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not blocked by the inhibition of either Rac1 or RhoA (Palazzo et al., 2001a).
Thus, it is quite possible that polarized activation of Cdc42 is one of the initial
steps in cells that are about to migrate. This is paralleled by its well-established
role in yeast, where Cdc42 localization provides the main cue for the polarity
of the actin cytoskeleton (Pruyne and Bretscher, 2000).
Microtubule stabilization downstream of RhoA
Partly as a result of centrosome position, the microtubule array itself is
polarized and microtubules tend to be aligned along the axis of cell migration
with the majority of microtubule plus ends facing the leading edge. It has been
observed in fibroblasts that many of these orientated microtubules are
composed in large part of tubulin that has been post-translationally
detyrosinated at its C-terminus (Gundersen and Bulinski, 1988). Detyrosina-
tion is a slow process as compared with microtubule turnover by dynamic
instability, and thus serves as an indicator of microtubule stabilization.
Detyrosination does not stabilize microtubules by itself, but it has been
suggested that dynamic instability in detyrosinated microtubules is blocked by
an ATP-sensitive plus end cap (Infante et al., 2000). However, the mechanism
by which microtubules become detyrosinated is still mysterious and no tubulin
carboxypeptidase has been identified to date. In addition, the intracellular
function of detyrosinated microtubules is not well understood, although there
is some evidence that certain types of intracellular transport might
preferentially occur along detyrosinated microtubule tracks (Lin et al.,
2002). Thus, in migrating cells, these stabilized microtubules could serve
specifically to deliver cargo to the leading edge.
In fibroblasts, in addition to its effects on actin stress fibre formation, RhoA
activation by lysophosphatidic acid increases the number of orientated,
detyrosinated microtubules and induces long episodes of pauses in a subset of
microtubule plus ends (Cook et al., 1998) (Figure 13.3b). The RhoA-mediated
induction of these microtubules has been attributed to its downstream effector
mDia. mDia binds to microtubules and might thus directly regulate
microtubule dynamic instability (Palazzo et al., 2001b). Overexpression of
activated mDia also results in the alignment of microtubules with actin
bundles (Ishizaki et al., 2001). However, this might be an indirect effect, since
mDia induces stress fibre formation, and microtubules often align along stress
fibres (Salmon et al., 2002).
In contrast to this mDia-mediated microtubule stabilization, in neuro-
blastoma cells, RhoA activation results in increased phosphorylation of
the microtubule-associated protein tau, which should promote its dissociation
from microtubules and result in their destabilization (Sayas et al., 1999)
(Figure 13.3c). Whether RhoA has
similar
effects on non-neuronal
