b-Arrestins: Modulators of Small GTPase Activation and Function - Progress in Molecular Biology and Translational Science - page 154

directly ARFGAP21 through a region that transects the RhoA effector GAP
domain. This interaction was enhanced by Ang II stimulation and as a con-
sequence was shown to have great impact on the level of active RhoA. Dis-
ruption of the interaction led to increased activation of the GAP, attenuation
of RhoA activity, and less efficient stress fiber formation. 11 Binding to GEF
and/or GAPs might provide an additional way for b -arrestin proteins to reg-
ulate monomeric G protein function.

3.2. Rac The GTPase associated with membrane ruffling

and protrusions
Rac1 was first discovered as Ras-related C3 botulinium toxin substrate 1 and
is the most studied member of the three Rac isoforms. Expression of Rac1 is
ubiquitous, while Rac2 is present only in hematopoietic cells and Rac3 is
most highly expressed in brain. All Rac isoforms are highly homologous,
and their main role is to promote the actin assembly required for formation
of lamellipodia and membrane ruffling. Activation of Rac is therefore often
associated with cell migration. RhoG, the most divergent isoform, was
suggested to be important for the cell cycle. However, other functions have
been attributed to this isoform, namely, the activation of Rac1 through
DOCK180. 68-70 Altogether, Rac GTPases play numerous roles in addition
to cytoskeletal remodeling. These vary from cell growth and adhesion to
axonal guidance and superoxide production. 71
The role of b -arrestins in the control of Rac activation remains contro-
versial since conflicting results have been reported over the years. First,
enhanced recruitment of Rac1 to plasma membranes was observed in MEFs
lacking the two b -arrestin isoforms, at basal levels and upon stimulation with
IL-8, suggesting that the presence of b -arrestin limited the degree of Rac
activation. This b -arrestin/Rac axis, when intact, would limit the NADPH
oxidase-dependent oxidative burst and protect against cell death. 20 Alterna-
tively, it was reported that activation of Rac1 by Wnt-5A was blocked
in b -arrestin knock-out MEFs. Measurements of the basal activation level
of Rac1 were similar in control and double b -arrestin 1/2 cells, but levels
of GTP-bound Rac1 were enhanced upon Wnt-5A stimulation only in
arrestin replete MEFs. Furthermore, overexpression of b -arrestin 2
increased activation of the GTPase in MEFs. 21 Similar results were observed
in another system model, Xenopus laevis. 21 If one assumes that translocation
of Rac1 reflects its activity, the observations reported by these two groups,
who have used the same cells, appear contradictory.

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