17.10: How Cells are Held Together and How They Communicate

Proteins and glycoproteins on cell surfaces play a major role in how cells interact with their surroundings and with other cells. We’ll look first at some of the proteins in the glycocalyx of adjacent cells that interact to form different kinds of cell-cell junctions. Then we’ll see how some of these proteins interact with extracellular proteins and carbohydrates to form the extracellular matrix (ECM). Still other membrane proteins are part of receptor systems that bind hormones and other signaling molecules at the cell surface, conveying information into the cell by signal transduction.

17.10.1 Cell Junctions

Cell junctions serve different functions in cells and tissues. In healthy cells they serve to bind cells tightly, to give tissues structural integrity, and to allow cells in contact with one another to pass chemical information directly between them. Electron micrographs and illustrations of different cell junctions are shown in Figure 17.24.

Figure 17.24: Tight, gap, and adherens junctions of animal cells involve different membrane proteins.

Tight Junctions (zonulae occludentes) are typical in sheets of epithelial cells that line the lumens of organs (e.g., intestines and lungs). Zonulae (singular: zonula) refers to the fact that these structures form a band encircling an entire cell, attaching it to all surrounding cells. Occludentes (singular: occludens) refers to the “watertight” seal, or occluding barrier of tight junctions that stops extracellular fluids from passing between cells to cross to the other side of a sheet of cells. Tight-junction membrane proteins (TJMPs) create this waterproof barrier.

Gap junctions enable chemical communication between cells. Connexon structures made of connexin proteins act as pores that open to allow direct movement of ions and small molecules between cells. Communication by ion or molecular movement is quite rapid, ensuring that all cells in a sheet or other tissue in one metabolic state can respond to each other and switch to another state simultaneously. In plants we have seen the plasmodesmata, which perform functions similar to those of gap junctions of animal cells.

Desmosomes (adherens junctions) essentially glue (adhere) cells together, giving tissues their strength. Belt desmosomes (zonula adherens) surround entire cells, strongly binding them to adjacent cells. Spot desmosomes (macula adherens) act like rivets, attaching cells at spots. In both cases, cadherin proteins cross cell membranes from intracellular plaque proteins, spanning the intercellular space to link adjacent cell membranes together. Plaques are connected to intermediate filaments (keratin) in the cytoskeleton, strengthening intercellular attachments and, thus, the tissue cell layer.

310-2 Cell-Junction Structure and Function

CHALLENGE

Do plant cells have (or need) tight junctions and desmosomes (or similar structures)? Explain your reasoning.

Many glycocalyx proteins that interact to form junctions between cells are glycoproteins. Generally, proteins that interact to bind cells together are called ICAMs (Intercellular Cell Adhesion Molecules), or just CAMs.

• Selectins are one kind of ICAM. During blood clotting, selectins on one platelet recognize and bind to specific receptors on other platelets, contributing to the clot.
• NCAMs are another kind of ICAM, ones with sugary immunoglobulin domains that interact specifically to enable neural connections.
• We’ve already seen the calcium-dependent cadherins involved in forming adherens junctions (desmosomes). These are essentially the “glue” that binds cells together to form strong cohesive tissues and sheets of cells. Cell-cell binding begins with recognition and connection via the glycocalyx and extracellular matrix.

Figure 17.25 (below) illustrates several examples of membrane proteins that enable cell-cell recognition and adhesion.

Figure 17.25: Glycocalyx protein interactions play roles in cell-cell recognition, attachment, and junctions. Asterisks indicate plasma membrane bilayers between attached cells.

CHALLENGE

What kind of experiment might you do to show that NCAM interactions in neuron-neuron attachments are not \(\rm Ca^{++}\)-dependent?

