11/24/08




      Cell Adhesion and Cell
             Migration
   Antonia Jameson Jordan, DVM, Ph.D.
            Novembe...
11/24/08




    Four functional classes of cell junctions in animal tissues:
      •  Anchoring junctions
               ...
11/24/08




                              Anchoring junctions:




Table 19-2 Molecular Biology of the Cell (© Garland Sc...
11/24/08




       The cadherin superfamily includes hundreds of
                     different proteins:
               ...
11/24/08




       Cadherins mediate homophilic adhesion:
          •  Cadherins of a specific subtype on one cell will b...
11/24/08




                The “Velcro” principle of adhesion:
          •  Low-affinity binding to ligand
          •  ...
11/24/08




 Cadherins control the selective assortment of cells:



                                                    ...
11/24/08




    Twist is a transcription factor that regulates
       epithelial-mesenchymal transitions:
       •  Epith...
11/24/08




        Adherens junctions coordinate the actin-
           based motility of adjacent cells:
       •  Allow...
11/24/08




               Desmosome junctions give epithelia
                     mechanical strength:
       •  Structu...
11/24/08




          Desmosomes, hemidesmosomes, and the
              intermediate filament network:
       •  Form a s...
11/24/08




     Clinical importance of desmosomal
                  junctions:
•  Pemphigus
    –  Auto-antibodies again...
11/24/08




                  Beta-catenin has dual functions:
              •  Anchor protein at adherens junctions
    ...
11/24/08




            Organization of cell junctions in epithelia:
       •  Relative positions of the junctions are th...
11/24/08




      The role of tight junctions in allowing epithelia
         to serve as barriers to solute diffusion:
  ...
11/24/08




Electron micrograph of a bile
         canaliculus
  http://cellimages.ascb.org/cdm4/
  item_viewer.php?CISOR...
11/24/08




                           How a tight junction works:
       •  Branching networks of sealing strands encirc...
11/24/08




         Scaffold proteins in junctional complexes
            play a key part in the control of cell
       ...
11/24/08




         The connections between cell adhesion,
                ECM, and cell migration:
              •  To ...
11/24/08




         Strong integrin-mediated adhesions are
        required for extravasation of leukocytes:
     •  Leu...
11/24/08




            Cells have to be able to degrade matrix:
       •    Physiologic examples:
             –  Leukoc...
11/24/08




         Cell adhesion and traction allow cells to
                 pull themselves forward:
                ...
11/24/08




            FAK in “command and control” of cell
                        motility:




Figure 6.24b The Biolo...
11/24/08




     24
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Cell Adhesion and Cell Migration

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I give this lecture on cell adhesion and cell migration in the Cell Biology and Genetics course for first-year veterinary students. The core material comes from Molecular Biology of the Cell, Fifth Edition, but I have added multiple clinical examples and placed the material in the context of the translational medicine component of the course.

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Cell Adhesion and Cell Migration

