Introduction

You already know that tissue is a group of similar cells working together. As you might expect, if cells are to work together, they must communicate with each other, just as you need to with others if you work on a group project. Consider how cells interact with their environment and communicate with each other. Cell-surface proteins govern interactions between a cell and its environment or with other cells. This Topic examines a subset of those interactions: direct cell contact with either other cells or the extracellular matrix (ECM).

The ECM is a general term for the extremely large proteins and polysaccharides secreted by some cells in a multicellular organism. They act 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 and suspended in a web of extracellular matrix.

Unit 3, Topic 6—To Do List	Suggested Average Time to Complete (min.)
Read, make summary notes, and complete the self-check questions for Unit 3, Topic 6 of TRU Cell and Molecular Biology.	60
Complete Learning Activity: Cell-extracellular matrix mechanobiology.	10
Complete Learning Activity: Extracellular matrix.	10
Complete Learning Activity: Extracellular matrix—Khan Academy.	15
Complete Learning Activity: Integrins: The receptors that keep it together.	6
Complete Learning Activity: Cell junctions.	10
Go to Moodle and complete the Unit 3 Quiz.	7
Go to Moodle and complete the Unit 3 Assignment.	100

The Extracellular Matrix of Animal Cells

While cells in most multicellular organisms release materials into the extracellular space, animal cells specifically will be discussed here. The extracellular matrix (ECM) consists of proteins and polysaccharides secreted by cells and assembled into an organised meshwork external to the cell. ECM is a generic term encompassing mixtures of polysaccharides and proteins, including collagens, fibronectins, laminins, and proteoglycans, all secreted by the cell (Figure 1). The primary components of the ECM are proteins, and the most abundant protein is collagen. Collagen fibres interweave with proteoglycans, which are carbohydrate-containing protein molecules.

 

The amount and type of ECM varies from tissue to tissue, and different types of ECM perform specific functions. ECM comes in two relatively different examples. First is the basement membrane underlying the epidermis of the skin. The basement membrane is a thin, almost two-dimensional layer that helps organize skin cells into a nearly impenetrable barrier to most simple biological insults. Second is the massive three-dimensional matrix surrounding each chondrocyte in cartilaginous tissue. The ability of the cartilage in a person’s knee to withstand the repeated shock of their footsteps is due to the ECM proteins in which the cells are embedded, not to the cells that are relatively few and sparsely distributed. Although both ECM types share some components in common, they are clearly distinguishable in their function, appearance, proportions, and identity of the constituent molecules. The extracellular matrix holds the cells together to form tissues and allows the cells within the tissue to communicate with each other. The ECM also serves as a reservoir for extracellular signalling molecules that control cell growth, migration, and differentiation.

Blood clotting is an example of the extracellular matrix’s role in cell communication. When the cells lining a blood vessel are damaged, they display a protein receptor called tissue factor. When tissue factor binds with another factor in the extracellular matrix, it causes platelets to adhere to the damaged blood vessel’s wall, stimulates the adjacent smooth muscle cells in the blood vessel to contract (thus constricting the blood vessel), and initiates a series of steps that stimulate the platelets to produce clotting factors.

In most animal tissues, the extracellular matrix is secreted mainly by cells called fibroblasts, and the main component is a gel-like substance with embedded proteins. The gel is composed of polysaccharides called glycosaminoglycans (GAGs), which are often attached to proteins to form heavily glycosylated proteins called proteoglycans. The GAGs are negatively charged and attract positively charged ions, particularly sodium ions. The high positive ion concentration leads to water moving via diffusion into the matrix, which gives the matrix its gel-like properties, including the ability to resist compression.

Three major types of macromolecules make up the extracellular matrix:

• Structural proteins
• Adhesive proteins
• Proteoglycans

Structural Proteins

The two matrix proteins are collagen and elastin, both fibrous proteins.

Collagen is the main protein in the extracellular matrix. It accounts for 25% of the total protein content in a human organism. Collagen consists of three polypeptide chains wound around one another to form a triple helical structure. Gly-X-Y is the primary amino acid sequence, whereby X is often proline.

