Chapter 15

The extracellular matrix and cell adhesion

By George Plopper

15.1 Introduction
Cell-cell junctions are specialized protein complexes that allow neighboring cells to:
adhere to one another communicate with one another

The extracellular matrix is a dense network of proteins that:

lies between cells is made by the cells within the network

15.1 Introduction

Cells express receptors for extracellular matrix proteins. The proteins in the extracellular matrix and cell junctions control:
the three-dimensional organization of cells in tissues the growth, movement, shape, and differentiation of these cells

15.2 A brief history of research on the extracellular matrix

The study of the extracellular matrix and cell junctions has occurred in four historical stages.
Each is defined by the technological advances that allowed increasingly detailed examination of these structures.

Current research in this field is focused on determining how the proteins in the extracellular matrix and cell junctions control cell behavior.

15.3 Collagen provides structural support to tissues

The principal function of collagens is to provide structural support to tissues.
Collagens are a family of over 20 different extracellular matrix proteins.
Together they are the most abundant proteins in the animal kingdom.

15.3 Collagen provides structural support to tissues

All collagens are organized into triple helical, coiled-coil collagen subunits.
They are composed of three separate collagen polypeptides.

Collagen subunits are:

secreted from cells then assembled into larger fibrils and fibers in the extracellular space

15.3 Collagen provides structural support to tissues

Mutations of collagen genes can lead to a wide range of diseases, from mild wrinkling to brittle bones to fatal blistering of the skin.

15.4 Fibronectins connect cells to collagenous matrices

The principal function of the extracellular matrix protein fibronectin is to connect cells to matrices that contain fibrillar collagen.
At least 20 different forms of fibronectin have been identified.
All of them arise from alternative splicing of a single fibronectin gene.

15.4 Fibronectins connect cells to collagenous matrices

The soluble forms of fibronectin are found in tissue fluids. The insoluble forms are organized into fibers in the extracellular matrix.

15.4 Fibronectins connect cells to collagenous matrices

Fibronectin fibers consist of crosslinked polymers of fibronectin homodimers. Fibronectin proteins contain six structural regions.
Each has a series of repeating units.

15.4 Fibronectins connect cells to collagenous matrices

Fibrin, heparan sulfate proteoglycan, and collagen:

bind to distinct regions in fibronectin integrate fibronectin fibers into the extracellular matrix network

Some cells express integrin receptors that bind to the Arg-Gly-Asp (RGD) sequence of fibronectin.

15.5 Elastic fibers impart flexibility to tissues

The principal function of elastin is to impart elasticity to tissues.
Elastin monomers (known as tropoelastin subunits) are organized into fibers.
The fibers are so strong and stable they can last a lifetime.

15.5 Elastic fibers impart flexibility to tissues

The strength of elastic fibers arises from covalent crosslinks formed between lysine side chains in adjacent elastin monomers. The elasticity of elastic fibers arises from the hydrophobic regions, which:
are stretched out by tensile forces spontaneously reaggregate when the force is released

15.5 Elastic fibers impart flexibility to tissues

Assembly of tropoelastin into fibers:

occurs in the extracellular space is controlled by a threestep process

Mutations in elastin give rise to a variety of disorders, ranging from mild skin wrinkling to death in early childhood.

15.6 Laminins provide an adhesive substrate for cells

Laminins are a family of extracellular matrix proteins.
They are found in virtually all tissues of vertebrate and invertebrate animals.

The principal functions of laminins are:

to provide an adhesive substrate for cells to resist tensile forces in tissues

15.6 Laminins provide an adhesive substrate for cells

Laminins are heterotrimers comprising three different subunits wrapped together in a coiled-coil configuration.

Laminin heterotrimers do not form fibers.

They bind to linker proteins that enable them to form complex webs in the extracellular matrix.

15.6 Laminins provide an adhesive substrate for cells

A large number of proteins bind to laminins, including more than 20 different cell surface receptors.

15.7 Vitronectin facilitates targeted cell adhesion during blood clotting

Vitronectin is an extracellular matrix protein.
It circulates in blood plasma in its soluble form.

Vitronectin can bind to many different types of proteins, such as:

collagens integrins clotting factors cell lysis factors extracellular proteases

15.7 Vitronectin facilitates targeted cell adhesion during blood clotting

Vitronectin facilitates blood clot formation in damaged tissues. In order to target deposition of clotting factors in tissues, vitronectin must convert from the soluble form to the insoluble form, which binds clotting factors.

