13: Extracellular Matrix and Cell Adhesion

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Interactions between a cell and its environment or with other cells are governed by cell-surface proteins. This chapter examines a subset of those interactions: direct cell contact with either other cells or extracellular matrix (ECM). Extracellular matrix is a general term for the extremely large proteins and polysaccharides that are secreted by some cells in a multicellular organism, and which acts as connective material to hold cells in a defined space. Cell density can vary greatly between different tissues of an animal, from tightly-packed muscle cells with many direct cell-to-cell contacts to liver tissue, in which some of the cells are only loosely organized, suspended in a web of extracellular matrix.

13.1: Introduction to Extracellular Matrix and Cell Adhesion
The extracellular matrix is a generic term encompassing mixtures of polysaccharides and proteins, including collagens, bronectins, laminins, and proteoglycans, all secreted by the cell. The proportions of these components can vary greatly depending on tissue type. Two, quite different, examples of extracellular matrices are the basement membrane underlying the epidermis of the skin.
13.2: Collagen
The largest and most prominent of the extracellular matrix proteins, constituting a quarter of the dry mass of the human body, are the members of the collagen family. Collagens are polymers that can be categorized into fibrillar and non fibrillar types. The fibrillar collagens are made up of triple helical monomers of either identical (homotrimer) or different (heterotrimer) subunits.
13.3: Proteoglycans
The protein component of proteoglycans are not as large as fibrillar collagens in general, but they often ll a massive volume because of heavy glycosylation. The sugars, many of which are sulfated or carboxylated, are hygroscopic to begin with, but being negatively charged, attract positive ions, which in turn brings in more water. Sugars attached to the core proteins are usually repeating disaccharide units such as chondroitin, chondroitin sulfate, heparin, heparan sulfate, keratan sulfate, or
13.4: Fibronectins
Fibronectin and laminin are significantly smaller than either collagens or proteoglycans, and play different roles in the extracellular matrix. Fibronectin is formed by the joining of two similar polypeptide subunits via a pair of disulfide bonds near the C-terminal of each (fig. 5). Each subunit is arranged as a linear sequence of 30 functional domains (varies slightly by species). Within each subunit, each domain acts as a semi-independent unit with respect to secondary and even tertiary struc
13.5: Laminins
Although there are many other less abundant proteins in the extracellular matrix, laminin is the final ECM molecule to be discussed in this chapter. Laminins are a family of secreted glycoproteins that are found in many ECM formations, and like fibronectin, bind to cells via integrin receptors. The laminin protein is composed of three subunits (α, β, γ) arranged in a cruciform shape. There are multiple isoforms of each subunit yielding the variety (15) of laminin proteins catalogued to date.
13.6: Integrins
The integrins have thus far been introduced as receptors for fibronectin and laminin, but it is a large family with a wide variety of substrates. For example, the focal adhesion (fig. 8) shows an an integrin receptor bound to collagen. Focal adhesions are usually transient, and seen as points of contact as fibroblasts or other migratory cells crawl on a culture dish or slide coated with ECM proteins.
13.7: Hemidesmosomes
Hemidesmosomes, particularly those attaching epithelial cells to their basement membrane, are the tightest adhesive interactions in an animal body. This close contact, and the reinforced structure of these contacts, is crucial for the protective resilience of epithelial layers. Remember the α6β4 integrin? That would be the one that links with intermediate filaments instead of f-actin. Intermediate filaments, as we’ve already noted, are not dynamic, but about as stable as a cellular component can
13.8: Dystrophin Glycoprotein Complex
Another type of cell-ECM connection is the dystrophin glycoprotein complex (DGC) of skeletal muscle cells. Similar complexes are found in smooth muscle and in some non-muscle tissues. Muscle cells, of course are subject to frequent mechanical stress, and connectivity to the ECM is important in supporting the cell integrity. The DGC uses the large transmembrane glycoprotein, dystroglycan, as its primary binding partner to basal lamina laminin
13.9: Desmosomes
An example of a cell-cell interaction with many similarities to a cell-ECM interaction, but using different adhesion molecules, is the desmosome. Like its basal-lamina-attached counterpart, the hemidesmosome, the desmosome is found in epithelial sheets, and its purpose is to link cells together so that pressure is spread across many cells rather than concentrated on one or a few. Desmosomes are necessary for the structural integrity of epithelial layers, and are the most common cell-cell junctio
13.10: Cadherins
The cadherin superfamily is comprised of the desmogleins (of which 4 have been identified in humans) and desmocollins (3 in humans), the cadherins (>20), and the protocadherins (~20) as well as other related proteins. They share structural similarity and a dependence on Ca2+ for adhesive activity, and they can be found in most tissues, and for that matter, most metazoan species. Cadherins are single-transmembrane modular proteins.
13.11: Tight Junctions
Sometimes, holding cells together, even with great strength, is not enough. In epithelia especially, a layer of cells may need to not only hold together but form a complete seal to separate whatever is in contact with the apical side from whatever is in contact with the basal side. That would be a job for The Tight Junction! Well, more accurately, for many tight junctions in an array near the apical surface. Perhaps the best example of the utility of tight junctions is in the digestive tract.
13.12: Ig Superfamily CAMs
Junction adhesion molecules (JAMs) have recently been found in tight junctions. These molecules are members of a gigantic superfamily of cell adhesion molecules known as the Ig (immunoglobulin domain) superfamily because all of these proteins contain an immunoglobulin loop domain that plays an important part in the adhesion mechanism. The purpose of immunoglobulins (antibodies) is to recognize and adhere to other molecules.
13.13: Selectins
The last major cell adhesion molecule family to discuss is the selectins. Selectins bind heterophilically to oligosaccharide moieties on glycoproteins. In fact the name of the family is based on lectin, a generic term for proteins that bind sugars. The selectins, like cadherins and IgSF molecules are modular glycoproteins that pass through the membrane once.
13.14: Gap Junctions
Unlike the other types of cell-cell adhesion, the gap junction (sometimes called a nexus) connects not only the outside of two cells, it connects their cytoplasm as well. Each cell has a connexon (aka hemichannel) made of six connexin proteins. The connexins may be all of the same type, or combinations of different ones, of which there are 20 known in humans and mice. The connexon interacts with a connexon on an adjacent cell to connect the cytoplasm of both cells in a gap junction.

Thumbnail: Illustration depicting extracellular matrix (basement membrane and interstitial matrix) in relation to epithelium, endothelium and connective tissue. (Public Domain; Twooars via Wikipedia).