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and Mitchison, 1997; Mitchison and Kirschner, 1984). A transition from
polymerization to depolymerization is called a 'catastrophe', while the
opposite is referred to as a 'rescue'. In most migrating cell types, the
centrosome is positioned between the nucleus and the leading edge, and
the bulk of microtubule plus ends are orientated towards the leading edge. In
addition, microtubules in migrating fibroblasts appear to target sites of
substrate adhesion and somehow regulate their turnover (Kaverina et al.,
1998, 1999; Small and Kaverina, 2003).
The observation that microtubules, like actin, exhibit specific, polarized
organization and growth dynamics in migrating cells raises the important
question of whether microtubules, like actin, might be regulated downstream
of Rho GTPases. Indeed, recent evidence suggests that specific Rho GTPases
affect specific aspects of microtubule organization and assembly/disassembly
dynamics, and this shall be the focus of the remainder of this chapter.
Centrosome reorientation downstream of Cdc42
The most striking polarization of the microtubule cytoskeleton in many
migrating cells is the repositioning of the centrosome, the organizing centre of
the radial interphase microtubule network. When fibroblasts are activated to
migrate by scratching a wound in a cell monolayer, the centrosome rapidly
changes its place from a random orientation relative to the nucleus to a
position between the nucleus and the leading edge (Gotlieb et al., 1981;
Malech et al., 1977). Centrosome reorientation depends on an intact
microtubule cytoskeleton, but is not observed in all cell types and the
significance of centrosome reorientation remains unclear (Euteneuer and
Schliwa, 1992; Gotlieb et al., 1983; Schliwa and Ho¨ ner, 1993; Yvon et al.,
2002). It was originally speculated that the primary reason for repositioning of
the centrosome and the bulk of microtubules towards the direction of
migration is the requirement to orientate the secretory apparatus. Indeed,
secretion that is preferentially polarized towards the leading edge has been
observed in migrating fibroblasts (Bergmann et al., 1983; Hopkins et al.,
1994). The requirement of microtubule-based transport for cell locomotion
was also demonstrated by microinjection of kinesin-specific antibodies, which
inhibited cell motility in a way similar to microtubule depolymerization
(Rodionov et al., 1993). However, microtubule-dependent transport in
migrating cells might not be limited to membrane organelles, but might
include molecules required for the regulation of protrusion formation or focal
adhesion turnover (Krylyshkina et al., 2002).
Recently, it has become apparent that Rho GTPases are involved in
controlling centrosome orientation. It was first demonstrated in T cells that
Cdc42 is required for the reorientation of the centrosome and Golgi apparatus