15.8 Proteoglycans provide hydration to tissues

Proteoglycans consist of a central protein core to which long, linear chains of disaccharides, called glycosaminoglycans (GAGs), are attached.
GAG chains on proteoglycans are negatively charged.
This gives the proteoglycans a rodlike, bristly shape due to charge repulsion.

15.8 Proteoglycans provide hydration to tissues

The GAG bristles act as filters to limit the diffusion of viruses and bacteria in tissues. Proteoglycans attract water to form gels that:
keep cells hydrated cushion tissues against hydrostatic pressure

15.8 Proteoglycans provide hydration to tissues

Proteoglycans can bind to a variety of extracellular matrix components, including:

growth factors structural proteins cell surface receptors

Expression of proteoglycans is:

cell type specific developmentally regulated

15.9 Hyaluronan is a glycosaminoglycan enriched in connective tissues

Hyaluronan is a glycosaminoglycan.
It forms enormous complexes with proteoglycans in the extracellular matrix.

These complexes are especially abundant in cartilage.

There, hyaluronan is associated with the proteoglycan aggrecan, via a linker protein.

15.9 Hyaluronan is a glycosaminoglycan enriched in connective tissues

Hyaluronan is highly negatively charged.

It binds to cations and water in the extracellular space.
This increases the stiffness of the extracellular matrix . This provides a water cushion between cells that absorbs compressive forces.

Hyaluronan consists of repeating disaccharides linked into long chains.

15.9 Hyaluronan is a glycosaminoglycan enriched in connective tissues

Unlike other glycosaminoglycans, hyaluronans chains are:

synthesized on the cytosolic surface of the plasma membrane translocated out of the cell

Cells bind to hyaluronan via a family of receptors known as hyladherins.

Hyladherins initiate signaling pathways that control:
cell migration assembly of the cytoskeleton

15.10 Heparan sulfate proteoglycans are cell surface coreceptors

Heparan sulfate proteoglycans are a subset of proteoglycans.
They contain chains of the glycosaminoglycan heparan sulfate.

Most heparan sulfate is found on two families of membrane-bound proteoglycans:

the syndecans the glypicans

15.10 Heparan sulfate proteoglycans are cell surface coreceptors

Heparan sulfates are composed of distinct combinations of more than 30 different sugar subunits.
This allows for great variety in heparan sulfate proteoglycan structure and function.

Cell surface heparan sulfate proteoglycans:

are expressed on many types of cells bind to over 70 different proteins

15.10 Heparan sulfate proteoglycans are cell surface coreceptors

Cell surface heparan sulfate proteoglycans

assist in the internalization of some proteins act as coreceptors for:
soluble proteins such as growth factors insoluble proteins such as extracellular matrix proteins

Genetic studies in fruit flies show that heparan sulfate proteoglycans function in:
growth factor signaling

15.11 The basal lamina is a specialized extracellular matrix

The basal lamina is a thin sheet of extracellular matrix
is composed of at least two distinct layers is found at:
the basal surface of epithelial sheets neuromuscular junctions

15.11 The basal lamina is a specialized extracellular matrix

The basement membrane consists of the basal lamina connected to a network of collagen fibers. The basal lamina functions as:
a supportive network to maintain epithelial tissues a diffusion barrier a collection site for soluble proteins such as growth factors a guidance signal for migrating neurons

15.11 The basal lamina is a specialized extracellular matrix

The components of the basal lamina vary in different tissue types. But most share four principal extracellular matrix components:
sheets of collagen IV and laminin are held together by:
heparan sulfate proteoglycans the linker protein nidogen

15.12 Proteases degrade extracellular matrix components

Cells must routinely degrade and replace their extracellular matrix as a normal part of
development wound healing

15.12 Proteases degrade extracellular matrix components

Extracellular matrix proteins are degraded by specific proteases, which cells secrete in an inactive form.

These proteases are only activated in the tissues where they are needed. Activation usually occurs by proteolytic cleavage of a propeptide on the protease.

15.12 Proteases degrade extracellular matrix components

The matrix metalloproteinase (MMP) family is one of the most abundant classes of these proteases.
It can degrade all of the major classes of extracellular matrix proteins.

MMPs can activate one another by cleaving off their propeptides.

This results in a cascade-like effect of protease activation that can lead to rapid degradation of extracellular matrix proteins.

15.12 Proteases degrade extracellular matrix components

ADAMs are a second class of proteases that degrade the extracellular matrix. These proteases also bind to integrin extracellular matrix receptors.
Thus, they help regulate extracellular matrix assembly and degradation.

15.12 Proteases degrade extracellular matrix components

Cells secrete inhibitors of these proteases to protect themselves from unnecessary degradation. Mutations in the matrix metalloproteinase-2 gene give rise to numerous skeletal abnormalities in humans.
This reflects the importance of extracellular matrix remodeling during development.

