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will not be able to release once-formed adhesions). Cross-talk between focal
adhesions and microtubules could provide an effective local mechanism to
interfere with the self-accelerating growth of focal adhesions.
As described above, microtubules oppose cell contractility; their dis-
ruption induces cell contraction accompanied by myosin II light chain
phosphorylation (Kolodney and Elson, 1995). It is likely that the inhibitory
effect of microtubules on myosin II activity is local. Several experiments
have dissected the interplay between myosin II, focal adhesions and
microtubules. Microtubule disruption leads to significant augmentation of
focal adhesions, which can be prevented by suppression of myosin II-
contractility (Bershadsky et al., 1996; Helfman et al., 1999). Moreover, local
application of myosin II inhibitors by micropipette allows the restoration of
normal migration ability of the cells lacking microtubules, most probably by
normalizing the size and distribution of the focal adhesions (Kaverina et al.,
2000). Observations of microtubule dynamics in living cells suggest that
tension developing in the regions of cell attachment to the substrate
promotes rapid microtubule ingrowth, and subsequent cortical targeting
(Kaverina, 2002; Suter et al., 1998). Direct targeting of microtubule ends to
the focal adhesion plaques was observed in fibroblasts (Kaverina et al.,
1998); this targeting was accompanied by cessation of focal adhesion
growth, and often by their disassembly (Kaverina et al., 1999). These studies
suggest that microtubules are attracted to focal adhesions, locally suppress
the tension forces applied to these structures, and thereby interrupt the
positive feedback loop described above (for a more detailed discussion, see
Small et al. (2002)).
Which factors coordinate these processes of tension-dependent growth of
focal adhesions with the subsequent advent of microtubules relaxing the
tension? To put this question in the context of signalling, it is important to
remember that formation and maintenance of classical focal adhesions
depends on the activity of Rho (Ridley and Hall, 1992; Rottner et al., 1999).
Two targets of Rho were shown to be necessary and sucient to mediate
Rho's function in this process: Rho associated kinase (ROCK), and the
formin homology protein, mDia1 (Tominaga et al., 2000; Watanabe et al.,
1999). ROCK is known to activate myosin II (Fukata et al., 2001; Kimura et
al., 1996); our experiments revealed that the function of ROCK in focal
adhesion formation is through the activation of myosin II-driven forces
applied to these structures (Riveline et al., 2001). Function of the second Rho
target, mDia1, appears to be more complex. Under conditions of external
force application, mDia1 is necessary and su cient to mediate the Rho-signal,
dictating focal adhesion assembly (Riveline et al., 2001). Moreover, a model
explaining the potential mechanism of coordination between microtubules
and focal adhesions is suggested by our findings that mDia1 can participate in
the regulation of microtubule dynamics and targeting.
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