Cell Junctions & Cell–Matrix Adhesions

Learning Objectives

Identify junctions located along the lateral and basal domains of cells
Describe the structure of all major cell–cell and cell–matrix junctions
List and explain every component of the classical epithelial junctional complex
Correlate each junction with its physiological role in tissues (adhesion, permeability control, force transmission, signaling, communication)

Cells, Tissues, and the Need for Junctions

A few cell types wander freely through the body
- Blood cells
- Many immune‐system cells
The overwhelming majority of cells are packed into cooperative communities ➜ tissues
- A tissue = an assembly of similar cells + their extracellular matrix (ECM) that share common embryonic origin and function
Organs arise from the functional grouping of several tissue types (e.g., liver contains epithelial bile-duct cells, vascular connective tissue, nerve tissue, etc.)
Two large mechanical/architectural strategies:
1. Epithelial tissue – cells bear mechanical loads; stresses pass from cell-to-cell through cytoskeletal filaments anchored in junctions
2. Connective tissue – ECM macromolecules (collagen, proteoglycans, ground substance) bear stress; cells are often sparsely distributed and seldom connected directly

Definition and General Functions of Cell Junctions

Multiprotein complexes that create contact between:
1. Neighbouring cells
2. A cell and the ECM
Six key functional outputs
- $\mathbf{1}$ Bond cells into cohesive units
- $\mathbf{2}$ Reduce mechanical stress on individual cells
- $\mathbf{3}$ Build, or reinforce, the paracellular barrier of epithelia
- $\mathbf{4}$ Control paracellular transport
- $\mathbf{5}$ Permit intercellular chemical/electrical communication
- $\mathbf{6}$ Anchor cells to the ECM and transmit mechanosensory information

Overview of Junction Types

Cell–Cell Junctions

Tight junctions (zonula occludens)
Anchoring junctions
- a. Adherens junctions
- b. Desmosomes
Gap junctions (communicating junctions)

Cell–Matrix Junctions

Anchoring junctions
- a. Actin-linked cell–matrix junctions ("focal adhesions")
- b. Hemidesmosomes

Junctional Complex of Polarised Epithelial Cells

Sits at the extreme apical region of the lateral membrane
Classical vertical order (apical → basal):
1. Tight junction (zonula occludens)
2. Adherens junction (zonula adherens)
3. Desmosome (macula adherens)
Roles
- Regulate cell polarity (apical vs. basolateral membranes)
- Fine-tune paracellular permeability
- Provide mechanical coupling between cells

Tight Junctions (Zonula Occludens)

Principal seal between epithelial cells; prevents uncontrolled flow across the paracellular space
Permeability profile
- Impermeable to macromolecules
- Variable permeability to ions and small solutes ➜ selective, tissue-specific paracellular transport
- Gap width: virtually $0\,\text{nm}$ (membranes fuse), visible as "kiss" points in EM
Core transmembrane proteins
- Claudins (≈ $27$ family members) – form selective pores
- Occludin – modulates barrier properties
Cytoplasmic plaque proteins: ZO-1, ZO-2, ZO-3 bind claudins/occludin to actin
Typical locations: intestinal mucosa, renal tubule, urinary bladder, respiratory epithelium
Pathology: Disruption ➜ "leaky gut" syndrome, inflammatory bowel disease, pathogen invasion

Cell–Cell Anchoring Junctions

Shared Design Principles

Cadherins = Ca ${}^{2+}$ -dependent adhesion receptors
- Extracellular domains require $\text{Ca}^{2+}$ (stiffens, prevents proteolysis)
- Homophilic binding → adjacent cells link identical cadherins ➜ tissue sorting during development
Cytoplasmic tails dock to adaptor proteins (catenins, plakoglobins, etc.) that tether to the cytoskeleton

Adherens Junctions (Zonula Adherens / Adhesion Belt)

Link an actin filament bundle in one cell to an equivalent bundle in the next
Spatially located just basal to tight junctions; often form a circumferential belt encircling every cell
Roles
- Shape and morphogenesis (e.g., epithelial folding, neurulation)
- Dynamic remodeling during wound healing
Anchoring apparatus
- Classical cadherins → β-catenin/α-catenin → actin

Desmosomes (Macula Adherens)

