.
In mammals, 18 α-subunits & 8 β-subunits combine to form 24 different integrins.
Recognize specific motifs in ECM proteins (e.g., RGD motif in fibronectin).
Integrin Activation & Binding Sites
4 cation binding sites regulate integrin activation.
β-subunit has metal ion coordination sites (important for ligand binding and conformational changes).
Ligand specificity relies on both α & β subunits.
Cytoskeletal Linkage & Regulation
Talin & α-actinin bind to vinculin, reinforcing actin connections.
Focal Adhesion Kinase (FAK):
A tyrosine kinase that regulates focal adhesion turnover.
Helps in cell migration and mechanotransduction.
PIP5 Kinase & Rho GTPase:
PIP5K is regulated by Rho GTPase.
Rho regulates α-actinin & vinculin, influencing actin cytoskeletal dynamics.
check whether 24 or 20
integrins?
chatgpt check: General Properties of Integrins
Ubiquitously expressed across different cell types.
24 heterodimers in vertebrates (18 α + 8 β subunits).
Large proteins (each subunit is >1000 amino acids).
Weak individual interactions, but strong adhesion occurs when integrins cluster.
Often inactive until activated by specific signals.
Key Integrin Subtypes & Functions
β1 Integrins
The most versatile β-subunit.
α5β1 binds fibronectin (via the RGD motif).
α1β1 & α2β1 bind collagen.
β2 Integrins (Leukocyte Integrins)
Allow leukocytes to leave blood vessels and migrate into tissues.
Example: αLβ2 (LFA-1) binds to ICAMs on endothelial cells.
α6β4 Integrin (Special Case)
Found in hemidesmosomes (not desmosomes!).
Links to intermediate filaments (keratins) instead of actin.
Has a much longer cytoplasmic tail (~1000 aa vs. ~50 aa in other integrins) → important for signaling.
Activation Mechanism (Ca²⁺ vs. Mg²⁺ Binding)
When bound to Ca²⁺, integrins are inactive (bent conformation, binding site near plasma membrane).
When Mg²⁺ replaces Ca²⁺, the integrin straightens → activates binding to ECM proteins like fibronectin or vitronectin.
The RGD motif (Arginine-Glycine-Aspartic acid) is the key sequence in ECM proteins that integrins recognize.
α6β4?
chatgpt check: α6β4 is NOT in desmosomes; it is in hemidesmosomes.
It connects epithelial cells to the basement membrane, linking keratin intermediate filaments to laminin in the ECM.
Desmosomes use desmogleins and desmocollins, not integrins.
factors reg integrin function (?)
integrin -signal
pH
Calcium concentration
Inositol lipid turnover
Phosphorylation
Dephosphorylation
Proteolysis
regulation of integrin adhesion and signaling?
Outside-In Regulation
- “Active” integrin binds ECM ligand and transmits
intracellular signal. Similar to GF-RTK interaction.
Inside-Out Regulation
-Extracellular agonists (growth factor, cytokine, etc.) stimulate
intracellular signals that “activate” integrin extracellular
adhesion functions.
- Most integrins on the cell surface and/or “hidden” inside the
cell are “inactive”.
