thumb|300px|Schematic of cell adhesion

Cell adhesion is the process by which cells interact and attach to neighbouring cells through specialised molecules of the cell surface. This process can occur either through direct contact between cell surfaces such as cell junctions or indirect interaction, where cells attach to surrounding extracellular matrix (ECM), a gel-like structure containing molecules released by cells into spaces between them. Cell adhesion occurs from the interactions between cell adhesion molecules (CAMs), transmembrane proteins located in the cell membrane. Cell adhesion links cells in different ways and can be involved in signal transduction for cells to detect and respond to changes in the surroundings. Other cellular processes regulated by cell adhesion include cell migration and tissue development in multicellular organisms. Alterations in cell adhesion can disrupt important cellular processes and lead to a variety of diseases, including cancer and arthritis. Cell adhesion is also essential for infectious organisms, such as bacteria or viruses, to cause disease.

General mechanism

thumb|600px|Overview diagram of different types of cell junctions present in epithelial cells, including cell–cell junctions and cell–matrix junctions.

Cell adhesion molecules (CAMs) are classified into four major families: integrins, immunoglobulin superfamily, cadherins, and selectins. When this region comes into contact with Ca<sup>2+</sup> 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. 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. 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. 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. 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. 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 undergo heterophilic bindings, as its extracellular domain binds to carbohydrates on adjacent cells instead of other selectins, while it also require Ca<sup>2+</sup> ions to function, same as cadherins. 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. 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. 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.

thumb|500px|Hemidesmosomes diagram showing interaction between integrins and laminin, including how integrins are linked to keratin intermediate filaments

Hemidesmosomes

In hemidesmosomes, integrins attach to extracellular matrix proteins called laminins in the basal lamina, which is the extracellular matrix secreted by epithelial cells. 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. 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. Molecules that are either nutrients or signals required for growth are transported, either passively or selectively, between plant cells through plasmodesmata. cell–cell adhesion is key for pathogenic protozoans to attach en enter their host cells. An example of a pathogenic protozoan is the malarial parasite (Plasmodium falciparum), which uses one adhesion molecule called the circumsporozoite protein to bind to liver cells, and another adhesion molecule called the merozoite surface protein to bind red blood cells.

Pathogenic fungi use adhesion molecules present on its cell wall to attach, either through protein-protein or protein-carbohydrate interactions, to host cells or fibronectins in the extracellular matrix.

Prokaryotes

Prokaryotes have adhesion molecules on their cell surface termed bacterial adhesins, apart from using its pili (fimbriae) and flagella for cell adhesion.

Adhesins can recognise a variety of ligands present on the host cell surfaces and also components in the extracellular matrix. These molecules also control host specificity and regulate tropism (tissue- or cell-specific interactions) through their interaction with their ligands.

Viruses

Viruses also have adhesion molecules required for viral binding to host cells. For example, influenza virus has a hemagglutinin on its surface that is required for recognition of the sugar sialic acid on host cell surface molecules. HIV has an adhesion molecule termed gp120 that binds to its ligand CD4, which is expressed on lymphocytes. Viruses can also target components of cell junctions to enter host cells, which is what happens when the hepatitis C virus targets occludins and claudins in tight junctions to enter liver cells. Due to the link between CAMs and cancer metastasis, these molecules could be potential therapeutic targets for cancer treatment.

There are also other human genetic diseases caused by an inability to express specific adhesion molecules. An example is leukocyte adhesion deficiency-I (LAD-I), where expression of the β<sub>2</sub> integrin subunit is reduced or lost. This leads to reduced expression of β<sub>2</sub> integrin heterodimers, which are required for leukocytes to firmly attach to the endothelial wall at sites of inflammation in order to fight infections. Leukocytes from LAD-I patients are unable to adhere to endothelial cells and patients exhibit serious episodes of infection that can be life-threatening.

An autoimmune disease called pemphigus is also caused by loss of cell adhesion, as it results from autoantibodies targeting a person's own desmosomal cadherins which leads to epidermal cells detaching from each other and causes skin blistering.

Pathogenic microorganisms, including bacteria, viruses and protozoans, have to first adhere to host cells in order to infect and cause diseases. Anti-adhesion therapy can be used to prevent infection by targeting adhesion molecules either on the pathogen or on the host cell. Apart from altering the production of adhesion molecules, competitive inhibitors that bind to adhesion molecules to prevent binding between cells can also be used, acting as anti-adhesive agents.

See also

  • Differential adhesion hypothesis
  • Role of cell adhesions in neural development

References

  • The Cell by G. Cooper (online textbook)
  • Molecular Cell Biology by Lodish et al. (online textbook)
  • Molecular Biology of the Cell by Alberts et al. (online textbook)
  • Cell Adhesion and Extracellular Matrix - The Virtual Library of Biochemistry, Molecular Biology and Cell Biology