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1The extracellular matrix and cell adhesion By George Plopper Chapter 15The extracellular matrix and cell adhesionByGeorge Plopper
215.1 IntroductionCell-cell junctions are specialized protein complexes that allow neighboring cells to:adhere to one anothercommunicate with one anotherThe extracellular matrix is a dense network of proteins that:lies between cellsis made by the cells within the network
3Cells express receptors for extracellular matrix proteins. 15.1 IntroductionCells express receptors for extracellular matrix proteins.The proteins in the extracellular matrix and cell junctions control:the three-dimensional organization of cells in tissuesthe growth, movement, shape, and differentiation of these cells
415.2 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.
515.3 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.
6Collagen subunits are: 15.3 Collagen provides structural support to tissuesAll collagens are organized into triple helical, coiled-coil “collagen subunits.”They are composed of three separate collagen polypeptides.Collagen subunits are:secreted from cellsthen assembled into larger fibrils and fibers in the extracellular space
715.3 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.
815.4 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.
9The soluble forms of fibronectin are found in tissue fluids. 15.4 Fibronectins connect cells to collagenous matricesThe soluble forms of fibronectin are found in tissue fluids.The insoluble forms are organized into fibers in the extracellular matrix.
10Fibronectin proteins contain six structural regions. 15.4 Fibronectins connect cells to collagenous matricesFibronectin fibers consist of crosslinked polymers of fibronectin homodimers.Fibronectin proteins contain six structural regions.Each has a series of repeating units.
11Fibrin, heparan sulfate proteoglycan, and collagen: 15.4 Fibronectins connect cells to collagenous matricesFibrin, heparan sulfate proteoglycan, and collagen:bind to distinct regions in fibronectinintegrate fibronectin fibers into the extracellular matrix networkSome cells express integrin receptors that bind to the Arg-Gly-Asp (RGD) sequence of fibronectin.
1215.5 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.
1315.5 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 forcesspontaneously reaggregate when the force is released
14Assembly of tropoelastin into fibers: 15.5 Elastic fibers impart flexibility to tissuesAssembly of tropoelastin into fibers:occurs in the extracellular spaceis controlled by a threestep processMutations in elastin give rise to a variety of disorders, ranging from mild skin wrinkling to death in early childhood.
1515.6 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 cellsto resist tensile forces in tissues
16Laminin heterotrimers do not form fibers. 15.6 Laminins provide an adhesive substrate for cellsLaminins 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.
1715.6 Laminins provide an adhesive substrate for cells A large number of proteins bind to laminins, including more than 20 different cell surface receptors.
1815.7 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:collagensintegrinsclotting factorscell lysis factorsextracellular proteases
19Vitronectin facilitates blood clot formation in damaged tissues. 15.7 Vitronectin facilitates targeted cell adhesion during blood clottingVitronectin 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.
2015.8 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.
21Proteoglycans attract water to form gels that: 15.8 Proteoglycans provide hydration to tissuesThe GAG bristles act as filters to limit the diffusion of viruses and bacteria in tissues.Proteoglycans attract water to form gels that:keep cells hydratedcushion tissues against hydrostatic pressure
22Expression of proteoglycans is: 15.8 Proteoglycans provide hydration to tissuesProteoglycans can bind to a variety of extracellular matrix components, including:growth factorsstructural proteinscell surface receptorsExpression of proteoglycans is:cell type specificdevelopmentally regulated
2315.9 Hyaluronan is a glycosaminoglycan enriched in connective tissues 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.
24Hyaluronan is highly negatively charged. 15.9 Hyaluronan is a glycosaminoglycan enriched in connective tissuesHyaluronan 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.
25Unlike other glycosaminoglycans, hyaluronans chains are: 15.9 Hyaluronan is a glycosaminoglycan enriched in connective tissuesUnlike other glycosaminoglycans, hyaluronans chains are:synthesized on the cytosolic surface of the plasma membranetranslocated out of the cellCells bind to hyaluronan via a family of receptors known as hyladherins.Hyladherins initiate signaling pathways that control:cell migrationassembly of the cytoskeleton
2615.10 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 syndecansthe glypicans
27Cell surface heparan sulfate proteoglycans: 15.10 Heparan sulfate proteoglycans are cell surface coreceptorsHeparan 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 cellsbind to over 70 different proteins
28Cell surface heparan sulfate proteoglycans 15.10 Heparan sulfate proteoglycans are cell surface coreceptorsCell surface heparan sulfate proteoglycansassist in the internalization of some proteinsact as coreceptors for:soluble proteins such as growth factorsinsoluble proteins such as extracellular matrix proteinsGenetic studies in fruit flies show that heparan sulfate proteoglycans function in:growth factor signalingdevelopment
2915.11 The basal lamina is a specialized extracellular matrix The basal lamina is a thin sheet of extracellular matrixis composed of at least two distinct layersis found at:the basal surface of epithelial sheetsneuromuscular junctions
30The basal lamina functions as: 15.11 The basal lamina is a specialized extracellular matrixThe 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 tissuesa diffusion barriera collection site for soluble proteins such as growth factorsa guidance signal for migrating neurons
31The components of the basal lamina vary in different tissue types. 15.11 The basal lamina is a specialized extracellular matrixThe 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 proteoglycansthe linker protein nidogen
3215.12 Proteases degrade extracellular matrix components Cells must routinely degrade and replace their extracellular matrix as a normal part ofdevelopmentwound healing
3315.12 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.
