Chapter07.ppt

© 2020 Elsevier Inc. All rights reserved.
Chapter 7
Cell Adhesion and the
Extracellular Matrix

© 2020 Elsevier Inc. All rights reserved. 2
Figure 7–1. Types of cell adhesion molecules.

Figure 7–2. Structural features of selectins and PSGL-1. (Adapted from Kappelmayer, Nagy. Biomed Res Int 2017,
https://doi.org/10.1155/2017/6138145, by permission with added colors.)

Figure 7–3. Integrin activation and clustering.
(A) Domain structure of integrin subunits, (B) activation and clustering of integrins.

Figure 7–4. Hierarchical organization of integrin clusters in migrating cell. Image of a mouse embryonic fibroblast spread on
fibronectin-coated substrate for 30 min. dSTORM imaging of endogenous paxillin conjugated (labeled with paxillin antibody, BD
biosciences) to antibody tagged with AlexaFlour-647 (antimouse secondary antibody conjugated to AlexaFlour-647). Gray scale shows
the TIRF image, whereas false color image shows the reconstructed superresolution image. Color code (top left corner, from left to right)
indicates increasing intensity of molecules. Encircled in dotted lines from left- to right-cell edge, nascent adhesions, maturing adhesions,
mature adhesions. Scale bar 2 μm. (Adapted from Changede, Sheetz. BioEssays 2016;39:1, 1600123, by permission.)

Figure 7–5. Intercellular junctions and the junctional complex. Simple epithelial cells have a junctional complex at their apicolateral
borders. The components are the tight junction, the adherens junction, and the desmosome. The tight and adherens junctions are
zonular, extending right around the cells, whereas desmosomes are punctate. Desmosomes are also present beneath the junctional
complex, as is another punctate junction, the gap junction.

Figure 7–6. Tight junctions are anastomosing strands of multiprotein complexes. (A) The close relationship between the organization of the junctional
complex, and that of the terminal web in the small intestine is illustrated in this thin-section electron micrograph. In the cytoplasm at the level of the tight junction (TJ),
the core microfilaments appear as compact bundles enmeshed in a matrix of 70 Å filaments. Mats of 70 Å filaments line the membranes of the zonula adherens (ZA) or
intermediate junction, and the bundles of core microfilaments became more diffuse in the adherens zone. Numerous tonofilaments course through the plaque of the spot
desmosome (SD); some of these tonofilaments enter the adherens zone, while others form the basal zone. 80,000 ×. The inset image is a higher magnification of TJ
region showing the “kisses.” (B) An evenly cross-linked tight junction network found between the absorptive cells of the small intestine of a Xenopus laevis, stage 57.
Short ridges or grooves on the protoplasmic (PF) or extracellular (EF) faces, respectively, intersect at acute angles to form a series of adjoining, similarly shaped
polygons, which display no predominant orientation relative to the cell surface. Bar denotes 0.25 μm in the electron micrographs unless marked otherwise. 60,000 ×. (C)
Line drawing of the apical junctional complex of an intestinal epithelial cell. Tight junction proteins include claudins, occluding, junctional adhesion molecule (JAM), and
zonula occludens-1 (ZO-1), whereas E-cadherin, α-catenin, and β-catenin interact to form the adherens junction. Myosin light chain kinase (MLCK) is associated with
the perijunctional actomyosin ring. Gap junctions are tubelike connections between adjacent cells formed by assembly of connexins. Desmosomes are formed by
interactions between desmoglein, desmocollin, desmoplakin, and keratin filaments. (D) Occludin has four transmembrane domains with two extracellular loops. The first
loop is characterized by a high content (~ 60%) of glycine and tyrosine residues. Claudin-1 also has four transmembrane domains but shows no sequence similarity to
occludin. Note that the cytoplasmic tail of claudin-1 is shorter than that of occludin. Junctional adhesion molecule (JAM) has a single transmembrane domain, and its
extracellular portion bears two immunoglobulin-like loops that are formed by disulfide bonds.
([A] Adapted from Hull, Staelin. J Cell Biol 1979;81:67–82, by permission; Tsukita, Furose, Itoh. Nat Rev 2001;2:285, by permission; [B] Adapted from Hull, Staelin. J
Cell Biol 1976;68:688–704, by permission; [C] From Turner JR. Intestinal mucosal barrier function in health and disease. Nat Rev Immunol 2009;9:799–809, by
permission; [D] Adapted from Tsukita, Furose, Itoh. Nat Rev 2001;2:285, by permission.)