  1. 1. 11/24/08 Cell Adhesion and Cell Migration Antonia Jameson Jordan, DVM, Ph.D. November 24, 2008 Outline: •  Overview of the kinds of adhesions that cells make •  Anchoring junctions –  adherens junctions –  desmosomes •  The organization of adhesions at epithelia •  Tight junctions •  Migration 1
  2. 2. 11/24/08 Four functional classes of cell junctions in animal tissues: •  Anchoring junctions –  Cell-cell and cell-matrix •  Transmit stresses through tethering to cytoskeleton •  Occluding junctions –  Seal gaps between cells to make an impermeable barrier •  Channel-forming junctions (gap junctions) –  Link cytoplasms of adjacent cells •  Signal-relaying junctions –  Synapses in nervous system, immunological Figure 19-2 Molecular Biology of the Cell (© Garland Science 2008) Anchoring junctions transmit stresses and are tethered to the cytoskeletal elements: •  Connective tissue - –  Main stress-bearing component is the ECM •  Epithelial tissue –  Cytoskeletons transmit mechanical stresses Figure 19-1 Molecular Biology of the Cell (© Garland Science 2008) 2
  3. 3. 11/24/08 Anchoring junctions: Table 19-2 Molecular Biology of the Cell (© Garland Science 2008) Transmembrane adhesion proteins link the cytoskeleton to extracellular structures: •  Cell-cell adhesions usually mediated by cadherins •  Cell-matrix adhesions usually mediated by integrins •  Internal linkage to cytoskeleton is mediated by intracellular anchor proteins Figure 19-4 Molecular Biology of the Cell (© Garland Science 2008) 3
  4. 4. 11/24/08 The cadherin superfamily includes hundreds of different proteins: •  Take their name from their dependence on calcium •  Extracellular domain containing multiple copies of the cadherin motif •  Intracellular portions varied •  Adhesive and signaling functions Figure 19-7 Molecular Biology of the Cell (© Garland Science 2008) Cadherins mediate Ca2+-dependent cell-cell adhesion in all animals: •  Main adhesion molecules holding cells together in early embryonic tissues Figure 19-5 Molecular Biology of the Cell (© Garland Science 2008) 4
  5. 5. 11/24/08 Cadherins mediate homophilic adhesion: •  Cadherins of a specific subtype on one cell will bind cadherins of the same type on another cell Figure 19-9a Molecular Biology of the Cell (© Garland Science 2008) In the absence of calcium the structure becomes floppy: •  Series of compact domains (cadherin repeats) joined by flexible hinges Figure 19-9b Molecular Biology of the Cell (© Garland Science 2008) 5
  6. 6. 11/24/08 The “Velcro” principle of adhesion: •  Low-affinity binding to ligand •  Strength comes from multiple bonds in parallel •  Allows for easy disassembly Figure 19-9c Molecular Biology of the Cell (© Garland Science 2008) Selective cell-cell adhesion enables dissociated vertebrate cells to reassemble into organized tissues: •  Homophilic attachment allows for highly selective recognition •  Cells of similar type stick together and stay segregated from other cell types Figure 19-10 Molecular Biology of the Cell (© Garland Science 2008) 6
  7. 7. 11/24/08 Cadherins control the selective assortment of cells: •  Appearance and disappearance of specific cadherins •  A. is labeled for E-cadherin •  B. is labeled for N-cadherin Figure 19-12a,b Molecular Biology of the Cell (© Garland Science 2008) Selective dispersal and reassembly of cells to form tissues in a vertebrate embryo: •  Cells from epithelial neural tube alter their adhesive properties •  Epithelial-mesenchymal transition •  Migrate –  Chemotaxis –  Chemorepulsion –  Contact guidance •  Re-aggregate Figure 19-11 Molecular Biology of the Cell (© Garland Science 2008) 7
  8. 8. 11/24/08 Twist is a transcription factor that regulates epithelial-mesenchymal transitions: •  Epithelial cells can dis-assemble, migrate away from parent tissue as individual cells -- epithelial- mesenchymal transition •  Part of normal development, e.g., neural crest •  Twist is essential for neural crest cell development in embryogenesis •  Twist represses transcription of E-cadherin •  Twist contributes to metastasis in human breast cancers Figure 19-12c Molecular Biology of the Cell (© Garland Science 2008) Catenins link classical cadherins to the actin cytoskeleton: •  Intracellular domains of the cadherins provide anchorage for cytoskeletal filaments •  Intracellular anchor proteins assemble on the tail of the cadherin •  Catenins –  β, γ, p120-catenin Figure 19-14 Molecular Biology of the Cell (© Garland Science 2008) 8