15.13 Most integrins are receptors for extracellular matrix proteins

Virtually all animal cells express integrins.
They are the most abundant and widely expressed class of extracellular matrix protein receptors.

Some integrins associate with other transmembrane proteins.

15.13 Most integrins are receptors for extracellular matrix proteins

Integrins are composed of two distinct subunits, known as and chains. The extracellular portions of both chains bind to extracellular matrix proteins The cytoplasmic portions bind to cytoskeletal and signaling proteins.

15.13 Most integrins are receptors for extracellular matrix proteins

In vertebrates, there are many and integrin subunits.

These combine to form at least 24 different heterodimeric receptors.

Most cells express more than one type of integrin receptor.

The types of receptor expressed by a cell can change:
over time or in response to different environmental conditions

15.13 Most integrins are receptors for extracellular matrix proteins

Integrin receptors bind to specific amino acid sequences in a variety of extracellular matrix proteins.

All of the known sequences contain at least one acidic amino acid.

15.14 Integrin receptors participate in cell signaling

Integrins are signaling receptors that control both:
cell binding to extracellular matrix proteins intracellular responses following adhesion

Integrins have no enzymatic activity of their own.

Instead, they interact with adaptor proteins that link them to signaling proteins.

15.14 Integrin receptors participate in cell signaling

Two processes regulate the strength of integrin binding to extracellular matrix proteins:
affinity modulation
varying the binding strength of individual receptors

avidity modulation
varying the clustering of receptors

15.14 Integrin receptors participate in cell signaling

Changes in integrin receptor conformation are central to both types of modulation.

They can result from changes:

at the cytoplasmic tails of the receptor subunits or in the concentration of extracellular cations

15.14 Integrin receptors participate in cell signaling

In inside-out signaling, changes in receptor conformation result from intracellular signals that originate elsewhere in the cell.
For example, at another receptor

In outside-in signaling, signals initiated at a receptor are propagated to other parts of the cell.
For example, upon ligand binding

15.14 Integrin receptors participate in cell signaling

The cytoplasmic proteins associated with integrin clusters vary greatly depending on:
the types of integrins and extracellular matrix proteins engaged.

The resulting cellular responses to integrin outside-in signaling vary accordingly. Many of the integrin signaling pathways overlap with growth factor receptor pathways.

15.15 Integrins and extracellular matrix molecules play key roles in development
Gene knockout by homologous recombination has been applied in mice to;
over 40 different extracellular matrix proteins 21 integrin genes

Some genetic knockouts are lethal, while others have mild phenotypes.

15.15 Integrins and extracellular matrix molecules play key roles in development

Targeted disruption of the 1 integrin gene has revealed that it plays a critical role in:
the organization of the skin red blood cell development

15.16 Tight junctions form selectively permeable barriers between cells

Tight junctions are part of the junctional complex that forms between adjacent epithelial cells or endothelial cells.
Tight junctions regulate transport of particles between epithelial cells.

15.16 Tight junctions form selectively permeable barriers between cells

Tight junctions also preserve epithelial cell polarity by serving as a fence.

It prevents diffusion of plasma membrane proteins between the apical and basal regions.

15.17 Septate junctions in invertebrates are similar to tight junctions

The septate junction:
is found only in invertebrates is similar to the vertebrate tight junction

Septate junctions appear as a series of either straight or folded walls (septa) between the plasma membranes of adjacent epithelial cells.

15.17 Septate junctions in invertebrates are similar to tight junctions

Septate junctions function principally as barriers to paracellular diffusion. Septate junctions perform two functions not associated with tight junctions:
they control cell growth and cell shape during development.
A special set of proteins unique to septate junctions performs these functions.

15.18 Adherens junctions link adjacent cells

Adherens junctions are a family of related cell surface domains.
They link neighboring cells together.

Adherens junctions contain transmembrane cadherin receptors.

15.18 Adherens junctions link adjacent cells

The best-known adherens junction is the zonula adherens.

It is located within the junctional complex that forms between neighboring epithelial cells in some tissues.

Within the zonula adherens, adaptor proteins called catenins link cadherins to actin filaments.

15.19 Desmosomes are intermediate filamentbased cell adhesion complexes

The principal function of desmosomes is to:
provide structural integrity to sheets of epithelial cells by linking the intermediate filament networks of cells.

15.19 Desmosomes are intermediate filament-based cell adhesion complexes

Desmosomes are components of the junctional complex. At least seven proteins have been identified in desmosomes. The molecular composition of desmosomes varies in different cell and tissue types.

