As illustrated in Figure 1, at least three different major types of cell junctions can be classified: the small zone of tight junctions, located proximal to the apical cell surface, the adherens junctions, forming a wider region at the lateral cell-cell contact site, and finally the desmosomes, which are primarily present in mechanically stressed tissues.
Additionally, gap junctions connect two neighbouring cells like channels and the hemidesmosomes attach the cell to the basal lamina or the extracellular matrix at the basal side.
Figure 1 Cell junctions between epithelial cells
First of all the tight junctions, also termed zonulae occludentes, are positioned in a small belt nearby the apical cell surface. They have been shown to consist of distinct molecules like the zonula occludens proteins 1-3, cingulin, the claudin proteins or occludin (Stevenson et al., 1986;Furuse et al., 1993). In addition to a mechanical linking of adjacent cells, the tight junctions are responsible for the establishment of the paracellular diffusion barrier, sealing the intercellular space. Thereby they have been proved to show a distinct ion and size selectivity which varies from cell type and physiological requirements obviously according to its composition and expression levels of distinct tight junction proteins (reviewed by Anderson, 2001). Hence, for each epithelia a specific transepithelial electrical resistance (TER) can be measured, which is performed in vitro for closed monolayers grown on filter membranes which segregate the apical from the basal compartment / chamber. The TER is mainly composed of two factors: first the cell type and transcellular permeability and second, the mentioned sealing of the intercellular space by the formation of tight junctions. As
the first one is mostly constant in one epithelial type, the TER is widely used as a parameter for correct establishment of the tight junctions and thereby of cell polarity, too.
The molecular structure of the tight junctions turned out to be a strand-like formation of integral membrane proteins from juxtaposed cells, linked to a paired strand leading in a decrease of the intercellular space to almost zero.
Disturbance of these tight junctions is often linked with severe malfunctions and diseases due to an increased permeability of the paracellular barrier. For example mutations in the gene coding for claudin 14, a tight junction protein which is specifically expressed in the inner ear epithelia, cause deafness in man (Wilcox et al., 2001).
Adherens junctions are assumed to be large multiprotein clusters, consisting of various proteins mainly of the cadherin superfamily. The major function of the adherens junctions is to mediate cell-cell adhesion and to transfer extracellular signals. This is assured by their structural abilities in a calcium dependent fashion (see below).
Although they are two clearly separated formations without any physiological contact, the zonula occludens are functionally linked to the adherens junctions. A block of the latter ones with specific antibodies against major protein components (E-cadherin) leads to destruction of the tight junctions, too (Gumbiner et al., 1988;Contreras et al., 2002). Moreover, the establishment of proper adherens junctions is inevitable for the formation of zonula occludens, so that we can define a chronology of adherens events: the initial contact between two growing neighboring cells is constructed by small contact sites, called “puncta” (Vasioukhin et al., 2000). Here dynamic filopodia are formed and penetrate into the adjacent cell. This mechanism turned out to be facilitated by a calcium dependant, directed actin polymerization. From this starting point on, the adherens junction is elongated like a zipper and not before that, tight junctions between the two cells can be formed. Cadherins which are localized on the tip of these protrusions play a crucial role in the formation of these protruding domains embedding into neighbouring cells.
One striking difference in tethering two cells together is that up to now cadherins are believed to form in vivo only homophilic adherens complexes i.e. the formation of a linkage between two cells by a homodimer consisting of two cadherin molecules expressed by the same cell type (Yap, 1997). In contrast, establishment of tight junctions has been already shown to occur also between cell derived from different tissues and even different species (Gonzalez-Mariscal et al., 1989). Therefore, cadherins as the major components of adherens junctions are thought to be most important in cell-cell recognition and thereby in the correct establishment of an epithelial monolayer.
Thirdly, the desmosomes (macula adherens), are classified as “anchoring junctions”, coupling cytoskeletal components to the plasma membrane at sites of cell-cell contacts. In contrast to the related adherens junctions, the intracellular link occurs here to intermediate filaments like keratin or desmin instead of actin microfilaments.
Thereby, a dense network extended over numerous cells is constructed. Because of the strength of these connections, desmosomes are capable to maintain tissue integrity in organs underlying constant mechanical stress like the skin.
Components of desmosomes are assigned to three major families: cadherin related molecules (desmoglein 1-4, desmocollin 1-3), armadillo proteins (plakoglobin, plakophilin 1-3) and plakins (e,g, desmoplakin I and II, plectin) (Huber, 2003).
The molecular structure, determined by immunoelectron microscopy showed that proteins in desmosomes are arranged similar to those in adherens junctions.
Transmembrane adhesion proteins like desmoglein and desmocollin, which are expressed on the cell surface, are connected with the cytoskeleton by armadillo proteins, mostly plakoglobin, which binds in turn desmoplakin to facilitate the association with intermediate filaments.
Although this is a generally accepted model, desmosomes are supposed to contain a wider amount of interacting proteins and also a direct link between the transmembrane molecules and the intermediate filaments of the cytoskeleton (reviewed by Hatzfeld, 1999).
Beside the listed cell-cell contact complexes there exist also the integrin family, expressed as a heterodimeric structure consisting of an α- and a β-subunit. Integrins are present in focal areas of cell adhesion. The luminal region of these membrane-anchored proteins binds to extracellular matrix proteins, e.g. collagen and proteoglycans. The link to the cell cytoskeleton is hereby mediated by the adaptor proteins α-actinin, talin, or filamin, forming a complex with vinculin and actin-filaments. Thereby, integrins establish cell contacts with the surrounding environment.
Finally the “gap junctions” shall be rather classified as “communicating junctions”.
They form channel like connections between adjacent cells and therefore their functions are predominately the intercellular exchange of substances and signals and not the anchoring of cells-cell contacts.