There are at least 30 different collagen peptide chains. Types I-IV are of primary significance. The most abundant type is collagen type I, one of the fibril-forming collagens that are the basic structural components of connective tissues. The principal function of collagen is to strengthen and organize the ECM.

Elastin is another matrix protein that is the main component of elastic fibres. An elastin molecule consists of flexible polypeptide chains and can reversibly unroll under mechanical stretching forces. These fibres provide elasticity to blood vessels, the lungs, skin, and the ligaments.

Adhesive Proteins

Matrix adhesive proteins, like fibronectin and laminin, mediate the connection between the components of the matrix to one another and to the surfaces of cells. Fibronectin is one of the adhesive glycoproteins providing the attachment of cells to the extracellular matrix. Laminins mediate the attachment of parenchymal cells to type IV collagen, thereby providing the interaction between cells and basement membranes. Other extracellular matrix glycoproteins are nidogens, tenascins, and fibulins.

Proteoglycans

Proteoglycans are composed of proteins covalently attached to long nonbranched chains of polysaccharides, glycosaminoglycans.

The polysaccharide content is more than 95% in the proteoglycans. These polysaccharides are highly negatively charged and bind positively charged ions and water molecules to form hydrated gels; this characteristic controls how small molecules diffuse and resist compressive forces. Glycosaminoglycans occupy large volumes in tissues, forming strongly hydrated gels that cause tissue turgor. The turgor gives the tissue the ability to resist compression forces. For example, an articular cartilage can resist mechanical pressures of a hundred atmospheres.

Proteoglycans can form huge polymeric complexes in the extracellular matrix. Besides providing tissue turgor, proteoglycans can also connect to other extracellular matrix proteins, forming complex structures (e.g., basement membranes).

Intercellular Junctions

Cells can also communicate with each other via direct contact or intercellular junctions. There are differences in how plant, animal, and fungal cells communicate. Plasmodesmata are junctions between plant cells; whereas, animal cell contacts include tight junctions, gap junctions, and desmosomes (Figure 2).

Epithelial tissue, composed of closely packed sheets of cells, has several types of cell junctions, each with specific functions and formed by different specialized proteins. In vertebrates, there are the following three major types of cell junctions:

• Tight junctions (occluding junctions)
• Adherens junctions, desmosomes and hemidesmosomes (anchoring junctions)
• Gap junctions (communicating junctions)

Plasmodesmata

In general, long stretches of the plasma membranes of neighbouring plant cells cannot touch one another because the cell wall surrounding each cell separates them. Then, how can a plant transfer water and other soil nutrients from its roots, through its stems, and to its leaves? Such transport primarily uses the vascular tissues (xylem and phloem). Structural modifications, called plasmodesmata (singular plasmodesma), also exist. Numerous channels passing between adjacent plant cells’ cell walls connect their cytoplasm and enable the transport of materials from cell to cell and, thus, throughout the plant (Figure 3).

Tight Junctions

A tight junction is a watertight seal between two adjacent animal cells (Figure 4). Protein complexes tightly hold the cells against each other. The basic functional units forming adhesive contacts across cells are the tight junction strands, which are composed of transmembrane proteins such as claudin, occludin and tricullulin. Assembling these strands requires them to associate with a cytoplasmic plaque of adaptor proteins, such as the ZO proteins, which link them to several regulatory and signalling molecules and to the cortical cytoskeleton. Coordinated interactions amongst the molecular core regulate tight junction assembly by ensuring proper localization of tight junction components and stabilizing the junctional complex.

 

This tight adherence prevents materials from leaking between the cells; tight junctions are typically found in epithelial tissues lining internal organs and cavities and comprise most of the skin. For example, epithelial cells lining the urinary bladder have tight junctions to prevent urine from leaking into the extracellular space. In the digestive system, they help prevent digestive enzymes from leaking into the bloodstream. Tight junctions also serve as a structural support mechanism that helps keep the epithelium together.

Adherens Junctions

Adherens junctions are cell-cell adhesion complexes that the body continuously assembles and disassembles, allowing cells within tissue to respond to forces, biochemical signals and structural changes in their microenvironment. Adherens junctions are also called zonula adherens, intermediate junctions, or belt desmosomes. Zonula means small zone or belt-like, and adherens refers to adhesion (sticking together). As a result, the zonula adherens often run like a belt in a continuous fashion around the entire cell and act as an adhesion belt. It contains contractile bundles of actin filaments, usually located near the apical surface of polarized epithelial cells.