Spot-like “rivets” that connect intermediate filaments (keratin, desmin, vimentin) of neighbouring cells
Specialized cadherins: desmogleins + desmocollins
Plaque: desmoplakin, plakoglobin, plakophilin → bind IFs
Provide shear resistance; abundant in skin epidermis, cardiac muscle, uterine cervix, bladder epithelia
Clinical note: Auto-antibodies against desmoglein-3 cause pemphigus vulgaris (epithelial blistering)

Gap Junctions (Communicating Junctions)

Hexameric connexons (connexin $_6$ hemichannel) from two cells align → aqueous pore
Diameter ≈ $1.5\,\text{nm}$ ; passes solutes < $\approx 1\,\text{kDa}$ (ions, cAMP, IP $_3$ , glucose)
Gap width between membranes: $2\text{–}4\,\text{nm}$
Electrical & metabolic coupling
- Heart: synchronous contraction; connexins form critical part of intercalated discs
- Smooth muscle: propagate peristaltic waves along gut
- Astrocyte/oligodendrocyte networks in CNS
Gating is dynamic (pH, $\text{Ca}^{2+}$ , phosphorylation)

Cell–Cell Junctions: Consolidated Comparison

Tight junction ➜ seal / fence
Adherens ➜ actin belt, morphogenesis
Desmosome ➜ IF rivet, tensile strength
Gap ➜ channel, communication

Cell–Matrix Anchoring Junctions (Integrin-Based)

Integrin Fundamentals

$\approx 24$ αβ heterodimers; extracellular domain binds ECM ligands (collagen, fibronectin, laminin, RGD motifs)
Bidirectional signalling:
- "Inside-out" – talin/kindlin binding alters integrin affinity
- "Outside-in" – ECM engagement triggers FAK, Src, MAPK ➜ influences development, proliferation, survival, migration, haemostasis

Actin-Linked Cell–Matrix Junctions (Focal Adhesions)

Anchor actin stress fibres to ECM via integrins
Range from transient (migrating cells) to massive, stable adhesions (tendon fibroblasts)
Key adaptors: talin, vinculin, paxillin, α-actinin, FAK
Act as mechanosensors; convert ECM stiffness into Rho-GTPase signalling → cytoskeletal remodelling

Hemidesmosomes

Morphologically resemble half-desmosomes; occur at basal plasma membrane of epithelial cells
Integrin α6β4 binds laminin-332 in the basement membrane ➜ links to intracellular keratin IFs via plectin, BP230
Provide long-term, high-strength adhesion of epidermis to dermis; defects produce epidermolysis bullosa

Vertical Distribution of Junctions in a Polarised Epithelial Cell

Apical surface
- Tight junction
- Adherens junction
- Desmosomes
- Gap junctions (scattered along lateral membrane)
Basal domain
- Hemidesmosomes attach to basal lamina

Pathophysiological & Practical Notes

"Leaky" tight junctions ➜ diarrhoea, inflammatory bowel disease, cholestasis
Desmosomal mutations → cardiomyopathies, skin fragility disorders
Gap junction mutational spectrum involves deafness, cataracts, peripheral neuropathy
Integrin antagonists exploited as anti-thrombotic, anti-cancer, and anti-fibrotic drugs

Multimedia & Further Study (links cited in lecture)

Tight junction overview: https://www.youtube.com/watch?v=vpYsjMDwsRk&t=5s
Tight junction animation: https://www.youtube.com/watch?v=Zf4C-Plk908
Cadherin dynamics: https://www.youtube.com/watch?v=pBUIb5jchVo
Adherens junction belt: https://www.youtube.com/watch?v=PXCP6QE-WXW
Cardiac desmosomes & gap junctions: https://www.youtube.com/watch?v=K9TwazkS7nQ
Integrin introduction: https://www.youtube.com/watch?v=4k60P3Pnh30 | https://www.youtube.com/watch?v=6iJVCBw4e00
Focal adhesion formation: https://www.youtube.com/watch?v=tQDb5qiAf7I

Glossary

Cadherin – Ca ${}^{2+}$ -dependent cell–cell adhesion molecule
Claudin/Occludin – main sealing proteins of tight junctions
Connexin – protein subunit of gap-junction channel
Integrin – heterodimeric ECM receptor linking cytoskeleton to matrix
Desmoglein/Desmocollin – desmosomal cadherins
Catenin – adaptor linking cadherins to actin
Talin/Kindlin – intracellular integrin activators

End of comprehensive study notes – review frequently and cross-reference with histology slides for maximal retention.