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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:

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chapter 15

Chapter 15

The extracellular matrix and cell adhesion

By

George Plopper

15 1 introduction
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
slide3

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
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
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.
slide6

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
slide7

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
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.
slide9

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.
slide10

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.
slide11

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
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.
slide13

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
slide14

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
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
slide16

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.
slide17

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
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
slide19

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
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.
slide21

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
slide22

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
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.
slide24

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.
slide25

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
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
slide27

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
slide28

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
    • development
15 11 the basal lamina is a specialized extracellular matrix
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
slide30

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
slide31

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
15.12 Proteases degrade extracellular matrix components
  • Cells must routinely degrade and replace their extracellular matrix as a normal part of
    • development
    • wound healing
slide33

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.
slide34

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.
slide35

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.
slide36

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
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.
slide38

15.13 Most integrins are receptors for extracellular matrix proteins

  • Integrins are composed of two distinct subunits, known as α and βchains.
  • The extracellular portions of both chains bind to extracellular matrix proteins
  • The cytoplasmic portions bind to cytoskeletal and signaling proteins.
slide39

15.13 Most integrins are receptors for extracellular matrix proteins

  • In vertebrates, there are many αand βintegrin subunits.
    • These combine to form at least 24 different αβheterodimeric 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
slide40

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
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.
slide42

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
slide43

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
slide44

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
slide45

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
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.
slide47

15.15 Integrins and extracellular matrix molecules play key roles in development

  • Targeted disruption of the β1 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
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.
slide49

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
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.
slide51

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
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.
slide53

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
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.
slide55

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.
slide56

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
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.
slide58

15.20 Hemidesmosomes attach epithelial cells to the basal lamina

  • Hemidesmosomes are structurally distinct from desmosomes.
  • They contain at least six unique proteins.
slide59

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
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.
slide61

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.
slide62

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
slide63

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
slide64

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
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.
slide66

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
slide67

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.
slide68

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
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.
slide70

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.
slide71

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
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
slide73

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 cell-cell 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.