Cellular Junctions

Cell Adhesion Molecules (CAMs) are proteins located on the cell surface that mediate cell-cell interactions. They are involved in binding cells together and in binding cells to the extracellular matrix. CAMs are transmembrane receptors and are composed of three domains: an intracellular domain that interacts with the cytoskeleton, a transmembrane domain and an extracellular domain that interacts with an identical CAM on an opposing cell (a process known as homophilic binding) or alternatively with other CAM family members (a process known as heterophilic binding).

Most CAMs belong to 4 protein families: The calcium independent immunoglobulin families and integrins and the calcium dependent cadherins and selectins.

The Immunoglobulin superfamily of CAMs (IgCAMs) are composed of Ca2+-independent surface cell surface glycoproteins which form connections between cells. They contain an immunoglobulin-like extracellular domain. They are either homophilic or heterophilic and bind to proteoglycans, integrins, or to different Immunoglobulin CAMs. One of the most extensively studied immunoglobulin CAMs is the neural cell adhesion molecule (NCAM). NCAM is implicated in neural differentiation, axonal guidance and axonal branching.

The Cadherin family of cell adhesion molecules mediate cell adhesion mostly via homophilic binding. They exist on cell surfaces as monomers. Dimerization of cadherins leads to cell-cell adhesion. They include E-cadherins (epithelial), P-cadherins (placental) and N-cadherins (neural). Desmocollins and desmogleins, also members of the cadherin superfamily, mediate adhesion at desmosomal junctions. Cadherins guide the organization of developing tissues and are required for the maintenance of solid tissues. They are expressed at high levels in all solid tissues of adults.

The selectins are a family of heterophilic CAMs that bind fucosylated and sialylated carbohydrates (they are thus considered to be lectins). As opposed to most other cell adhesion molecules, selectin function is primarily restricted to leukocyte interactions with the vascular endothelium. Indeed, they are implicated in the recruitment of leucocytes to sites of inflammation and tissue damage. Selectins are expressed on the surface of leukocytes, endothelial cells, and platelets. P-selectin expressed on platelets is thought to mediate neutrophil accumulation onto venous thrombi. Neutrophils move to sites of inflammation by virtue of an adhesion cascade that involves the activation of endothelial cells and the upregulation of E- and P-selectins. 

Integrins are a family of heterophilic cell adhesion molecules that bind to Immunoglobulin CAMs or to extracellular matrix proteins such as fibronectin, laminin, and osteopontin. The primary role of integrins seems to be the mediation of cell-ECM interactions. Integrins are heterodimers, consisting of two non-covalently linked alpha and beta subunits. Focal contacts form when integrin extracellular domains adhere to the extracellular matrix. Binding of integrins to ligands is also thought to instigate signal transduction events that are propagated through the cytoskeleton. Integrins are thus thought to play a role in the transduction of signals that originate from outside the cell to the inside of the cell.

A cell junction that is implicated in cell-cell adhesions is known as tight junctions (also known as zona occludens) which occupy the most apical position and are characterized by a a band-like ridge shape. Located at the border between apical and lateral membranes, tight junctions tightly seal gaps between epithelial cells. They restrict the passage of molecules and ions through the space between cells. This creates stricter control over the passage of materials through tissues as they then must enter by diffusion or active transport. Tight junctions also block the movement of integral membrane proteins between the apical and basolateral surfaces of the cell. This helps to maintain the polarity of cells in that the characteristic functions of each surface, eg endocytosis mediated by receptors at the apical level and exocytosis at the basolateral level are conserved. A tight junction is made up of many important proteins that are either directly involved in its composition or involved in the connection of the tight junction to cells. These proteins include: a) Occludins, which maintain the barrier between adjacent cells. b) The claudins, which form the backbone of the tight junction strands. c) Junctional Adhesion Molecules (JAMs) are immunoglobulin (antibody) proteins that help seal the intercellular space between two cells. Zonula occludens (ZO) are proteins that help connect the tight junction to the cytoskeleton of each cell. The occludins and claudins are the major components of tight junction strands. The tight junction associated proteins (ZO-1, ZO-2 and ZO-3) function as cross-linkers and anchor the TJ strand proteins to the actin cytoskeleton. ZO-1 and ZO-2 bind to actin filaments at their COOH terminal domains.

Another band of cell junctions that is directly below the zona occludens is known as the zona adherens. Unlike the zona occludens which is formed by a ridge, this band is formed by actin filaments. Unlike the zona occludens as well, this band is quite permeable to water and to ions. Zona adherens are common in endothelial and epithelial cells. They are also known as adherens junctions. At adherens junctions, cells bind to neighbouring cells via actin filaments. The adherens junctions essentially connect an actin filament bundle in one cell with another actin filament bundle in another cell. In adherens junctions, the extracellular domains of cadherins bind to each other while the intracellular domains of the same cadherins bind to catenins to form a cadherin-catenin complex. This complex binds to vinculin and alpha-actinin; these two proteins then connects the cadherin-catenin complex to the the actin microfilaments of the cytoskeleton. Thus, adherens junctions are made up of: a) the actin microfilaments of the cytoskeleton b) anchor proteins known as alpha-catenin, beta-catenin, gamma-catenin (aka plakoglobin), vinculin, and alpha-actinin which connect actin microfilaments to cadherins c) the previously described transmembrane adhesion proteins known as cadherins. The extracellular domains of cadherin molecules in adjacent cells are linked together by calcium ions.

Cells are also bound to their neighbouring cells via intermediate filaments. This happens at structures known as desmosomes which are located below adherens junctions. Desmogleins and desmocollins, members of the cadherin superfamily, are involved in adhesion at the desmosome level. The cytoplasmic domains of the desmosomal cadherins associate with a range of cytoplasmic proteins to form plaques, which serve to recruit intermediate filaments to desmosome assembly sites. These components of the desmosomal plaque include plakoglobin and plakophilins. Binding to the cytoskeleton is mediated by the intermediate filament binding protein, desmoplakin, which associates with both plakoglobin and plakophilins. Desmosomes are mainly found in epithelia and in the heart of vertebrates. They lend structural stability in addition to their role in cell-cell adhesion.

Cells are anchored to the extracellular matrix via actin filaments. Actin-linked focal adhesion molecules anchor actin filaments in the cell to the extracellular matrix. Cells are also anchored to the extracellular matrix via intermediate filaments. Structures known as hemidesmosomes anchor intermediate filaments in the cell to the extracellular matrix.

Gap junctions are comprised of a pair of hemichannels or connexons inserted into the membranes of adjacent cells. Each connexon is made up of six connexins enclosing a central channel. The connexin polypeptide chains transverse the plasma membrane four times. Connexons of adjacent cells form a continuous channel permitting the passage of substances from cell to cell. When intracellular calcium concentrations are low, the gap junction channels are open; when intracellular calcium concentrations are high, the channels are closed. High intracellular calcium concentrations are associated with cell damage and cell death. And, thus, gap junction closing in response to such a stimulus helps isolate normal cells from high intracellular concentrations of damaged cells.

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