18.2 Cell-cell junctions and adhesion molecules

Cell-Cell Junctions

Cell-cell junctions hold tissues together and allow neighboring cells to communicate. Without them, tissues would fall apart under mechanical stress, lose their polarity, and fail to coordinate basic functions like contraction and secretion.

Types of Cell-Cell Junctions

There are four major types, each with a distinct job:

• Tight junctions seal the space between adjacent cells, blocking molecules from slipping through the gaps (paracellular transport). They also maintain cell polarity by preventing membrane proteins from drifting between the apical and basolateral surfaces. Found prominently in epithelial cells lining the gut and kidney tubules.
• Adherens junctions provide strong mechanical links between cells by connecting the actin cytoskeletons of neighboring cells. Common in epithelial and endothelial tissues where cells need to resist stretching forces.
• Desmosomes also provide mechanical strength, but they connect intermediate filaments rather than actin. This makes them especially good at resisting shearing forces. You'll find them in tissues under heavy mechanical stress, like skin epidermis and cardiac muscle.
• Gap junctions are the communication junctions. They form channels that let small molecules (under ~1 kDa) and ions pass directly between cells. In cardiac muscle, this is what allows the electrical coupling that coordinates heartbeats.

Molecular Composition of Cell-Cell Junctions

Each junction type is built from a specific set of transmembrane and intracellular proteins:

• Tight junctions: The transmembrane proteins claudins and occludin form the actual seal between cells. On the cytoplasmic side, ZO proteins (ZO-1, ZO-2, ZO-3) link these transmembrane components to the underlying actin cytoskeleton. Different claudin family members create tight junctions with different permeability properties depending on the tissue.
• Adherens junctions: Classical cadherins (typically E-cadherin in epithelia) span the membrane and form calcium-dependent homophilic bonds with cadherins on the neighboring cell. Inside the cell, catenins ($\alpha$-, $\beta$-, and p120-catenin) connect the cadherin cytoplasmic tail to actin filaments. $\beta$-catenin also has a signaling role in the Wnt pathway, which links adhesion to gene regulation.
• Gap junctions: Six connexin proteins assemble into a ring called a connexon (or hemichannel). One connexon from each cell docks together to form a complete channel. Different connexin isoforms (e.g., connexin 43 in cardiac muscle) give channels different gating and permeability properties.
• Desmosomes: The transmembrane adhesion proteins are desmoglein and desmocollin, both members of the cadherin superfamily. They form homophilic interactions across the intercellular space. On the cytoplasmic side, plakoglobin and plakophilin link to desmoplakin, which anchors the complex to intermediate filaments (typically keratins in epithelial cells, desmin in cardiac muscle).

Adhesion Molecules and Cell-Cell Interactions

Key Adhesion Molecule Families

Cadherins are calcium-dependent adhesion molecules. They require extracellular $Ca^{2+}$ ions to maintain their rigid, extended conformation; remove the calcium, and they become floppy and non-functional. Cadherins form homophilic interactions, meaning E-cadherin on one cell binds E-cadherin on the adjacent cell, not a different cadherin type. This selectivity matters during development: cells expressing the same cadherin type tend to sort together, which is how tissues with distinct boundaries form during morphogenesis.

The major subtypes are named for where they were first identified:

• E-cadherin (epithelial) maintains epithelial sheet integrity. Loss of E-cadherin is a hallmark of the epithelial-to-mesenchymal transition (EMT) seen in cancer metastasis.
• N-cadherin (neural) is found in neurons, mesenchymal cells, and cardiac muscle.
• P-cadherin (placental) is found in the placenta and epidermis.

Integrins are heterodimeric transmembrane receptors composed of one $\alpha$ and one $\beta$ subunit. They primarily mediate cell-ECM adhesion by binding extracellular matrix ligands like fibronectin and laminin. Some integrins also participate in cell-cell adhesion (e.g., leukocyte integrins binding ICAMs on endothelial cells during immune cell migration). Integrins signal bidirectionally: "inside-out" signaling activates the integrin's ligand-binding ability, while "outside-in" signaling transmits information about the extracellular environment into the cell.

Functional Importance of Cell-Cell Junctions

• Mechanical integrity: Adherens junctions and desmosomes distribute mechanical forces across tissues, preventing individual cells from tearing away. This is why genetic defects in desmosomal proteins cause blistering skin diseases (like pemphigus) and cardiac arrhythmias.
• Barrier function and polarity: Tight junctions create distinct apical and basolateral membrane domains in epithelial cells. Each domain has different protein and lipid compositions, which is essential for directional transport (e.g., nutrient absorption in the intestine).
• Intercellular communication: Gap junctions enable electrical coupling (critical for synchronized cardiac contraction) and metabolic coupling (sharing of second messengers like $Ca^{2+}$ and cAMP between cells), helping tissues coordinate responses as a unit.