Introduction to the Human Cell. Danton PhD O'Day
structure and function. Later, we'll look in detail at some of the cell adhesion molecules that are present in these junctions, some of which also work independently.
Cell Adhesion Mechanisms
The following diagram shows that cells can adhere via various mechanisms (Figure 3.2). Many of these cell adhesions mediate other cellular functions, as we will see throughout this volume. The image that is shown is based on the organization of junctional adhesion complexes that are seen in the human gut.
Figure 3.2. The localization and components of cell adhesion junctions in intestinal epithelial cells.
Cells adhere to each other via:
•Junctional adhesion mechanisms (tight junctions, adherens junctions, desmosomes, gap junctions)
•Cell adhesion molecules (next chapter)
Cells adhere to the substratum, basal lamina or extracellular matrix via:
•Hemidesmosomes
•Focal contacts (detailed in later chapters)
•Integrins (detailed in later chapters)
•Integral membrane proteoglycans (summarized in a later chapter)
As shown in the following figure, groups of junctions including tight and adherens junctions and desmosomes make up junctional adhesion complexes as seen in epithelial and cardiac tissues (Figure 3.3). These junctional adhesion complexes provide strong binding between these cells that are often subjected to great stresses. They also mediate intercellular communication and play a critical role in cell polarity. Links to the cytoskeleton (actin, keratin) are also present. The following transmission electron microscope photo shows the junctional adhesion complex present in the apical region of the intestinal mucosa (Figure 3.3).
Figure 3.3. An ultrastructural image of the localization of cell adhesion junctions in intestinal epithelial cells.
Junctional Adhesion Molecules
Cell junctions are made up of many proteins with diverse functions. Often Junctional Adhesion Molecules (JAMs) are related to other protein isoforms or variants that appear in other contexts (e.g., cadherins and integrins function as JAMs and as individual cell adhesion molecules). In contrast, some junctions contain unique proteins (e.g., connexin proteins of gap junctions).
In the following figure, notice that cadherins are involved in cell-cell adhesion as part of desmosomes and adherens junctions while integrins mediate cell-substratum adhesions via hemi-desmosomes and focal adhesions (Figure 3.4). As discussed in the next chapter, cadherins and integrins are also cell adhesion molecules that function independently from their role in cell junctions. Thus certain proteins can serve dual or even multiple functions in a cell. More often than not, the specific cell adhesion proteins (e.g., cadherins, integrins) are variant proteins either coded for by another gene or resulting from post-translational modifications once the gene has been transcribed as will be covered in the next chapter.
Figure 3.4. Types of cell and junctional adhesion proteins.
Tight Junctions
The tight junction was first resolved in the electron microscope as tightly associated regions between the cell membranes of adjacent cells. Tight junctions are also known as “occluding junctions” or “zonula occludens.” They prevent the flow of water and molecules between cells, thus restricting them from exiting the extracellular environment to penetrate the intercellular space. This is called “paracellular movement.”
Tight junctions serve another critical role because they also prevent the movement of membrane components between the top (apical) and bottom (basal) sides of the cell. Thus they serve to restrict protein movements that would otherwise be possible because of the fluidity of the cell membrane. Restricting where certain proteins are localized is a critical event in establishing the polarity of cells. In the example used here, the tight junctions clearly define where the microvilli can form (i.e., apical) versus the cell’s interaction with and adhesion to the basement membrane (i.e., basal).
Figure 3.5. An ultrastructural side view of a tight junction.
The image above reveals the way the tight junction looks at the ultrastructural level (Figure 3.5). A model of a tight junction structure is shown below (Figure 3.6). Tightly aligned rows of tight junction proteins serve to stitch the membrane together effectively sealing the association between adjacent cells. This serves to block the movement of materials through the intercellular space. While we will only cover a couple of the major players in the structure and function of tight junctions, it’s important to understand that the protein complexes that stitch up the membrane are quite complex and form a protein scaffold which can interact with various components in the cytoplasm especially the cytoskeleton.
Figure 3.6. A diagrammatic representation of a tight junction.
Tight Junction Proteins: Claudins, Occludins and ZO1
The four major proteins found in tight junctions are called claudins, occludins, junctional adhesion molecule-1 (JAM-1) and zonula occludin proteins 1-3 (ZO1-3). These are shown in the following figure (Figure 3.7). The claudins are small 26 kDa (kiloDalton) proteins that are critical to the structural integrity of tight junctions. Occludins are larger at 65 kDa and are the major proteins found in these junctional complexes. These integral proteins are not essential since knockout mutants for occludin proteins do not prevent tight junction formation. It has been suggested that they are accessory proteins that don’t provide any structural basis. Knocking out ZO1 interferes with tight junction formation indicating it is a critical protein.
Figure 3.7. A diagrammatic representation of the organization of tight junction proteins.
The zonula occludin protein ZO1 was the first cloned tight junction protein. It lies at the inner side of the cell membrane where it organizes the other junctional adhesion molecules. It is indicated as one of the linker proteins in the figure. ZO1 and occludin both share an interesting and important function: they signal the integrity of the junctional adhesion complex. Thus they make the cell aware of its status regarding its adhesion with other cells.
Adherens Junctions
Adherens junctions are mainly found in epithelial cells where they lie just below tight junctions. Cadherins are the central proteins found in these junctions. As with other cadherins involved in cell adhesion, these proteins bind to ß-catenins in the cytoplasm which in turn associate with vinculin. These proteins are involved in binding to actin filaments. Thus there is a direct link between adherens junctions and the cytoskeleton. These junctions are most often organized as a “belt” that surrounds the complete cell.
Figure 3.8. The structure of an adherens junction.
Adherens junctions are important in keeping endothelial