34MMPs can activate one another by cleaving off their propeptides. 15.12 Proteases degrade extracellular matrix componentsThe 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.
35These proteases also bind to integrin extracellular matrix receptors. 15.12 Proteases degrade extracellular matrix componentsADAMs 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.
3615.12 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.
3715.13 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.
38The cytoplasmic portions bind to cytoskeletal and signaling proteins. 15.13 Most integrins are receptors for extracellular matrix proteinsIntegrins are composed of two distinct subunits, known as α and β chains.The extracellular portions of both chains bind to extracellular matrix proteinsThe cytoplasmic portions bind to cytoskeletal and signaling proteins.
39In vertebrates, there are many α and β integrin subunits. 15.13 Most integrins are receptors for extracellular matrix proteinsIn vertebrates, there are many α and β integrin subunits.These combine to form at least 24 different αβ heterodimeric receptors.Most cells express more than one type of integrin receptor.The types of receptor expressed by a cell can change:over time orin response to different environmental conditions
40All of the known sequences contain at least one acidic amino acid. 15.13 Most integrins are receptors for extracellular matrix proteinsIntegrin 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.
4115.14 Integrin receptors participate in cell signaling Integrins are signaling receptors that control both:cell binding to extracellular matrix proteinsintracellular responses following adhesionIntegrins have no enzymatic activity of their own.Instead, they interact with adaptor proteins that link them to signaling proteins.
4215.14 Integrin receptors participate in cell signaling Two processes regulate the strength of integrin binding to extracellular matrix proteins:affinity modulationvarying the binding strength of individual receptorsavidity modulationvarying the clustering of receptors
43They can result from changes: 15.14 Integrin receptors participate in cell signalingChanges in integrin receptor conformation are central to both types of modulation.They can result from changes:at the cytoplasmic tails of the receptor subunits orin the concentration of extracellular cations
4415.14 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 receptorIn outside-in signaling, signals initiated at a receptor are propagated to other parts of the cell.For example, upon ligand binding
4515.14 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.
4615.15 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 proteins21 integrin genesSome genetic knockouts are lethal, while others have mild phenotypes.
4715.15 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 skinred blood cell development
4815.16 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.
4915.16 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.
5015.17 Septate junctions in invertebrates are similar to tight junctions The septate junction:is found only in invertebratesis similar to the vertebrate tight junctionSeptate junctions appear as a series of either straight or folded walls (septa) between the plasma membranes of adjacent epithelial cells.
5115.17 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.
5215.18 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.
53The best-known adherens junction is the zonula adherens. 15.18 Adherens junctions link adjacent cellsThe 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.
5415.19 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.
55Desmosomes are components of the junctional complex. 15.19 Desmosomes are intermediate filament-based cell adhesion complexesDesmosomes 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.
56Desmosomes function as both: 15.19 Desmosomes are intermediate filament-based cell adhesion complexesDesmosomes function as both:adhesive structuressignal transducing complexesMutations in desmosomal components result in fragile epithelial structures.These mutations can be lethal, especially if they affect the organization of the skin.
5715.20 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.
58Hemidesmosomes are structurally distinct from desmosomes. 15.20 Hemidesmosomes attach epithelial cells to the basal laminaHemidesmosomes are structurally distinct from desmosomes.They contain at least six unique proteins.
5915.20 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.
6015.21 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.
6115.21 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 membranespan a 2-3 nm gap between adjacent cellsThe gap junction channels consist of two halves, called connexons or hemichannels.Each consists of six protein subunits called connexins.
62Over 20 different connexin genes are found in humans. 15.21 Gap junctions allow direct transfer of molecules between adjacent cellsOver 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 sizeexclude passage of molecules 2000 daltons
63Gating is controlled by changes in 15.21 Gap junctions allow direct transfer of molecules between adjacent cellsGap junction permeability is regulated by opening and closing of the gap junction channels, a process called “gating.”Gating is controlled by changes inintracellular pHcalcium ion fluxdirect phosphorylation of connexin subunits
6415.21 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.
6515.22 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.
66Classical cadherins function as clusters of dimers. 15.22 Calcium-dependent cadherins mediate adhesion between cellsClassical cadherins function as clusters of dimers.The strength of adhesion is regulated by varying both:the number of dimers expressed on the cell surfacethe degree of clustering
6715.22 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.
6815.22 Calcium-dependent cadherins mediate adhesion between cells Classical cadherins are essential for tissue morphogenesis, primarily by controlling:specificity of cell-cell adhesionchanges in cell shape and movement
6915.23 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.
70Nerve cells express three different types of NCAM proteins. 15.23 Calcium-independent NCAMs mediate adhesion between neural cellsNerve cells express three different types of NCAM proteins.They arise from alternative splicing of a single NCAM gene.
7115.23 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.
7215.24 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-selectinP-selectinE-selectin
7315.24 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.