Keratin filaments are grouped into bundles by the action of a basic protein containing histidine called filagrine. The physiological process implies a cellular stratification and a regulation of the differentiation of specific epithelial gene products. The keratinized cells move from the epithelial basal layer to the surface of the tissue, undergoing during their migration a series of morphological changes that reflect differential epithelial gene expression. The result of the differentiation is the formation of the horny layer due to the processing of a series of proteins and the degradation of the cell organelles. The keratins, protagonists of the keratinization process, are a vast family of related proteins.
They are insoluble, contain cysteine, and have molecular weights ranging from 40 kDa to 67 kDa. They are present in the cells of the epidermis, hair, and nails and form the characteristic cytoskeleton of epithelial cells, including those found in the gastrointestinal and urothelial areas and the orogenital mucosa. They consist of intermediate filaments 7-10 nm in diameter. There are six types of intermediate filaments: type I (hard keratin, basic epithelial keratin), type 2 (hard keratin, acidic epithelial keratin), type 3 (GFAP, desmin, vimentin, peripherin), type 4 (neurofilaments, NF-L, NF-M, NF-H, alpha-internexin), type 5 (nuclear laminins A,B,C), and type 6 (nestin). Of these intermediate filaments the most important examples are vimentin, present in the mesenchymal cells, GFAP acidic protein, which composes the glial filaments of the glial cells, the neurofilaments present in the neurones, desmin of the muscle cells, and the proteins of and the nuclear matrix, nuclear laminins A,B,C.
The polypeptide structures of all the intermediate filaments have a similar skeletal part composed of structural blocks of polypeptide subunits. The number of subunits varies between 1 and 30. The proteins are products of separate genes that, by cross-hybridization, fall into two gene families: type I (basic) and type 2 (acidic). The epithelial keratins are classified numerically and are, therefore, divided into two groups: basic keratins (1-8) and acidic keratins (9-19).
The fundamental polypeptide chain of keratin is a classical alpha helix with repeated groups of seven. It is composed of four separate helical zones linked by interhelical sequences and is preceded and followed by nonhelical carboxyterminal and aminoterminal sequences. During keratinization two polypeptide chains are assembled as a heterodimer called a protofilament. Two protofilaments then assemble into larger protofilaments, so forming a protofibril, the basic element of the keratin fibre heterodimer. It is possible that type 2 keratins are present in the cell before type I keratins and is thought likely that the former induce the synthesis of the latter. In epithelial cells keratin filaments radiate from the perinuclear region to the internal face of the plasma membrane. Bundles of these filaments are associated with specialized structures of the plasma membrane called desmosomes. Looking at their chemical structure it is evident that keratin filaments are heterogenous. This heterogeneity explains how the filaments perform diverse functions in different cells. Many keratins are produced in fixed associations as well as in particular cell types.
The most important keratins of the basal layer are keratins 5 and 14. These are synthesized only in the basal cells and are transported in the suprabasal compartment. In epibasal cells the keratinocytes synthesize a new pair of keratins, keratins I and 10, which are characteristic of epidermal differentiation. Recent studies have considered the Fos family of proteins, transcriptional activators that are rapidly induced by extracellular stimuli. The Fos proteins are expressed immediately before cell death and the formation of the horny layer in keratinized tissue. It is supposed that they play an important role in the transcriptional activation of the genes mediating the formation of the horny layer. The keratinized epithelial cells that express the Fos proteins must be the target of a differentiation signal that is as yet unknown.
A small number of basal cells will determine the differentiation of the keratin leaving the basal layer. After minimal posttranscriptional modification they are transported in the cell layers of granules, where after the release of filagrin by keratohyalin bodies the keratins are processed to allow their alignment into macrofibres. Filagrin is the substance produced by keratohyalin granules that link the tonofilaments. During the passage of the cells toward the horny layer profilagrin is cleaved by a specific phosphatase to produce the filagrin, which interacts with keratin filaments so promoting their aggregation and forming the interfilamentous matrix in the corneocytes.
The degradation of filagrin produces amino acids that help the horny layer to retain water. The assembly of protofilaments occurs along the vertical axis of the helical regions, the nonhelical parts probably playing a role in their stabilization. To allow this alignment some regions are eliminated, meaning the loss of keratin antigens and a reduction in molecular weight. It has been observed in vitro that retinoids can stimulate the production of epithelial keratin n 19, which implies that in vivo they would be able to influence the expression of keratin. Currently studies involving keratins 6 and 16 are particularly interesting; they hypothesize a possible role for these proteins in cellular migration and mitosis. Their mRNAs are found in normal skin and could be responsible for the rapid cellular synthesis, though this suggests the presence of post-transcriptional regulation.
It has further been proposed that keratin 19 may play the part of activator, stabilizing the type 2 keratins until type 1 keratins are synthesized. It has in fact been found in large quantities in squamous epithelium, in the basal cells of the mucosa and hair follicles, junction regions, areas of fast turnover, and close to staminal cells. The role of extracellular calcium has been controversial since it was demonstrated that a low level of calcium in vitro causes the loss of stratification and formations of desmosomes with production of stratified cultures.
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