This type of cell junction is located right below tight junctions and provides a strong bond between the sides of adjacent epithelial cell membranes (Figure 2). While other junctions, like tight junctions, provide some support for and fusion of adjacent cells, their resistance to mechanical stress is relatively small compared to the much stronger adherens junctions. Adherens junctions come in many forms: In cardiac cells, adherens junctions anchor contractile bundles², while in nonepithelial tissues, adherens junctions link cortical actin filaments between cells (Figure 5).

 

The zonula adherens is composed of the following different proteins (Figure 6):

• Actin microfilaments of the cytoskeleton (the internal skeleton of the cell)
• Cadherins, namely E-cadherin. These are transmembrane adhesion proteins, whose main portions are in the extracellular space.
• Anchor proteins are inside each cell. These are called α-catenin, β-catenin, γ-catenin (aka plakoglobin), vinculin, and α-actinin. They link the actin microfilaments to the cadherins.

The extracellular part of one cell’s cadherin binds to the extracellular part of the adjacent cell’s cadherin in the space between the two cells. Each cell’s cadherin molecule also contains a tail that inserts itself inside its respective cell (Figure 7).

 

This intracellular tail then links to catenin proteins to form the cadherin–catenin complex. Catenins are a family of proteins found in complexes with cadherin cell adhesion molecules of animal cells. The first two catenins identified³ became known as α-catenin and β-catenin. α-Catenin can bind to β-catenin and F-actin.⁴ β-Catenin binds directly to the cytoplasmic tail of classical cadherins (Figure 7). This complex binds to vinculin and α-actinin; these two proteins link the cadherin–catenin complex to the cell’s internal skeletal framework (the actin microfilaments).

Bonding the extracellular portions of the cadherin molecules in adjacent cells together requires calcium ions (or another protein in some cases). This means that the functional and morphological integrity of the adherens junctions are calcium-dependent. Removing calcium would result in this type of cell junction disintegrating.

Desmosomes

Only animal cells have desmosomes, which act like spot welds between adjacent epithelial cells (Figure 8). These junctions link intermediate filaments to the plasma membrane and, in doing so, provide mechanical stability to cells, which is particularly important for tissues and organs under high mechanical stress (e.g., myocardium, skin, and bladder).

 

Desmosomes comprise desmosomal cadherins (desmogleins and desmocollins) that facilitate linkage between apposing cells via their extracellular domains and bind other desmosomal components intracellularly via their cytoplasmic tails (Figure 9). Cytoplasmic desmosomal components include plakoglobin and plakophilins, which bind intermediate filaments via desmoplakin. These cadherins connect two adjacent cells and maintain the cells in a sheet-like formation in organs and tissues that stretch, like the skin, heart, and muscles.

 

Gap Junctions

Gap junctions in animal cells are like plasmodesmata in plant cells in that they are channels between adjacent cells that allow for transporting ions, nutrients, and other substances that enable cells to communicate. Structurally, however, gap junctions and plasmodesmata differ. Gap junctions are in many places throughout the body, including the epithelia (covering body surfaces), nerves, cardiac (heart) muscle, and smooth muscle (e.g., the intestines). Their primary role is to coordinate the activity of adjacent cells. For example, when heart cells need to beat in unison, gap junctions allow for the transmission of electrical signals between the cells.

Each gap junction channel has two half channels (hemichannels), one in each cell’s membrane (Figure 10). Each of these half channels is called a connexon. Each connexon has six symmetrical integral membrane protein units called connexins. This composition means each channel has 12 circularly arranged protein units. These half channels join together, bridge the extracellular space in the process, and form the entire channel that spans both cell membranes (Figure 11).

 

 

When the connexon’s pores (“doughnut holes”) in adjacent animal cells align, a channel between the two cells forms. Gap junctions are especially crucial in cardiac muscle. The electrical signal for the muscle to contract passes efficiently through gap junctions and allows the heart muscle cells to contract in tandem. The molecules that may cross this channel include ions, regulatory proteins, and metabolites (products of metabolism). Examples include calcium ions and cAMP (cyclic adenosine monophosphate).