Figure 7–7. Disrupted tight junction strands in intestinal disease. Freeze-fracture electron microscopy of epithelial tight junctions
from the jejunum of control subject and acute celiac disease patient. The jejunum from celiac disease patient shows significant reduction
in the number or horizontally oriented strands and the depth of the tight junctional strand network. Additionally, strand discontinuities
appeared in celiac disease. (Adapted from Rosenthal, Barmeyer, Schulzke. Tissue Barriers 2015;3:1–2, e977176, by permission.)

Figure 7–8. Fluorescence labeling of epithelial tight junctions. (A) Frozen section of mouse colon was stained for occludin (green)
and ZO-1 (red) by immunofluorescence method. Nucleus was stained by a DNA-binding fluorescent dye (blue). Confocal fluorescence
microscopic image shows organization of tight junctions on the apical ends of colonic epithelial cells. (B) TNF-α induces redistribution of
occludin from the junctions to cytoplasm. Mice were injected with vehicle or TNF-α. Cryosections of jejunum were stained for occludin
(green) by immunofluorescence method. Filamentous actin (red) was stained by binding to fluorescently labeled phalloidin, and nucleus
(blue) was stained by binding to fluorescent dye. The images show the TNF-α disrupts tight junctions. In one group of mice, the jejunum
was perfused with divertin (MLCK inhibitor), which shows that divertin blocks TNF-α-mediated disruption of tight junctions.
([A] From Rao et al. Unpublished; [B] Adapted from Graham et al. Nat Med 2019, https://doi.org/10.1038/s41591-019-0393-7, by
permission.)

Figure 7–9. Structure and function of tight junctions. (A) The “gate” function of the tight junction refers to its property of regulating the
permeability of the paracellular channels, and the “fence” function maintains the separation of molecules in the apical and basolateral cell
membranes. (B) The low permeability of tight junctions causes high electrical resistance across the epithelial cell layer between the apical
and basal compartments. (C) Some of the molecules that contribute to the structure and function of the tight junction are shown.

Figure 7–10. Fluorescence labeling of epithelial adherens junctions. Frozen section of mouse ileum was stained for E-cadherin
(green) and β-catenin (red) by immunofluorescence method. Nucleus was stained by a DNA-binding fluorescent dye (blue). Confocal
fluorescence microscopic image shows organization of adherens junctions along the lateral membranes of colonic epithelial cells.
(Adapted from Shukla, Meena, et al. Am J Physiol (GI&Liv) 2016;310: G705, by permission.)

Figure 7–11. Functions of the adherens junction. (A) Initial cell contact is made by filopodia. These interdigitate and punctate
adherens junctions are formed to constitute an adhesion zipper. The adhesion is then expanded and stabilized by the formation of
desmosomes. (B) Bending of epithelial cell sheets during embryonic development is accomplished by contraction of the actin filament ring
underlying the apicolateral adherens junctions. This acts like a purse-string to narrow the apices of the cells. This process can result in
tube formation as in generation of the neural tube.

Figure 7–12. Molecular structure of the adherens junction. Two types of adhesion molecule are involved, E-cadherin and the
immunoglobulin (Ig) family protein nectin. The cytoplasmic domain of E-cadherin binds β-catenin, which, in turn, binds α-catenin. This
complex may link E-cadherin to the cytoskeleton, but an alternative view (inset) suggests that the whole complex cannot form
simultaneously. Nectin is linked to actin by afadin.

Figure 7–13. Wnt signaling pathway. In the absence of Wnt (left), cytosolic β-catenin is continually phosphorylated by casein kinase-1α
(CK1) and glycogen synthase kinase-3β (GSK3β) within an APC-axin scaffold complex. This phosphorylation allows β-catenin to be
ubiquitylated and rapidly degraded by proteasome. During Wnt activation (right), GSK3β activity is inhibited directly by Lrp5/6, which
allows β-catenin to accumulate, enter the nucleus, interact with LEF/TCF family members, and promote transcription.
(Adapted from McEwen, Escobar, Gottardi. Subcell Biochem 2012;60:171. https://doi.org/10.1007/978-94-007-4186-7_8, by permission.)

