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Objective
To gain an understanding of the physiological
importance and molecular mechanisms governing
cell migration and motility
Outline
1. When and why do cells move?
Morphogenesis, wound healing, metastasis,
the immune response, neurite outgrowth,
reproduction
2. How do cells move?
Steps in migration
*Generation of cell polarity
*Membrane protrusion and adhesion at the cell front
*Loss of adhesion at the cell rear
*Movement of the cell body forward and retraction
of the rear
Regulators of cell movement
* Chemotactic agents and growth factors
* Rho GTPases: Rho, Rac and Cdc42
Cdc42 and cell polarity
Rac and actin polymerization
Rho and cell contraction
2. Microtubule-dependent cell motility (Cilia and flagella)
Structure and function of cilia and flagella
The axoneme
Ciliary dynein
Kartageners syndrome
Leukocyte Transmigration
Wound healing
Tumor Metastasis
Angiogenesis
Actin-binding
proteins
Fibronectin is a
component of the
ECM
Adhesion
Site
Actin
Filament
Stress
Fiber
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12
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Electron micrographs of
the leading edge
showing actin filaments
in the lamellipodia at the
characteristic 70o angles
due to actin filament
nucleation by Arp2/3
complexes
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Weak adhesions
Activation of Myosin II
Generates Contractile Forces
Strong adhesions
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(Rho-Family of GTPases)
Actin-Binding Proteins
Actin
Polymerization
Adhesion
Contractility
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Extracellular Signals
OFF
Rho-GDP
Rho-GTP
ON
Extracellular Signals
*Similar for Rac and Cdc42
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Actin-binding
proteins
vinculin
focal adhesion
Adhesion
Site
Actin
Filament
Stress
Fiber
Rho-GTP
Rho kinase
(Rock)
LIM kinase
Formins
MLC
phosphatase
Cofilin
MLC (P)
Increased Myosin
Activity
Actin bundle
growth
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Rac-GTP
PI(4)P2
kinase
WASP
family
PI(4,5)P2
Arp2/3
complex
Capping
proteins
Nucleation of actin
polymerization
(Increased barbed
ends and actin
polymerization)
Lamellipodia Formation
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Cdc42-GTP
Polarized membrane
towards the leading edge
Delivery of membrane
and proteins such as
integrins to leading edge
Formin
Nucleation/elongation
of actin bundles
Filapodia
Formation
Directional
Migration
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Microtubule Cytoskeleton
and Cell Migration
microtubule
Membrane vesicles
from the golgi or
recycling endosomes
golgi
Rear
Front
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Summary
Actin Cytoskeleton and Cell Migration
Rear
Adhesion
Disassembly
retracting rear
Front
Rho
contractility
Rac
Actin
Polymerization
Adhesion
Assembly
protruding front
Direction of Migration
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Microtubule-Dependent Motility
Motile Cilia and Flagella
Microtubule-Dependent
Cell Motility
Motile Cilia
Beating Motion
of Cilia
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Microtubule-Dependent Motility
Cilia and Flagella
Flagellum/Flagella
Wave-like motion of flagella
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Axoneme
Cross-section of an Axoneme
Major components
**Nine doublet microtubules arranged
around a pair of single microtubules
These microtubules extend the length
of the axoneme making up the cilium or
flagellum
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Generation of Movement
**Ciliary dynein is a large multisubunit motor protein
that moves towards the minus ends of microtubules.
**The tail of ciliary dynein binds to the A tubule
independent of ATP.
**The heads of ciliary dynein bind to the B tubule in
an ATP-dependent manner.
**When the heads hydrolyze ATP, the heads move
towards the minus ends of the B tubule
**Because the A and B tubules are link together the
movement of ciliary dynein along the B tubule
causes a bending motion
ciliary
dynein
isolated
microtubule
doublet
Dynein activation
causes microtubule
sliding
Dynein activation
causes microtubule
bending
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Kartageners Syndrome
Cause
Hereditary Defects in Ciliary Dynein
Characteristics
Male sterility due to immotile sperm
High susceptibility to lung infections due
to the failure of cilia in the respiratory
tract to clear bacteria
Defects in determination of the left-right
axis of the body during early embryonic
development
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