Depending on the type of gap junction in question, molecules can pass evenly in both directions or asymmetrically, meaning the molecules move in one direction faster than in the other direction. The channels in a gap junction are not always open. They fluctuate between being open and closed. The ability of the channel to open or close is made possible in part due to calcium ions, which induce a reversible conformational change in the connexin molecules, leading to a channel closing at its extracellular surface. The cytoplasmic end of each connexon can also be closed if necessary.

Key Concepts and Summary

The cells of animal tissues are held together by the extracellular matrix and by cell junctions.

The extracellular matrix in animals consists of a hydrated mixture of glycosaminoglycans (GAGs) and proteoglycans, in which various proteins, especially fibrous proteins like collagen, are embedded. The properties of the matrix, which vary from tissue to tissue, determine the nature of the protein.

Cells of epithelia are closely connected and not separated by intracellular material. Three basic types of connections allow varying degrees of interaction between the cells: tight junctions, anchoring junctions (adherens, desmosomes) and gap junctions.

• Tight junctions are found in epithelial and endothelial cells and primarily function as diffusion barriers.
• Adherens junctions regulate cell shape, maintain tissue integrity and translate actomyosin-generated forces throughout a tissue.
• A gap junction is a channel of two half channels called connexons that allow various molecules and ions to pass freely between cells. Gap junctions allow for electrical communication between cells, which is why they are most notable in neurons and cardiac cells.

Cell junctions form from specialized membrane proteins that connect to various cytoskeletal components such as actin filaments (adherens junctions) or intermediate filaments (desmosomes).

Various cadherin molecules comprise adherens junctions and desmosomes.

All three previously mentioned junctions in vertebrate epithelia have defined spatial organizations, with tight junctions located most apically, followed by adherens junctions and desmosomes.

Key Terms

adherens junctions

multi-molecular complexes beneath tight junctions that link the actin cytoskeleton to the plasma membrane via transmembrane proteins (cadherins) and intracellular proteins, thereby forming adhesive belts between cells

anchoring junctions

(includes adherens junctions, desmosomes and hemidesmosomes). Intercellular junctions that are present in many types of animal tissues and serve to hold the constituent cells to each other and to the surrounding extracellular matrix respectively, via transmembrane proteins, cadherins

basal lamina

a specialized layer of extracellular matrix lying basal to epithelial cells and separating them from the underlying connective tissue. The basal lamina is secreted by both epithelial cells and connective tissue cells and is primarily composed of glycoproteins and proteoglycans

cadherin

any of a class of transmembrane proteins important in maintaining tissue structure

catenin

a family of proteins found in complexes with cadherin cell adhesion molecules of animal cells; the first two catenins that were identified became known as α-catenin and β-catenin

cell adhesion molecule

help cells stick to each other and to their surroundings; the proteins located on the cell surface bind with other cells or with the extracellular matrix (ECM)

claudins

proteins that form the backbone of the tight junction strands

collagen

a protein that is abundant in the extracellular matrix. There are several types of collagen; it can form long thin fibres and provide structure, strength and flexibility to many tissues

desmosome

linkages between adjacent epithelial cells that form when cadherins in the plasma membrane attach to intermediate filaments

extracellular matrix (ECM)

non-cellular material secreted from animal or fungal cells that provides mechanical protection and anchoring for the cells in the tissue

gap junction

is a type of junction mediated by membrane channels called connexons that are used to transfer information between neighbouring cells (e.g., electrical signals, chemical messengers, etc.)

peptidoglycan

major component of bacterial cell walls. It is a polymer of high molecular mass, composed of two complex monosaccharides derived from glucose, which are linked together by amino acids, including three amino acids that are not found naturally in proteins

plasmodesma (plural plasmodesmata)

channel that passes between adjacent plant cells’ cell walls, connects their cytoplasm, and allows transporting of materials from cell to cell

tight junctions

a type of junction that forms tight contacts between cells in animal tissues such as epithelia. Tight junctions prevent the lateral movement of other membrane proteins, thus allowing different regions of the cell membrane to have different functional properties (e.g., transport characteristics)