Figure 7–14. The desmosome-intermediate filament complex strengthens epithelia, particularly the epidermis. (A) Fluorescence
micrograph showing desmosome-intermediate filament complex in cultured epithelial cells. Desmosomes stained by anti-desmoplakin
antibody (magenta), intermediate filament stained by anti-keratin antibody (green), and nuclei (blue). (B) Diagram showing the
desmosome-intermediate-hemidesmosome complex in the basal epidermis. ([A] From Moch M, Schwarz N, Windoffer R, Leube RE.
Keratin-desmosome scaffold: pivotal role of desmosomes for keratin network morphogenesis. Cell Mol Life Sci 2019;77:543–558, by
permission; [B] modified from Ellison JE, Garrod DR. J Cell Sci 1984;72:163–172, with permission.)

Figure 7–15. Electron micrograph of a desmosome from bovine tongue. IDP, inner dense plaque; ODP, outer dense plaque; and P,
plasma membrane. The desmosome is about 0.5 μm wide. (From Yin T, Green K. Regulation of Desmosome Assembly and Adhesion.
Semin Cell Dev Biol 2004;18:665–667, by permission.)

Figure 7–16. Molecular composition of the desmosome.

Figure 7–17. Cont’d

Figure 7–17. Molecular structure and function of the gap junctions. (A) Electron micrograph of a gap junction showing the close (2
nm) approach of the cell membranes. Scale bar = 0.6 μm. (B) Electron micrograph of surface view of an isolated gap junction showing
connexons with central pores. Scale bar = 33 nm. (C) Connexin has four transmembrane domains. (D) Six connexin molecules form the
channel of the connexon. (E) Docking of two hemichannels between adjacent cells establishes intercellular communication. (F) Adjacent
cells are coupled electrically by gap junctions. ([A] and [B] From Gilula NB. Gap junctional contact between cells. In: Edelman GM, Thiery
J-P, eds. The Cell in Contact: Adhesions and Junctions as Morphogenetic Determinants. New York: John Wiley & Sons, 1985, pp. 395–
405, by permission.)

Figure 7–18. Structure of the hemidesmosome as observed by electron microscopy. A Fib, anchoring fibril; A Fil, anchoring
filaments; IF, intermediate filaments; LD, lamina densa of basement membrane; and P, plaque. Scale bar = 0.4 μm. (From Ellison JE,
Garrod DR. J Cell Sci 1984;72:163–172, by permission.)

Figure 7–19. Molecular components of the hemidesmosome.

Figure 7–20. Fluorescence micrograph showing fibronectin produced by cells in culture. (From Mattey DL, Garrod DR. J Cell Sci
1984;67:171–188, by permission.)

Figure 7–21. Focal contacts and stress fibers of cells in culture. (A) Micrograph of cells under interference reflection microscopy
showing focal contacts. (B) Fluorescence micrograph showing actin stress fibers. Note how each stress fiber terminates at a focal contact.
(From Morgan J, Garrod DR. J Cell Sci 1984;66:133–145, by permission.)

Figure 7–22. Molecular composition of focal contact and mechanotransduction. ECM stiffness increases the loading rate of focal
adhesions (ECM-integrin-actin cytoskeleton machinery), while compliant ECM reduces its loading. The extracellular integrin head domain
binds the ECM, and the intracellular tail of integrins binds the F-actin through adaptor proteins, such as talin and vinculin. Actin protein
polymerization and extension of F-actin at the leading edge of a cell lead to retrograde flow of the actin filaments and directional
migration, which is also facilitated by myosin II-mediated pulling forces in the cells. Besides cell motility, mechanotransduction also
regulates cell response to ECM mechanical property by regulating GTPases, Rho/Rac activity, and nuclear translocation of transcriptional
factor YAP/TAZ.

Figure 7–23. Cell adhesion in epithelia. (A) Stratified and (B) simple epithelium showing distribution of adhesive properties.

Figure 7–24 . Model of collective migration. Leader cells (A, one or several cells at the front of the migrating group) determine the
direction of migration by forming protrusions or a leading edge in response to environmental cues. The front-rear polarity of leader cells
was determined by asymmetric environment of lateral and rear cell-cell adhesions and ECM contact at the front. Inner follower cells (B,
behind leader cells inside of the cluster) and peripheral follower cells (C, locate at the outside of the cluster) also contribute to the front-
rear polarity of the leader cells and directional movement of the group. Supracellular actomyosin cables formed in peripheral follower cells
at the outer surface of the cluster maintain cohesion of the migrating group.

