GTPase cascades choreographing cellular behavior: Movement, morphogenesis, and more

Over the last decade we have learned that most, if not atl, cellular behaviors are influenced by GTPases. Recent work on Ras-related GTPases that regulate the cytoskeleton has brought to our attention a new regulatory mechanism: multiple GTPase switches coupled directly in a cascade. In mammalian cells, a cascade of Cdc42 controlling Rac controlling Rho coordinates the actin cytoskeleton during cell movement. In yeast cells, a related cascade of BUD1 (RSR1) controlling CDC42 and possibly RHO proteins coordinates polarization of the cytoskeleton during cell division by budding. What is the benefit of GTPase cycles so tightly linked in a cascade? Combining GTPase switches in cascades can produce regulatory circuits of sufficient sophistication to choreograph complex cellular behaviors. In GTPase cascades, one GTPase controls the action of the next GTPase. Bifunctional linker molecules are now being discovered that directly link the actions of GTPases in these cascades. Evidence suggests that GTPase cascades are highly adaptable, with branches feeding in and out at different levels: each GTPase can be independently controlled by certain input signals, and each GTPase may produce an output independent of the activation of the other cascade members. With so many GTPases controlling different cellular processes, we anticipate that the GTPase cascade will prove to be a widespread mechanism of coordination and regulation. The Basic GTPase Switch GTPases have been found to control processes as diverse as growth control, apoptosis, translation, vesicular transport, cytoskeletal organization, and nuclear import (Boguski and McCormick, 1993). In its simplest form, the GTPase switch has two conformations: a GTP-bound form and a GDP-bound form. In some instances, such as Ras, the GTP-bound form is active, sending a signal, while the GDP form is inactive, sending no signal. In other instances, such as ADP-ribosylation factor, cycling of a GTPase switch may govern the formation or dissolution of multisubunit protein complexes (Rothman, 1994). For almost all Ras-related GTPase switches, the rate of conversion between the GDP-bound and GTP-bound conformations is modulated by regulators such as guanine nucletotide exchange factors (GEFs), which stimulate the replacement of GDP by GTP, and GTPase-activating proteins (GAPs), which stimulate the intrinsic GTPase activity of the GTPase. For certain GTPases, additional regulatory