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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 l.jpg

Chapter 15

The extracellular matrix and cell adhesion

By

George Plopper


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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


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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


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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.


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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.


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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


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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.


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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.


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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.


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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.


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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.


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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.


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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


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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.


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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


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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.


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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.


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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


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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.


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15.8 Proteoglycans provide hydration to tissues blood clotting

  • 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.


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15.8 Proteoglycans provide hydration to tissues blood clotting

  • 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


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15.8 Proteoglycans provide hydration to tissues blood clotting

  • 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


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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.


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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.


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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


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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


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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


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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


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15.11 The basal lamina is a specialized extracellular matrix coreceptors

  • 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


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15.11 The basal lamina is a specialized extracellular matrix coreceptors

  • 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


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15.11 The basal lamina is a specialized extracellular matrix coreceptors

  • 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


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15.12 Proteases degrade extracellular matrix components coreceptors

  • Cells must routinely degrade and replace their extracellular matrix as a normal part of

    • development

    • wound healing


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15.12 Proteases degrade extracellular matrix components coreceptors

  • 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.


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15.12 Proteases degrade extracellular matrix components coreceptors

  • 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.


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15.12 Proteases degrade extracellular matrix components coreceptors

  • 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.


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15.12 Proteases degrade extracellular matrix components coreceptors

  • 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.


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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.


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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.


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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


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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.


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15.14 Integrin receptors participate in cell signaling proteins

  • 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.


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15.14 Integrin receptors participate in cell signaling proteins

  • 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


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15.14 Integrin receptors participate in cell signaling proteins

  • 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


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15.14 Integrin receptors participate in cell signaling proteins

  • 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


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15.14 Integrin receptors participate in cell signaling proteins

  • 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.


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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.


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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


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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.


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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.


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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.


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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.


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15.18 Adherens junctions link adjacent cells tight junctions

  • Adherens junctions are a family of related cell surface domains.

    • They link neighboring cells together.

  • Adherens junctions contain transmembrane cadherin receptors.


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15.18 Adherens junctions link adjacent cells tight junctions

  • 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.


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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.


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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.


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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.


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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.


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15.20 Hemidesmosomes attach epithelial cells to the basal lamina

  • Hemidesmosomes are structurally distinct from desmosomes.

  • They contain at least six unique proteins.


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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.


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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.


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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.


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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


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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


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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.


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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.


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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


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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.


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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


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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.


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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.


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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.


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15.24 Selectins control adhesion of circulating immune cells neural 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


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15.24 Selectins control adhesion of circulating immune cells neural 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.