Cell adhesion

General mechanism

Cell adhesion molecules (CAMs) are classified into four major families: integrins, immunoglobulin superfamily, cadherins, and selectins. Cadherins and IgSF are homophilic CAMs, as they directly bind to the same type of CAMs on another cell, while integrins and selectins are heterophilic CAMs that bind to different types of CAMs. Each of these adhesion molecules has a different function and recognizes different ligands. Defects in cell adhesion are usually attributable to defects in expression of CAMs.

In multicellular organisms, bindings between CAMs allow cells to adhere to one another and creates structures called cell junctions. According to their functions, the cell junctions can be classified as:

• Anchoring junctions (adherens junctions, desmosomes and hemidesmosomes), which maintain cells together and strengthens contact between cells.
• Occluding junctions (tight junctions), which seal gaps between cells through cell–cell contact, making an impermeable barrier for diffusion
• Channel-forming junctions (gap junctions), which links cytoplasm of adjacent cells allowing transport of molecules to occur between cells
• Signal-relaying junctions, which can be synapses in the nervous system

Alternatively, cell junctions can be categorised into two main types according to what interacts with the cell: cell–cell junctions, mainly mediated by cadherins, and cell–matrix junctions, mainly mediated by integrins.

Cell–cell junctions

Cell–cell junctions can occur in different forms. In anchoring junctions between cells such as adherens junctions and desmosomes, the main CAMs present are the cadherins. This family of CAMs are membrane proteins that mediate cell–cell adhesion through its extracellular domains and require extracellular Ca²⁺ ions to function correctly. Cadherins forms homophilic attachment between themselves, which results in cells of a similar type sticking together and can lead to selective cell adhesion, allowing vertebrate cells to assemble into organised tissues. Cadherins are essential for cell–cell adhesion and cell signaling in multicellular animals and can be separated into two types: classical cadherins and non-classical cadherins.

Adherens junctions

Adherens junctions mainly function to maintain shape of tissues and hold cells together. In adherens junctions, classical cadherins between neighbouring cells interact through their extracellular domains. Classical cadherins share a conserved calcium-sensitive region in their extracellular domains. When this region comes into contact with Ca²⁺ ions, extracellular domains of cadherins change from the inactive flexible conformation to a more rigid conformation to undergo homophilic binding. Intracellular domains of classical cadherins are also highly conserved as they bind to proteins called catenins forming catenin-cadherin complexes, which links classical cadherins to actin filaments. This association with actin filaments is essential for adherens junctions to stabilises cell–cell adhesion. Interactions with actin filaments can also promote clustering of cadherins, involved in assembly of adherens junctions, as cadherin clusters promotes actin filaments polymerisation which in turn assembles adherens junctions by binding to cadherin–catenin complexes forming at the junction.

Desmosomes

Desmosomes are structurally similar to adherens junctions but composed of different components. Instead of classical cadherins, non-classical cadherins such as desmogleins and desmocollins act as adhesion molecules and they are linked to intermediate filaments instead of actin filaments. No catenin is present in desmosomes, as intracellular domains of desmosomal cadherins interact with desmosomal plaque proteins, which form the thick cytoplasmic plaques in desmosomes and link cadherins to intermediate filaments. Desmosomes provides strength and resistance to mechanical stress by unloading forces onto the flexible but resilient intermediate filaments, something that cannot occur with the rigid actin filaments. This makes desmosomes important in tissues that encounter high levels of mechanical stress, such as heart muscle and epithelial tissue, and explains why it appears frequently in these types of tissues.

Tight junctions

Tight junctions are normally present in epithelial and endothelial tissues, where they seal gaps and regulate paracellular transport of solutes and extracellular fluids in these tissues that function as barriers. Tight junction is formed by transmembrane proteins, including claudins, occludins and tricellulins, that bind closely to each other on adjacent membranes in a homophilic manner. Similar to anchoring junctions, intracellular domains of these tight junction proteins are bound with scaffold proteins that keep these proteins in clusters and link them to actin filaments in order to maintain structure of the tight junction. Claudins, essential for formation of tight junctions, form paracellular pores which allow selective passage of specific ions across tight junctions making the barrier selectively permeable.