  9. 9. 11/24/08 Adherens junctions coordinate the actin- based motility of adjacent cells: •  Allow cells to coordinate the activities of their cytoskeletons •  Form a continuous adhesion belt around each of the interacting cells in a sheet of epithelium •  Network can contract via myosin motor proteins –  Motile force for folding of epithelial sheets Figure 19-15 Molecular Biology of the Cell (© Garland Science 2008) Adherens junctions coordinate the actin- based motility of adjacent cells: •  Oriented contraction of bundles of actin filaments running along the adhesion belts causes narrowing of the cells at the apex Figure 19-16 Molecular Biology of the Cell (© Garland Science 2008) 9
  10. 10. 11/24/08 Desmosome junctions give epithelia mechanical strength: •  Structurally similar to adherens junctions •  Link to intermediate filaments Figure 19-17a Molecular Biology of the Cell (© Garland Science 2008) Molecular components of a desmosome: Figure 19-17b Molecular Biology of the Cell (© Garland Science 2008) 10
  11. 11. 11/24/08 Desmosomes, hemidesmosomes, and the intermediate filament network: •  Form a structural framework of great tensile strength Figure 19-18 Molecular Biology of the Cell (© Garland Science 2008) Desmoplakin mutations: •  Clinical features include varying degrees of keratoderma, blisters, nail dystrophy, wooly hair, cardiomyopathy From Clinical and Experimental Dermatology, 30, 261-266 (2005) 11
  12. 12. 11/24/08 Clinical importance of desmosomal junctions: •  Pemphigus –  Auto-antibodies against desmosomal cadherins •  Cells become “unglued” from each other –  Severe blistering of the skin Pemphigus foliacious – antibodies against desmoglein 1 Cell-cell junctions send signals into the cell interior: •  Cross-talk between adhesion machinery and cell signaling pathways allows cell to make or break attachments as dictated by circumstances –  Analagous to cross-talk between integrin signaling and other signaling pathways •  Contact inhibition –  In general, when cells are attached to other cells, proliferation is inhibited –  When attachments are broken, proliferation is stimulated •  Physiologic example –  Repair a breach in the epithelium 12
  13. 13. 11/24/08 Beta-catenin has dual functions: •  Anchor protein at adherens junctions •  Transcription factor •  Location (at adherens junction versus in the nucleus) determines its function at any given time Figure 6.26 The Biology of Cancer (© Garland Science 2007) Effect of epithelial-mesenchymal transition on β-catenin localization: Figure 14.14c The Biology of Cancer (© Garland Science 2007) 13
  14. 14. 11/24/08 Organization of cell junctions in epithelia: •  Relative positions of the junctions are the same in all epithelia Figure 19-3 Molecular Biology of the Cell (© Garland Science 2008) Tight junctions form a seal between cells and a fence between membrane domains: •  Cells need to segregate proteins to appropriate domain (apical or basolateral) •  Prevent backflow from one side of the epithelium to the other Figure 19-23 and 19-27 Molecular Biology of the Cell (© Garland Science 2008) 14
  15. 15. 11/24/08 The role of tight junctions in allowing epithelia to serve as barriers to solute diffusion: •  A small extracellular tracer molecule added to one side is prevented from diffusing to the other side by tight junctions •  Epithelial cells can transiently alter tight junctions to increase permeability of the tissue – paracellular transport Figure 19-24 Molecular Biology of the Cell (© Garland Science 2008) Downloaded from: StudentConsult (on 23 November 2008 06:19 PM) © 2005 Elsevier 15
  16. 16. 11/24/08 Electron micrograph of a bile canaliculus http://cellimages.ascb.org/cdm4/ item_viewer.php?CISOROOT=/ p4041coll12&CISOPTR=79&CIS OBOX=1&REC=1&DMROTATE= 90 Downloaded from: StudentConsult (on 23 November 2008 06:19 PM) © 2005 Elsevier 16
