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review articleRho GTPases in cell biologySandrine Etienne-Manneville* & Alan Hall** MRC Laboratory for Molecular Cell Biology and Cell Biology Unit, Cancer Research UK Oncogene and Signal Transduction Group; and Department of Biochemistry
and Molecular Biology, University College London, Gower Street, London WC1E 6BT, UK...............................................................................................................................................................................................................................................................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.GTPases are molecular switches that use a simple biochemical strategy to control complex cellular processes.
They cycle between two conformational states: one
bound to GTP (active state), the other bound to
GDP (inactive state), and they hydrolyse GTP to
GDP (Fig. 1). In the on (GTP) state, GTPases recognize target
proteins and generate a response until GTP hydrolysis returns the
switch to the off state. This idea has been elaborated throughout
evolution, and mammalian cells contain several hundred GTPase
switches. The Ras superfamily of GTPases is particularly interesting
to cell biologists, as its members have turned out to be master
regulators of many aspects of cell behaviour. These small, monomeric GTPases, which number over 60 in mammals, fall into five
major groups: Ras, Rho, Rab, Arf and Ran. This review focuses
specifically on Rho GTPases, emphasizing the insights they are
providing into the molecular mechanisms underlying cell biology.Although the Rho switch itself is straightforward, it is very
carefully regulated, and the human genome contains over 60
activators (guanine nucleotide exchange factors, GEFs) and over
70 inactivators (GTPase-activating proteins, GAPs) for this family
(Fig. 1). Unfortunately, target proteins do not contain a single
recognizable sequence motif useful in database searches, but for
Rho, Rac and Cdc42, the three best-characterized members of the
family, over 60 targets have so far been identified experimentally.
This is unparalleled complexity for a GTPase switch...