Epidermal growth and proliferation must be carefully balanced: too little proliferation results in thinning of the skin and loss of protection, and too much is a characteristic of hyperproliferative disorders, including psoriasis (see page 866) and cancers. During normal homeostasis the epidermis must be able to sense and replace basal vacancies, and when wounds occur cells must migrate and proliferate but also sense when to stop after wound closure. Finally, the epidermis must have an SOS system to recruit immune cells to fight infection and aid in wound repair, and to turn off the response once the wound has been closed. How does the epidermis achieve all this?
Basal cell proliferation relies on an underlying basement membrane that is rich in extracellular matrix (ECM) proteins and growth factors. Basal cells attach to this structure through two types of cell-junction adhesion complexes, composed of integrins. Hemidesmosomes contain a transmembrane core of α6
integrins that connect intracellularly to the keratin intermediate filament network and provide mechanical strength. Focal adhesions contain α3
integrins, which connect to the actin and microtubule networks. Both types of junction adhere extracellularly to laminin 5, the main ECM ligand for the epidermal basement membrane. αβ1
integrins seem to be especially important in assembling and organizing this membrane78,79
Integrins also function in growth control and migration. Although these growth regulatory circuitries are many and complex, they involve physical interactions with regulatory kinases. To permit migration in response to wounding, cell–substratum junctions must be dynamically turned over. Integrins differ in their relative roles in wound-repair: whereas cells lacking αβ1
integrins are less migratory, those lacking α6
integrins show increased migratory behaviour79-81
. The positive role of β1
integrin in migration seems to result in part from its ability to directly bind and control the activity of focal adhesion kinase (FAK). This is a non-receptor tyrosine kinase that, in turn, functions as a master switch in negatively regulating cellular tension imposed by an elaborate actin–myosin network associated with focal adhesions80,81
To function as a tissue, basal cells must also adhere to one another. They do this not only by means of desmosomes but also through adherens junctions (). Adherens junctions are composed of a transmembrane core of E-cadherin, which binds two related proteins, β-catenin and p120-catenin82
. Just as desmosomes and hemidesmosomes form an integral network with intermediate filaments, adherens junctions and focal adhesions orchestrate actin–myosin dynamics throughout the cells of the tissue. Adherens junctions do so by associating with an array of actin regulatory proteins, which include p120-catenin's interactions with Rho-GTPase proteins and β-catenin's association with α-catenin, an unrelated protein that can bind vasodilator-stimulated phosphoprotein (also known as ENA), formins, ajuba and α-actinin proteins82
. Exactly how adherens junctions and focal adhesions regulate the actin–myosin network to coordinate adhesion and migration is not yet clear but, typically, whenever cell–cell junctions are reinforced, integrin dynamics are diminished. This inverse regulation is likely to be essential during wound repair, in which epidermal outgrowth must occur in a polarized and orchestrated manner.
Model for control of epidermal proliferation
Recently, researchers have begun to realize that cellular junctions act as signalling centres and have functions that extend beyond their classical roles in cell adhesion and cytoskeletal dynamics. The longest standing example is β-catenin, which is now well known for its dual role in adhesion and transcription. p120-Catenin also functions not only in regulating Rho GTPases and adherens junction assembly, but also as a transcriptional cofactor83
. In addition, through a mechanism that is not fully understood but seems to involve the small Rho GTPases, p120-catenin and α-catenin can affect the transcriptional status of NF-κB, which, in turn, governs the production and secretion of cytokines and chemokines and the recruitment of immune cells84,85
. The abrogation of JunB, a downstream inhibitor of EGF signalling, also triggers chemokine/cytokine expression86
When sustained activation of NF-κB arises — for example, through dysfunction of p120-catenin, α-catenin and/or JunB — signalling from the epidermis to immune cells goes awry. This triggers a molecular war between the epidermis, which spews out cytokines and chemokines, and the recruited immune cells, which respond in a similar way and send proliferative signals to the epidermis. Further studies will be needed to ascertain the controls on these normal pathways for the repair of the epidermis in response to injury, stress and infection, and to elucidate the extent to which these various pathways intersect in recruiting immune cells to the skin. NF-κB regulation is particularly important because it also mediates a TNFR1-dependent hypoproliferative influence on healthy epidermis87
The consequences of α-catenin loss are particularly severe, and the epidermis progresses to a condition resembling invasive squamous-cell carcinoma29
. Although the mechanisms are not yet fully understood, they are likely to involve an upregulation in integrins and tyrosine kinase activity85,88,89
. An emerging view of adherens junctions is that they serve as molecular sensors for ‘crowd control’ and wound repair. In this model, when basal cell density is low or when the epidermis is severed, as in a wound, a reduction in adherens junctions triggers cell migration and proliferation, and immune cells are recruited to protect against possible infection. Once proper cell density has been achieved and adherens junction formation becomes optimal, the system returns to normal (). When this circuitry is defective — for example, when α-catenin or p120 is mutated — the system becomes imbalanced and chronic inflammation and hyperproliferative disorders, including cancer, can result.