Microtubule involvement in regulating cell contractility and adhesion-dependent signalling: a possible mechanism for polarization of cell motility.

The dynamic shape of an isolated cell results from an interplay between protrusion, adhesion and contraction activities. These are most closely associated with the actin cytoskeleton. In many cell types, microtubules have been shown to be involved in the development of morphological polarity required for directional migration. This suggests a role for the microtubule system in regulating both the actin cytoskeleton and the formation of cell-substrate adhesions. The most prominent role of microtubules in the cell is in transport of vesicles and organelles. Disruption of the microtubules, on the other hand, leads to a significant increase in actomyosin-driven contractility. This suggests the involvement of microtubules in the control of forces produced by the cell against the points at which it contacts the substrate or extracellular matrix. We show that microtubule disruption also activates an adhesion-dependent signal transduction cascade and promotes the formation of focal adhesions and associated actin microfilament bundles. Using overexpression of caldesmon, a regulatory protein which inhibits the interaction between actin and myosin, we show that these effects of microtubule disruption depend on the activation of contractility. Formation of focal adhesions induced by the small GTPase Rho is also blocked by the caldesmon inhibition of contractility. We infer that there is a step in the adhesion-dependent signalling pathway that requires mechanical tension applied to cell-substrate contacts. Although the experimental data are based on complete microtubule disruption, we suggest that a similar effect occurs locally following depolymerization of individual microtubules. We speculate that the interplay among microtubule dynamics, actomyosin contractility and adhesion-dependent signalling can produce a mechanism for the determination of cell polarity and direction of migration. In essence, microtubule depolymerization would create a local increase in contractile force, testing and promoting the maturation of nearby cell-substrate adhesions.