Rho GTPases are molecular switches that control a wide variety of signal transduction pathways in all eukaryotic cells. They are known principally for their pivotal role in regulating the actin cytoskeleton, but their ability to influence cell polarity, microtubule dynamics, membrane transport pathways and transcription factor activity is probably just as significant. Underlying this biological complexity is a simple biochemical idea, namely that by switching on a single GTPase, several distinct signalling pathways can be coordinately activated. With spatial and temporal activation of multiple switches factored in, it is not surprising to find Rho GTPases having such a prominent role in eukaryotic cell biology.

We describe here a signal transduction pathway controlling the establishment of mammalian cell polarity. Scratching a confluent monolayer of primary rat astrocytes leads to polarization of cells at the leading edge. The microtubule organizing center, the microtubule cytoskeleton, and the Golgi reorganize to face the new free space, and directed cell protrusion and migration specifically occur perpendicularly to the scratch. We show here that the interaction of integrins with extracellular matrix at the newly formed cell front leads to the activation and polarized recruitment of Cdc42, which in turn recruits and activates a cytoplasmic mPar6/PKCzeta complex. Localized PKCzeta activity, acting through the microtubule motor protein dynein, is required for all aspects of induced polarity in these cells.