  17. 17. 11/24/08 How a tight junction works: •  Branching networks of sealing strands encircle the apical end of cell in the sheet •  Each strand is composed of a long row of transmembrane adhesion proteins embedded in each of the two interacting plasma membranes •  Extracellular domains adhere to one another, occluding the intercellular space Figure 19-26 Molecular Biology of the Cell (© Garland Science 2008) Assembly of a junctional complex depends on scaffold proteins: •  Junctional complex –  Tight junction –  Adherens junction –  Desmosomal junction •  Intracellular scaffold proteins position and organize the tight junctions into the correct relationship with the other components of the junctional complex •  Tjp (Tight junction protein) family or ZO (zonula occludens) protein 17
  18. 18. 11/24/08 Scaffold proteins in junctional complexes play a key part in the control of cell proliferation: •  Loss of adhesive contacts with neighbors triggers proliferation –  Means to heal a defect in an epithelium •  Decreased expression of ZO protein in many tumors Cell-cell junctions and the basal lamina govern apico-basal polarity in epithelia: •  Cells need to establish polarity in orientation with surroundings •  Protein complexes that regulate polarity assemble at tight junctions so that neighboring cells are oriented correctly in relation to each other Figure 19-29 Molecular Biology of the Cell (© Garland Science 2008) 18
  19. 19. 11/24/08 The connections between cell adhesion, ECM, and cell migration: •  To get out of bloodstream to site of inflammation, they need to make an attachment to the endothelium •  Then they will have to traverse a basement membrane •  Then they will need to navigate through the ECM •  Cells crawl. They do not swim. Selectins mediate transient cell-cell adhesions in the bloodstream: •  Selectins are cell-surface carbohydrate-binding proteins that mediate transient cell-cell interactions –  At a site of inflammation, the endothelial cells express selectins that bind to oligosaccharides on the surface of a leukocyte Figure 19-19 Molecular Biology of the Cell (© Garland Science 2008) 19
  20. 20. 11/24/08 Strong integrin-mediated adhesions are required for extravasation of leukocytes: •  Leukocyte integrins bind endothelial cell proteins to make a stronger attachment –  Members of immunoglobulin superfamily •  ICAMs (intercellular adhesion molecules) •  VCAMs (vascular cell adhesion molecules) Figure 19-20 Molecular Biology of the Cell (© Garland Science 2008) Bovine leukocyte adhesion deficiency: •  Defect in neutrophil β2 integrin chain •  Neutrophils unable to leave bloodstream •  Clinical consequences: pneumonia, enteritis, stomatitis •  Autosomal recessive –  Bulls are routinely tested now 20
  21. 21. 11/24/08 Cells have to be able to degrade matrix: •  Physiologic examples: –  Leukocytes need to degrade the basal lamina of a blood vessel to escape –  Fibroblasts that are embedded in connective tissue need to degrade matrix in order to divide •  Two classes of proteases –  Matrix metalloproteinases •  Depend on Ca2+ or Zn2+ –  Serine proteases •  Protease activity must be tightly regulated –  Local activation •  Synthesized as inactive precursors –  Confinement by cell-surface receptors –  Secretion of inhibitors •  Tissue inhibitors of metalloproteases (TIMPs) •  Serpins Events necessary for cell motility: •  Actin polymerization •  Delivery of membrane to the leading edge •  Formation of attachments at leading edge to provide traction •  Contraction at rear •  Disassembly of attachments in rear of cell Figure 16-86 Molecular Biology of the Cell (© Garland Science 2008) 21
  22. 22. 11/24/08 Cell adhesion and traction allow cells to pull themselves forward: •  Cell forms integrin- mediated attachment sites at the leading edge – focal adhesions –  These allow the cell to generate traction and pull its body forward Figure 19-52a Molecular Biology of the Cell (© Garland Science 2008) Integrins recruit intracellular signaling proteins at sites of cell-substratum adhesion: •  Focal adhesion kinase (FAK) •  Tyrosine phosphorylation by FAK creates docking sites for other signaling proteins Figure 6.24a The Biology of Cancer (© Garland Science 2007) 22
  23. 23. 11/24/08 FAK in “command and control” of cell motility: Figure 6.24b The Biology of Cancer (© Garland Science 2007) Events that need to be coordinated during cell migration: 23
  24. 24. 11/24/08 24

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