Introduction to the Human Cell. Danton PhD O'Day

Introduction to the Human Cell - Danton PhD O'Day


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cells tightly bound as well. In blood vessels the tight association between endothelial cells maintains blood vessel integrity, keeping tissue cells out and blood cells contained within the blood vessel. The current view of adherens junctions is shown in Figure 3.8. Vinculin plays a key role in maintaining the tight association between endothelial cells and significant changes occur in the association of vinculin and actin in various diseases such as atherosclerosis and during cancer metastasis. The interplay between vinculin and actin as well as issues of metastasis are all covered in later chapters. The above and the following image show the homotypic binding between cadherins of two cells joined by an adherens junction. The alpha- and beta-catenins and vinculin mediate interaction with the actin cytoskeleton (Figure 3.9).

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      Figure 3.9. A diagram of the organization of adherens junction proteins.

      Proteins That Move Between the Nucleus and Junctional Adhesion Complexes

      When they were originally discovered cell junctions were considered to be relatively static structures. This was likely because they appeared to have a consistent, unchanging structure when viewed with the electron microscope. New techniques have revealed that proteins can move in and out of these junctions allowing the cell to sense the status of its intercellular adhesions. For example, occludin and ZO1, two proteins from tight junctions have been shown to move into the nucleus to regulate gene activity. Proteins that move between adhesion complexes have been termed NACos (Nucleus and Adhesion Complexes). β-catenins are the most well-studied NACos. The following graphics show what happens when an adherens junction is disrupted (Figure 3.10).

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      Figure 3.10. Beta-catenins can move from disrupted tight junctions into the nucleus to regulate gene transcription.

       A. Intact cells, B. One cell (left side) is damaged. C. β-catenins enter nucleus to regulate gene transcription.

      If epithelial tissues become disrupted such as by a cut in the skin or tear in the intestinal lining, it would lead to the disruption of adherens junctions in adjacent cells in turn releasing ß-catenins as well as other junctional proteins. The ß-catenins can then travel to the nucleus to initiate gene transcription to stimulate cell cycle events or other processes required in wound healing. A similar event happens when tight junctions are disrupted by a bacterial infection as discussed in the next section.

      Gastric Ulcers: H. pylori Infection Alters ZO1 Localization

      For many years the cause of gastric ulcers was always attributed to poor diet. Several years ago, scientists revealed that a common intestinal bacterium called Helicobacter pylori was actually the causative agent. These bacterial cells attach via adhesions to the cell surface of epithelial cells in the gastric mucosa. Through the secretion of various cytoxins they disrupt the intestinal epithelium causing gastritis and in some individuals gastric cancer. Research into how the H. pylori infects cells has shown that it alters the junctional adhesion complexes of the gastric epithelium of humans. As shown in the following diagram, ZO1 localizes to the surface of all of the cells showing a relatively consistent pattern (Figure 3.11). This localization is altered in infected cells with some of the protein not only disappearing from the cell surface junctions but also appearing within the cytoplasm. Some of the protein can also be seen in some of the nuclei. Based on the function of ZO1 as a NACo, the release of ZO1 proteins from tight junctions results in their movement as soluble proteins in the cytoplasm and from there into the nucleus where they can alter gene activity.

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      Figure 3.11. A diagrammatic representation of the Localization of ZO1 (green = ZO1; blue = nuclei) in normal (A) human gastric epithelial cells and those infected with H. pylori (B).

      Desmosomes

      Desmosomes were the first junctional adhesion complex members to be recognized. This is because they are the most distinct component appearing as paired dark and dense masses adjacent to the cell membrane of adjacent epithelial cells. Desmosomes provide strong adhesion between cells. They are typically found in epithelial cells and other cell types that are subjected to stress or shear (e.g., cardiac muscle, epithelium of skin, cervix of the vagina). The following electron microscope picture (left) is false-colored (right) to show the different components of the desmosome more clearly (Figure 3.12).

      The paired dark masses that reside on opposite sides of the intercellular space are called desmosomal adhesion plaques. Early work showed that mild digestion with dilute protein digesting enzymes (proteases), such as trypsin, caused the desmosomes to disappear and the cells to separate. Thus it became clear that these structures were primarily made up of proteins involved in cell adhesion. The adhesion plaques link to tonofilaments in the cytoplasm. It was discovered that the tonofilaments are keratin intermediate filaments, so both terms are used when desmosomes are discussed.

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      Figure 3.12. The ultrastructure of a desmosome.

      Adhesion between cells is mediated by desmogleins and desmocollins which are desmosomal forms of cadherins (Figure 3.13). These extend from the cell membrane across the intercellular space. They differ from other cadherins in their intracellular domains which is why desmosomal cadherins associate with keratin while those in adherens junctions are linked to actin filaments. The dense plaques on the inner side of the membrane are sites where the desmoplakin and plakoglobin linker molecules link the cytoplasmic tails of the desmogleins and desmocollins to the tonofilaments (keratin intermediate filaments). Plakoglobin for example is very similar to ß-catenin.

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      Figure 3.13. The structure of a desmosome and its protein components.

      A close-up of the proteins found in desmosomes is shown in the following figure (Figure 3.14). Homotypic binding occurs between the desmosomal cadherins desmoglein and desmocolin.

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      Figure 3.14. The organization of desmosomal proteins.

      Desmosomes and Disease

      Because desmosomes show such precise localizations and since they appear to have a consistent structure, we tend to think of them as static and uninteresting structures. This is compounded by other issues: they are linked to tight cell adhesions which maintain tissue integrity in the gut and other areas. But detailed studies using immunolocalization of desmosomes show their localization varies markedly in different normal human tissues. More to the point, these patterns are different when these tissues are infected or diseased. This reorganization of desmosomes is most evident in certain cancers (e.g., pulmonary squamous cell carcinoma). Alterations in desmosomes also underlie various skin disorders. For example, pemphigus vulgaris is an autoimmune disorder causing painful sores and blisters on the skin and in the mouth. It has been shown that sufferers produce antibodies against desmoglein 1 and 3. The presence of these antibodies interferes with the formation and maintenance of desmosomes which are central to the integrity of epithelial layers. The result is a breakdown in the skin. This ailment can also show up in people treated with certain medications such as certain heart drugs (e.g., acetylcholinesterase inhibitors). Other skin disorders are also being found to show desmosomal disruption.

      As with other intercellular junctions, the formation and breakdown of desmosomes has other implications to cells especially in signal transduction events that can regulate gene activity. The reason for this is that when proteins


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