Figure 7–25. Adhesion of blood platelets. (A) The adhesive environment. Diagram summarizing the molecular adhesive components
in blood plasma, platelets, and the endothelial cell basement membrane. (B) The adhesion receptors of platelets and their ligands. PSGL-
1, P-selectin glycoprotein ligand-1.

Figure 7–26. Cell adhesion in embryonic development. (A) Compaction in the mammalian embryo. (i) At the early eight-cell stage, the
embryonic cells, the blastomeres, are loosely attached. (ii) Without further cell division, they “zip up” their adhesive contacts. (B) At the
blastocyst stage the first epithelium, the trophectoderm, is formed. This contains the inner cell mass and the fluid-filled blastocoel cavity.
(C) Gastrulation is shown in the amphibian embryo because it is easier to visualize than in the mammal where gastrulation is more
complex because of the presence of extraembryonic tissue that forms the placenta. (i) Longitudinal and (ii) transverse sections of the
early gastrula. Cell invagination is just beginning with the formation of the blastopore lip (arrow). (iii, iv) Comparable sections of the late
gastrula where invagination is almost complete though the blastopore (arrow) is not quite closed. Ectoderm (blue), mesoderm (red), and
endoderm (yellow). A, archenteron, the future gut cavity; B, blastocoel. Vertical lines indicate the relationship between the sections. (D)
Formation of the neural tube, the future central nervous system, involves expression of different adhesion molecules.

Figure 7–27. Neural crest and its derivatives in the trunk. Arrows indicate paths of migration of neural crest cells. The ventral pathway
gives rise to ganglia and their associated nerves. The dorsal pathway gives rise to pigment cells of the skin. Cell adhesion plays a crucial
role in guiding the migration and final positioning.

Figure 7–28. Contact inhibition of cell movement. Cell 1 moving in the direction of the arrow makes contact with and adheres to cell 2
(shown completely stationary for the purpose of illustration). Movement in the initial direction is inhibited. Cell 1 forms a new leading
lamella or lamellipodium and moves off in a different direction.

Figure 7–29. Cell attachment, division, and death. (A) Normal cells are anchorage dependent requiring attachment to the substratum
to proliferate. (B) Cells that become detached from the substratum undergo anoikis, a form of programmed cell death or apoptosis. (C)
Many tumor cells both survive and proliferate in suspension.

Figure 7–30. Mammary gland. A good example of the regulation of cell survival and differentiation by cell adhesion signaling.

Figure 7–31. Molecular structure of fibrillar collagen. (A) Electron micrograph showing the banded appearance of a type I collagen
fiber from tendon. (Courtesy Drs. Helen Graham and Karl Kadler.) (B) Diagram showing the fiber assembly. The N- and C-propeptides of
procollagen are cleaved to give a collagen monomer that is triple-helical with nonhelical telopeptides at each end. Monomers assemble in
a regular manner to cause the banded collagen fibril.

Figure 7–32. How cells synthesize and assemble collagen fibrils into the parallel array that constitutes a tendon.

Figure 7–33. The repeating carbohydrate units that constitute sulfated and nonsulfated glycosaminoglycans.

Figure 7–34 . Structure of a large proteoglycan, aggrecan, from cartilage.

Figure 7–35. Elastic fibers. (A) Elastic fibers are composed of a central core of elastin surrounded by microfibrils of fibrillin. The whole is
cross-linked by γ-glutamyl-lysine bonds. (B) Elastin molecules consist of tandem repeats of hydrophilic (purple) and hydrophobic (pink)
domains. (C) The hydrophobic domains are responsible for elasticity.

Figure 7–36. Fibronectin dimer showing various binding sites.

Figure 7–37. Structure of laminin.

Figure 7–38. Molecular composition of the basement membrane.

Figure 7–39. Structure of the fibrin molecule and the branching fibers that it forms in blood clots.

Figure 7–40. Normal and abnormal adhesion of blood platelets. (i) von Willebrand factor (vWF) (blue) attaches to exposed
endothelial basement membrane collagen (green), and platelets adhere loosely, rolling under the force of blood flow. (ii) Platelets form
stable adhesions to collagen and more plates attach by aggregation mediated by vWF and fibrinogen (brown). The thrombus then
continues to grow. (iii) Platelets may adhere to the surfaces of endothelial cells initiating the formation of a thrombus by recruitment of
other plates and leukocytes and, eventually, development of atherosclerotic plaque.

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