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Chapter 15 The extracellular matrix and cell adhesion By George Plopper.

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1 Chapter 15 The extracellular matrix and cell adhesion By George Plopper

2 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

3 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 15.1 Introduction

4 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.

5 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.

6 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

7 Mutations of collagen genes can lead to a wide range of diseases, from mild wrinkling to brittle bones to fatal blistering of the skin Collagen provides structural support to tissues

8 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.

9 The soluble forms of fibronectin are found in tissue fluids. The insoluble forms are organized into fibers in the extracellular matrix Fibronectins connect cells to collagenous matrices

10 Fibronectin fibers consist of crosslinked polymers of fibronectin homodimers. Fibronectin proteins contain six structural regions. –Each has a series of repeating units Fibronectins connect cells to collagenous matrices

11 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 Fibronectins connect cells to collagenous matrices

12 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.

13 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

14 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 Elastic fibers impart flexibility to tissues

15 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

16 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 Laminins provide an adhesive substrate for cells

17 A large number of proteins bind to laminins, including more than 20 different cell surface receptors Laminins provide an adhesive substrate for cells

18 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

19 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 Vitronectin facilitates targeted cell adhesion during blood clotting

20 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.

21 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

22 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 15.8 Proteoglycans provide hydration to tissues

23 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.

24 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 Hyaluronan is a glycosaminoglycan enriched in connective tissues

25 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 15.9 Hyaluronan is a glycosaminoglycan enriched in connective tissues

26 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

27 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 Heparan sulfate proteoglycans are cell surface coreceptors

28 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 Heparan sulfate proteoglycans are cell surface coreceptors

29 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

30 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 The basal lamina is a specialized extracellular matrix

31 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 The basal lamina is a specialized extracellular matrix

32 15.12 Proteases degrade extracellular matrix components Cells must routinely degrade and replace their extracellular matrix as a normal part of –development –wound healing

33 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 Proteases degrade extracellular matrix components

34 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 Proteases degrade extracellular matrix components

35 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 Proteases degrade extracellular matrix components

36 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 Proteases degrade extracellular matrix components

37 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.

38 Integrins are composed of two distinct subunits, known as α and β  chains. The extracellular portions of both chains bind to extracellular matrix proteins The cytoplasmic portions bind to cytoskeletal and signaling proteins Most integrins are receptors for extracellular matrix proteins

39 In 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 or in response to different environmental conditions Most integrins are receptors for extracellular matrix proteins

40 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 Most integrins are receptors for extracellular matrix proteins

41 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.

42 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 Integrin receptors participate in cell signaling

43 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 Integrin receptors participate in cell signaling

44 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. –F or example, upon ligand binding Integrin receptors participate in cell signaling

45 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 Integrin receptors participate in cell signaling

46 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.

47 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 Integrins and extracellular matrix molecules play key roles in development

48 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.

49 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 Tight junctions form selectively permeable barriers between cells

50 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.

51 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 Septate junctions in invertebrates are similar to tight junctions

52 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.

53 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 Adherens junctions link adjacent cells

54 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.

55 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 Desmosomes are intermediate filament-based cell adhesion complexes

56 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 Desmosomes are intermediate filament-based cell adhesion complexes

57 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.

58 Hemidesmosomes are structurally distinct from desmosomes. They contain at least six unique proteins Hemidesmosomes attach epithelial cells to the basal lamina

59 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 Hemidesmosomes attach epithelial cells to the basal lamina

60 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.

61 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 Gap junctions allow direct transfer of molecules between adjacent cells

62 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 Gap junctions allow direct transfer of molecules between adjacent cells

63 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 Gap junctions allow direct transfer of molecules between adjacent cells

64 Two additional families of nonconnexin gap junction proteins have been discovered. –This suggests that gap junctions evolved more than once in the animal kingdom Gap junctions allow direct transfer of molecules between adjacent cells

65 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.

66 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 Calcium-dependent cadherins mediate adhesion between cells

67 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 Calcium-dependent cadherins mediate adhesion between cells

68 Classical cadherins are essential for tissue morphogenesis, primarily by controlling: –specificity of cell-cell adhesion –changes in cell shape and movement Calcium-dependent cadherins mediate adhesion between cells

69 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.

70 Nerve cells express three different types of NCAM proteins. –They arise from alternative splicing of a single NCAM gene Calcium-independent NCAMs mediate adhesion between neural cells

71 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 Calcium-independent NCAMs mediate adhesion between neural cells

72 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

73 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 Selectins control adhesion of circulating immune cells


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