15.19 Desmosomes are intermediate filament-based cell adhesion complexes

Desmosomes function as both:

adhesive structures signal transducing complexes

Mutations in desmosomal components result in fragile epithelial structures.

These mutations can be lethal, especially if they affect the organization of the skin.

15.20 Hemidesmosomes attach epithelial cells to the basal lamina

Hemidesmosomes, like desmosomes, provide structural stability to epithelial sheets.
Hemidesmosomes are found on the basal surface of epithelial cells.
There, they link the extracellular matrix to the intermediate filament network via transmembrane receptors.

15.20 Hemidesmosomes attach epithelial cells to the basal lamina

Hemidesmosomes are structurally distinct from desmosomes. They contain at least six unique proteins.

15.20 Hemidesmosomes attach epithelial cells to the basal lamina

Mutations in hemidesmosome genes give rise to diseases similar to those associated with desmosomal gene mutations. The signaling pathways responsible for regulating hemidesmosome assembly are not well understood.

15.21 Gap junctions allow direct transfer of molecules between adjacent cells
Gap junctions are protein structures that facilitate direct transfer of small molecules between adjacent cells.
They are found in most animal cells.

15.21 Gap junctions allow direct transfer of molecules between adjacent cells

Gap junctions consist of clusters of cylindrical gap junction channels, which:

project outward from the plasma membrane span a 2-3 nm gap between adjacent cells

The gap junction channels consist of two halves, called connexons or hemichannels.
Each consists of six protein subunits called connexins.

15.21 Gap junctions allow direct transfer of molecules between adjacent cells

Over 20 different connexin genes are found in humans.

These combine to form a variety of connexon types.

Gap junctions:
allow for free diffusion of molecules 1200 daltons in size exclude passage of molecules 2000 daltons

15.21 Gap junctions allow direct transfer of molecules between adjacent cells

Gap junction permeability is regulated by opening and closing of the gap junction channels, a process called gating. Gating is controlled by changes in
intracellular pH calcium ion flux direct phosphorylation of connexin subunits

15.21 Gap junctions allow direct transfer of molecules between adjacent cells

Two additional families of nonconnexin gap junction proteins have been discovered.
This suggests that gap junctions evolved more than once in the animal kingdom.

15.22 Calcium-dependent cadherins mediate adhesion between cells

Cadherins constitute a family of cell surface transmembrane receptor proteins that are organized into eight groups.
The best-known group of cadherins is called the classical cadherins.
It plays a role in establishing and maintaining cell-cell adhesion complexes such as the adherens junctions.

15.22 Calcium-dependent cadherins mediate adhesion between cells

Classical cadherins function as clusters of dimers. The strength of adhesion is regulated by varying both:
the number of dimers expressed on the cell surface the degree of clustering

15.22 Calcium-dependent cadherins mediate adhesion between cells

Classical cadherins bind to cytoplasmic adaptor proteins, called catenins.

Catenins link cadherins to the actin cytoskeleton.

Cadherin clusters regulate intracellular signaling by forming a cytoskeletal scaffold.

This organizes signaling proteins and their substrates into a three-dimensional complex.

15.22 Calcium-dependent cadherins mediate adhesion between cells

Classical cadherins are essential for tissue morphogenesis, primarily by controlling:

specificity of cell-cell adhesion changes in cell shape and movement

15.23 Calcium-independent NCAMs mediate adhesion between neural cells

Neural cell adhesion molecules (NCAMs) are expressed only in neural cells.
They function primarily as homotypic cell-cell adhesion and signaling receptors.

15.23 Calcium-independent NCAMs mediate adhesion between neural cells

Nerve cells express three different types of NCAM proteins.

They arise from alternative splicing of a single NCAM gene.

15.23 Calcium-independent NCAMs mediate adhesion between neural cells

Some NCAMs are covalently modified with long chains of polysialic acid (PSA).
This reduces the strength of homotypic binding.

This reduced adhesion may be important in developing neurons as they form and break contacts with other neurons.

15.24 Selectins control adhesion of circulating immune cells

Selectins are cell-cell adhesion receptors expressed exclusively on cells in the vascular system.
Three forms of selectin have been identified:
L-selectin P-selectin E-selectin

15.24 Selectins control adhesion of circulating immune cells

Selectins function to arrest circulating leukocytes in blood vessels so that they can crawl out into the surrounding tissue.

In a process called discontinuous cellcell adhesion, selectins on leukocytes bind weakly and transiently to glycoproteins on the endothelial cells.
The leukocytes come to a rolling stop along the blood vessel wall.