Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

CELL POLARIZATION AND MIGRATION
959
(A)
5 µm
neutrophil
back
(B)
Rho dominates,
actin–myosin
contraction
G 12/13
then activates the Arp 2/3 complex leading to lamellipodial protrusion. Through
an unknown mechanism, accumulation of the polarized actin web at the leading
edge causes further local enhancement of PI3K activity in a positive feedback
loop, strengthening the induction of protrusion. The PI(3,4,5)P 3 that activates Rac
cannot diffuse far from its site of synthesis, since it is rapidly converted back into
PI(4,5)P 2 by a constitutively active lipid phosphatase. At the same time, binding
of the chemoattractant ligand to its receptor activates another signaling pathway
that turns on Rho and enhances myosin-based contractility. The two processes
directly inhibit each other, such that Rac activation dominates in the front of the
cell and Rho activation dominates in the rear (Figure 16–86B). This enables the
cell to maintain its functional polarity with protrusion at the leading edge and
contraction at the back.
Nondiffusible chemical cues attached to the extracellular matrix or to the surface
of cells can also influence the direction of cell migration. When these signals
activate receptors, they MBoC6 can cause m16.101/16.89 increased cell adhesion and directed actin
polymerization. Most long-distance cell migrations in animals, including neuralcrest-cell
migration and the travels of neuronal growth cones, depend on a combination
of diffusible and nondiffusible signals to steer the locomoting cells or
growth cones to their proper destinations.
Communication Among Cytoskeletal Elements Coordinates
Whole-Cell Polarization and Locomotion
The interconnected cytoskeleton is crucial for cell migration. Although movement
is driven primarily by actin polymerization and myosin contractility, septins and
intermediate filaments also participate. For example, vimentin intermediate filament
networks associate with integrins at focal adhesions, and vimentin-deficient
fibroblasts display impaired mechanical stability, migration, and contractile
capacity. Furthermore, disruption of linker proteins that connect different cytoskeletal
elements, including several plakins and KASH proteins, leads to defects
in cell polarization and migration. Thus, interactions among cytoplasmic filament
systems, as well as mechanical linkage to the nucleus, are required for complex,
whole-cell behaviors such as migration.
Cells also use microtubules to help organize persistent movement in a specific
direction. In many locomoting cells, the position of the centrosome is influenced
by the location of protrusive actin polymerization. Activation of receptors
on the protruding front edge of a cell might locally activate dynein motor proteins
that move the centrosome by pulling on its microtubules. Several effector proteins
downstream of Rac and Rho modulate microtubule dynamics directly: for
example, a protein kinase activated by Rac can phosphorylate (and thereby
inhibit) the tubulin-binding protein stathmin (see Panel 16–4), thereby stabilizing
microtubules.
Rho
PI(3,4,5)P 3
Rac
G i
Rac dominates,
polymerization
(protrusion)
chemoattractant
front
receptor
bacterium
Figure 16–86 Neutrophil polarization
and chemotaxis. (A) The pipette tip at
the right is leaking a small amount of
the bacterial peptide formyl-Met-Leu-
Phe, which is recognized by the human
neutrophil as the product of a foreign
invader. The neutrophil quickly extends a
new lamellipodium toward the source of
the chemoattractant peptide (top). It then
extends this lamellipodium and polarizes
its cytoskeleton so that contractile myosin
II is located primarily at the rear, opposite
the position of the lamellipodium (middle).
Finally, the cell crawls toward the source
of the peptide (bottom). If a real bacterium
were the source of the peptide, rather than
an investigator’s pipette, the neutrophil
would engulf the bacterium and destroy
it (see also Figure 16–3 and Movie
16.14). (B) Binding of bacterial molecules
to G-protein-coupled receptors on the
neutrophil stimulates directed motility.
These receptors are found all over the
surface of the cell, but are more likely to be
bound to the bacterial ligand at the front.
Two distinct signaling pathways contribute
to the cell’s polarization. At the front of the
cell, stimulation of the Rac pathway leads,
via the trimeric G protein G i , to growth
of protrusive actin networks. Second
messengers within this pathway are shortlived,
so protrusion is limited to the region
of the cell closest to the stimulant. The
same receptor also stimulates a second
signaling pathway, via the trimeric G
proteins G 12 and G 13 , that triggers the
activation of Rho. The two pathways are
mutually antagonistic. Since Rac-based
protrusion is active at the front of the cell,
Rho is activated only at the rear of the cell,
stimulating contraction of the cell rear and
assisting directed movement. (A, from
O.D. Weiner et al., Nat. Cell Biol. 1:75–81,
1999. With permission from Macmillan
Publishers Ltd.)