Gap junctions

Gap junctions are composed of channels called connexons, which consist of transmembrane proteins called connexins clustered in groups of six. Connexons from adjacent cells form continuous channels when they come into contact and align with each other. These channels allow transport of ions and small molecules between cytoplasm of two adjacent cells, apart from holding cells together and provide structural stability like anchoring junctions or tight junctions. Gap junction channels are selectively permeable to specific ions depending on which connexins form the connexons, which allows gap junctions to be involved in cell signalling by regulating the transfer of molecules involved in signalling cascades. Channels can respond to many different stimuli and are regulated dynamically either by rapid mechanisms, such as voltage gating, or by slow mechanism, such as altering numbers of channels present in gap junctions.

Selectins

Selectins are a family of specialised CAMs involved in transient cell–cell adhesion occurring in the circulatory system. They mainly mediate the movement of white blood cells (leukocytes) in the bloodstream by allowing the white blood cells to "roll" on endothelial cells through reversible bindings of selections. Selectins undergo heterophilic bindings, as its extracellular domain binds to carbohydrates on adjacent cells instead of other selectins, while it also require Ca²⁺ ions to function, same as cadherins. Cell–cell adhesion of leukocytes to endothelial cells is important for immune responses as leukocytes can travel to sites of infection or injury through this mechanism. At these sites, integrins on the rolling white blood cells are activated and bind firmly to the local endothelial cells, allowing the leukocytes to stop migrating and move across the endothelial barrier.

Immunoglobulin superfamily

The immunoglobulin superfamily (IgSF) is one of the largest superfamily of proteins in the body and it contains many diverse CAMs involved in different functions. These transmembrane proteins have one or more immunoglobulin-like domains in their extracellular domains and undergo calcium-independent binding with ligands on adjacent cells. Some IgSF CAMs, such as neural cell adhesion molecules (NCAMs), can perform homophilic binding while others, such as intercellular cell adhesion molecules (ICAMs) or vascular cell adhesion molecules (VCAMs) undergo heterophilic binding with molecules like carbohydrates or integrins. Both ICAMs and VCAMs are expressed on vascular endothelial cells and they interact with integrins on the leukocytes to assist leukocyte attachment and its movement across the endothelial barrier.

Cell–matrix junctions

Cells create extracellular matrix by releasing molecules into its surrounding extracellular space. Cells have specific CAMs that will bind to molecules in the extracellular matrix and link the matrix to the intracellular cytoskeleton. Extracellular matrix can act as a support when organising cells into tissues and can also be involved in cell signalling by activating intracellular pathways when bound to the CAMs. Cell–matrix junctions are mainly mediated by integrins, which also clusters like cadherins to form firm adhesions. Integrins are transmembrane heterodimers formed by different α and β subunits, both subunits with different domain structures. Integrins can signal in both directions: inside-out signalling, intracellular signals modifying the intracellular domains, can regulate affinity of integrins for their ligands, while outside-in signalling, extracellular ligands binding to extracellular domains, can induce conformational changes in integrins and initiate signalling cascades. Extracellular domains of integrins can bind to different ligands through heterophilic binding while intracellular domains can either be linked to intermediate filaments, forming hemidesmosomes, or to actin filaments, forming focal adhesions.

Hemidesmosomes

In hemidesmosomes, integrins attach to extracellular matrix proteins called laminins in the basal lamina, which is the extracellular matrix secreted by epithelial cells. Integrins link extracellular matrix to keratin intermediate filaments, which interacts with intracellular domain of integrins via adapter proteins such as plectins and BP230. Hemidesmosomes are important in maintaining structural stability of epithelial cells by anchoring them together indirectly through the extracellular matrix.

Focal adhesions

In focal adhesions, integrins attach fibronectins, a component in the extracellular matrix, to actin filaments inside cells. Adapter proteins, such as talins, vinculins, α-actinins and filamins, form a complex at the intracellular domain of integrins and bind to actin filaments. This multi-protein complex linking integrins to actin filaments is important for assembly of signalling complexes that act as signals for cell growth and cell motility.