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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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11/24/08
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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
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Figure 19-2 Molecular Biology of the Cell (© Garland Science 2008)
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 19-1 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
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Table 19-2 Molecular Biology of the Cell (© Garland Science 2008)
Anchoring junctions:
Figure 19-4 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
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Figure 19-7 Molecular Biology of the Cell (© Garland Science 2008)
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
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)
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Figure 19-9a Molecular Biology of the Cell (© Garland Science 2008)
Cadherins mediate homophilic adhesion: • Cadherins of a specific subtype on one cell will bind
cadherins of the same type on another cell
Figure 19-9b 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
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Figure 19-9c Molecular Biology of the Cell (© Garland Science 2008)
The “Velcro” principle of adhesion: • Low-affinity binding to ligand • Strength comes from multiple bonds in parallel • Allows for easy disassembly
Figure 19-10 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
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Figure 19-12a,b Molecular Biology of the Cell (© Garland Science 2008)
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 19-11 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
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Figure 19-12c Molecular Biology of the Cell (© Garland Science 2008)
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 19-14 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
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Figure 19-15 Molecular Biology of the Cell (© Garland Science 2008)
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 19-16 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
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Figure 19-17a Molecular Biology of the Cell (© Garland Science 2008)
Desmosome junctions give epithelia mechanical strength:
• Structurally similar to adherens junctions • Link to intermediate filaments
Figure 19-17b Molecular Biology of the Cell (© Garland Science 2008)
Molecular components of a desmosome:
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Figure 19-18 Molecular Biology of the Cell (© Garland Science 2008)
Desmosomes, hemidesmosomes, and the intermediate filament network:
• Form a structural framework of great tensile strength
Desmoplakin mutations: • Clinical features include varying degrees of keratoderma,
blisters, nail dystrophy, wooly hair, cardiomyopathy
From Clinical and Experimental Dermatology, 30, 261-266 (2005)
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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
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Figure 6.26 The Biology of Cancer (© Garland Science 2007)
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 14.14c The Biology of Cancer (© Garland Science 2007)
Effect of epithelial-mesenchymal transition on β-catenin localization:
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Figure 19-3 Molecular Biology of the Cell (© Garland Science 2008)
Organization of cell junctions in epithelia: • Relative positions of the junctions are the same in all
epithelia
Figure 19-23 and 19-27 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
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Figure 19-24 Molecular Biology of the Cell (© Garland Science 2008)
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
Downloaded from: StudentConsult (on 23 November 2008 06:19 PM) © 2005 Elsevier
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http://cellimages.ascb.org/cdm4/item_viewer.php?CISOROOT=/p4041coll12&CISOPTR=79&CISOBOX=1&REC=1&DMROTATE=
90
Electron micrograph of a bile canaliculus
Downloaded from: StudentConsult (on 23 November 2008 06:19 PM) © 2005 Elsevier
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Figure 19-26 Molecular Biology of the Cell (© Garland Science 2008)
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
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
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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
Figure 19-29 Molecular Biology of the Cell (© Garland Science 2008)
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
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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.
Figure 19-19 Molecular Biology of the Cell (© Garland Science 2008)
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
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Figure 19-20 Molecular Biology of the Cell (© Garland Science 2008)
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)
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
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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
Figure 16-86 Molecular Biology of the Cell (© Garland Science 2008)
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
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Figure 19-52a Molecular Biology of the Cell (© Garland Science 2008)
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 6.24a The Biology of Cancer (© Garland Science 2007)
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
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Figure 6.24b The Biology of Cancer (© Garland Science 2007)
FAK in “command and control” of cell motility:
Events that need to be coordinated during cell migration:
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