The document discusses cell adhesion and migration. It outlines four classes of cell junctions: anchoring junctions, occluding junctions, channel-forming junctions, and signal-relaying junctions. Anchoring junctions like adherens junctions and desmosomes connect cells to each other and transmit stresses through connections to the cytoskeleton. Tight junctions form seals between cells and separate membrane domains. Cadherins are important cell adhesion molecules that mediate calcium-dependent cell-cell adhesion through homophilic binding. Regulation of cadherins and other cell adhesion molecules controls processes like epithelial-mesenchymal transition that are important for tissue development and cancer metastasis.

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
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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)
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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)
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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)
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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)
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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)
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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)
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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)
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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)
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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)
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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)
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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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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)
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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)
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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
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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
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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
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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
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)
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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.
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)
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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
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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
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)
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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)
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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:
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