• Introduction
• Cell Adhesion Mechanisms
• Junctional Adhesion Molecules
• Tight Junctions
• Adherens Junctions
• Desmosomes
• Cell Junctions are Dynamic Structures

The evolution of higher organisms required that single cells first formed multicellular associations. Once this was accomplished individual cells or groups of cells could then specialize for specific functions. Ultimately the evolution of tissues and organs was possible. But likely it all began with the first cell adhesion molecules that allowed two cells to stick together. In its simplest form, cell adhesion involves two identical molecules: homotypic cell adhesion. Binding between two different cell adhesion molecules is called heterotypic cell adhesion. These two simplest associations-as well as some others discussed in the next lecture-led to the next step in cell adhesion mechanisms: Clustering of cell adhesion molecules to form more complex adhesion structures. Today, these are seen as the highly organized adhesion junctions that consist of cell adhesion molecules as well as accessory and adaptor proteins that allow other interactions including links to the intracellular cytoskeleton and the extracellular matrix. Here, we examine the major junctions. Later, we'll look in detail at some of cell adhesion molecules.

The following diagram shows that cells can adhere via various mechanisms. Some of these also mediate other cellular functions, as we will see throughout the course. Cells adhere to each other via:

• Junctional adhesion mechanisms (Tight Junctions, Adherens Junctions, Desmosomes, Gap Junctions)
• Cell adhesion molecules (next lecture)

Cells adhere to the substratum, basal lamina or extracellular matrix via:

• Gap Junctions
• Hemidesmosomes
• Focal contacts (detailed in a future lecture)
• Integrins (next lecture)
• Integral membrane proteoglycans (detailed in a future lecture)

As indicated in the figure, groups of junctions (i.e., tight and adherens junctions and desmosomes) make up junctional adhesion complexes as seen mainly in epithelial tissues and in cardiac tissues. These provide strong binding between these cells that are often subjected to great stresses.

Cell junctions are made up of many proteins with diverse functions.

• JAMs = Junctional Adhesion Molecules
• Some junctions contain unique proteins (e.g., connexin proteins of gap junctions)
• Some contain proteins that appear in other contexts (e.g., cadherins, integrins function as JAMs and as individual cell adhesion molecules)

In the figure above 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. As discussed in the next lecture, cadherins and integrins are also cell adhesion molecules independent of their role in cell junctions.

The tight junction was first resolved in the electron microscope as tightly associated regions between the cell membranes of adjacent cells.

• Also called "Occluding junctions"
• Prevent movement between intercellular spaces

The model of a tight junction structure is shown below. 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.

• Mainly in epithelial cells
• Lie just below tight junctions
• Form a continuous "belt" of cadherin around cells
• Cadherin binds to ß-catenins in cytoplasm
• Associate with actin filaments (microfilaments) rather than intermediate filaments

• Strong adhesions found typically in epithelial cells and other cell types that are subjected to stress or shear (e.g., cardiac muscle, epithelium of skin, cervix)
• Mild digestion with dilute trypsin (protease) solution separates cells joined by desmosomes
• Characterized by dense plaques
• Adhesion via cadherins
• Linked to cytoskeletal tonofilaments (intermediate filaments) via proteins that interact with the cytoplasmic domain of cadherin

This electron microscope picture (left) is false-colored (right) to show the different components of the desmosome more clearly. Various techniques have been used to resolve the components of the desmosome that are illustrated in the following diagram. Desmogleins and desmocollins are desmosomal forms of cadherins. They differ in their intracellular domains. 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 intermediate filaments. Plakoglobin for example is very similar to ß-catenin.

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 adherens junctions have been shown to move into the nucleus to regulate gene activity. The interaction of junctional adhesion molecules with the cytoskeleton has also been shown to be a dynamic process that is still being elucidated (Burridge, 2006. Nature 440: 38-39).