In multicellular organisms, cell–cell contacts that are mediated by classic cadherins are essential in many fundamental processes, including morphogenesis, maintenance of tissue integrity, wound healing and cell polarity. The prototype classic cadherin is the transmembrane protein E-cadherin. This protein uses its extracellular domain to bind Ca2+ and interact with E-cadherin on adjacent cells, thereby forming adherens junctions. To establish efficient cell–cell junctions, E-cadherin uses its cytoplasmic domain to couple to catenins and the actin cytoskeleton. This association sets the classic cadherins apart form desmosomal cadherins, which form complexes with the intracellular proteins plakoglobin and desmoplakin to form a more robust Ca2+-induced adhesive interaction — the desmosome — that links the intermediate-filament cytoskeleton (see also the article by Lynne Chang and Robert Goldman in this issue). Many cells have both adherens junctions and desmosomes, which function coordinately in intercellular adhesion ().
|CLASSIC CADHERINS||Cadherins are transmembrane molecules that mediate Ca2+-dependent cell–cell adhesion. Classic cadherins are typified by an extracellular segment that consists of five distinct Ca2+-binding domains and a conserved cytoplasmic domain, which binds β-catenin. The extracellular part interacts homotypically with cadherins on the surface of neighbouring cells to form adherens junctions. The cytoplasmic tail links the actin cytoskeleton to adherens junctions.|
|ADHERENS JUNCTION||A specialized intercellular junction of the plasma membrane, in which the cadherin molecules of adjacent cells interact in a Ca2+-dependent manner. Actin filaments are linked to this structure through catenins that are located underneath the junction.|
|DESMOSOMES||Specialized junctional structures that form a tight connection between epithelial cells or cardiac myocytes. They consist of several transmembrane adhesive glycoproteins (desmogleins and desmocollins) and cytoplasmic plaque proteins (desmoplakins) that link to intermediate filaments.|
|INTERMEDIATE FILAMENTS||Proteins that acquired their name from the diameter of their polymeric structure, which is midway between the diameters of thin actin microfilaments and thick microtubules. Their ability to form very stable filaments enables them to confer mechanical strength on the cytoskeleton.|
Desmosomes use their attachments to intermediate filaments to provide mechanical strength to intercellular connections1-3
. They are particularly important in tissues that are subjected to substantial physical stress, such as muscle and epidermis. By contrast, adherens junctions use their connections to the actomyosin network
to remodel cell–cell interactions and provide flexible dynamic adhesion during wound repair of adult tissuesand embryonic development4-6
. Whereas desmosomes and their associated intermediate filaments function as molecular clamps to reinforce intercellular junctions, actin dynamics and adherens-junction formation have been implicated in the initial steps of bringing membranes together and in the final steps of sealing membranes into epithelial sheets.
|ACTOMYOSIN NETWORK||A complex of myosin and actin filaments that is responsible for a range of cellular movements in eukaryotic cells. Myosins can translocate vesicles or other cargo on actin filaments.|
Dysregulation of cadherin-mediated junctions can lead to severe developmental defects. Mutations in desmosomal genes often result in degenerative disorders, and several excellent reviews have recently described the composition and function of these robust adhesive structures1-3
. Curiously, however, although mutations in adherens-junction proteins can sometimes cause tissue degeneration, in other cases they can contribute to carcinogenesis and metastasis4-6
. With an increasing knowledge of the composition of adherens junctions, their assembly, and their relationship to other membrane junctions and receptors, new insights into some of these processes are beginning to unfold.
At the heart of the story lie the catenins, which associate with the cytoplasmic domain of cadherins to assemble a protein complex that can associate with the actin cytoskeleton, coordinate stable intercellular adhesion, and regulate indirect associations with desmosomes, tight junctions
, growth-factor receptors and microtubules4
. In addition, in response to WNT signalling, excess β-catenin that is not used in cell–cell junctions can accumulate and adopt a second function as a nuclear transcriptional co-activator for the lymphoid enhancer-binding factor-1 (LEF1)/T-cell-specific factor (TCF) family of DNA-binding proteins7-9
. As sustained stabilization of β-catenin has been associated with a range of human cancers, this regulatory function has been the main focus of the cancer–cadherin link. The reader is referred to several elegant reviews that have covered, in depth, the role of β-catenin in signalling and cancer7-9
. However, mutations in E-cadherin and α-catenin can also contribute to cancers10-17
, and gene-targeting studies indicate that the proliferation that is sometimes associated with such mutations does not always result from the activity of nuclear β-catenin18,19
|TIGHT JUNCTIONS||The most apical intercellular junctions, which function as selective (semi-permeable) diffusion barriers between individual cells. They are identified as a belt-like region in which two lipid-apposing membranes lie close together.|
In this review, we focus on α-catenin, which is the protein that connects E-cadherin–β-catenin complexes with the actin cytoskeleton20,21
. Whereas all other catenins (β-catenin, plakoglobin and p120 catenin) share considerable sequence similarity and belong to the Armadillo family of proteins, α-catenin differs notably in both sequence and structural organization. Although it was previously considered to be solely a structural protein, new roles have begun to emerge for α-catenin in both assembling the cytoskeleton and regulating its dynamics at cell–cell junctions. In addition, recent studies imply that the interactions of α-catenin with E-cadherin–β-catenin complexes might control the accessibility of these complexes to other cellular proteins. In the past few years, various binding partners for α-catenin have surfaced, which have shed new light on the functions of α-catenin and its underlying mechanisms of action ().
A multiprotein complex at adherens junctions