311-2 Glycocalyx Sugar Covalently Links to Plasma Membrane Proteins

312 Cell Adhesion Molecule Functions in the Glycocalyx

17.10.2 Microvesicles and Exosomes

Of the several ways cells take up material from their environment, pinocytosis, or bulk transport, seems to be a random process in which tiny bits of plasma membrane engulf small amounts of extracellular fluids along with ions, particles, and incidental solutes. Pinocytotic vesicles range from 0.5 to 5 mm in diameter. On the other hand, exosomes and microvesicles are spherical bits of plasma membrane and endosomes (respectively) that are shed by cells into the extracellular space. Known by several names, these extracellular vesicles (EVs) were first reported in the 1980s as small vesicles released by reticulocytes. At around 1,000 nm (1 mm), microvesicles are similar in size to pinocytotic vesicles. Exosomes are about a tenth the size of microvesicles, ranging in size from 40–100 nm in diameter (see Figure 17.26).

Figure 17.26: Left: Transmission electron micrograph of melanoma cell exosomes. Some of the larger vesicles show an irregular, cup-like shape (arrows). Right: Transmission electron micrograph of a reticulocyte endosome containing exosomes about to fuse with the plasma membrane.

There is much evidence that microvesicles and exosomes are not artifacts. For example:

• Microvesicles, such as those from melanoma cells (Figure 17.26, left panel), may be released normally, suggesting that they are not cellular waste products.
• Reticulocyte endosomal vesicles were caught in the act of fusing with the cell membrane, releasing exosomes with their contents (Figure 17.26, right panel).
• Microvesicles released by dendritic cells can stimulate T cells, both of which are cells of the immune system.

We can conclude that microvesicles are physiologically significant structures. We know that cells talk to each other by releasing chemicals that can act over short or long distances. Familiar examples include information transfer by hormones from endocrine glands, chemicals released into the intercellular space, and the neurotransmitters of the nervous system. Microvesicle activity may be part of intercellular communication pathways, and they are clearly involved in normal reticulocyte maturation to erythrocytes. Perhaps exosomes are yet another unique mechanism of intercellular communication. For a review, see Exosomes & Intercellular Communication.

17.10.3 Cancer and Cell Junctions

During embryogenesis, cells migrate from a point of origin by attaching to and moving along an extracellular matrix (ECM), which acts as a path to each cell’s destination. This ECM (or basal lamina) is made up of secretions from other cells…, or from the migrating cells themselves! One major secretion is fibronectin, one of whose functions is to bind to integrins, integral membrane proteins that attach cells to the ECM.

During development, integrins respond to fibronectin by signaling cell and tissue differentiation, complete with the formation of appropriate cell junctions. An orderly sequence of gene expression and membrane protein syntheses enables developing cells to recognize each other as different or the same (summarized in the drawing below (Figure 17.27).

Figure 17.27: Migration and attachment of cells during development requires the synthesis of membrane proteins that recognize and bind proteins on the membranes and glycocalyx of other cells, forming cell junctions that enable tissue formation.

An early difference between eukaryotic normal and cancer cells is how they grow in culture. Normal cells settle to the bottom of a culture dish when placed in growth medium. Then they grow and divide, increasing in number until they reach confluence, when a single layer of cells completely covers the bottom of the dish. The cells in this monolayer seem to “know” to stop dividing, as if they had completed formation of a tissue (e.g., a layer of epithelial cells). This phenomenon, originally called contact inhibition, implies that cells let each other know when they have finished forming a tissue and can stop cycling and dividing. In contrast, cancer cells do not stop dividing at confluence. Instead, they continue to grow and divide, piling up in multiple layers.

Among other deficiencies, cancer cells do not form gap junctions and typically have fewer cadherins and integrins in their membranes. Thus, cancer cells cannot inform each other of when they reach confluence. Neither can they form firm adherens junctions. In vivo, a paucity of integrins would inhibit cancer cells from binding and responding to fibronectin. As a result, they also have difficulty attaching firmly to an extracellular matrix, which may explain why many cancers metastasize, or spread from their original site of formation. These differences in growth in culture between normal and cancer cells are shown in Figure 17.28.

Figure 17.28: Density-dependent inhibition (contact inhibition) occurs when cells multiplying and spreading on a surface cease dividing when there is no more room on the surface. Cancer cells have lost the property of contact inhibition and keep growing over one another in layers. Loss of contact inhibition is correlated with an absence of gap junctions in cancer cells.

313 Formation of Glycocalyx: Normal Development and Cancer

314-2 Role of the Extracellular Matrix in Cell Migration & Development