Weitere ähnliche Inhalte Kürzlich hochgeladen (20) 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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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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