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expression. The third family, the Rabs, includes more than 60 isoforms.
Their main function in cells is to finely tune many steps of vesicle trafficking
(vesicle formation, vesicle movement, and membrane fusion). The fourth
family is the ADP-ribosylation factors (ARFs), which also regulate vesicle
budding through regulation of coat polymerization and disassembly. Some
ARF isoforms are also involved in actin rearrangement and lipid remo-
deling. The last family of GTPases consists of only one member, Ran
(Ras-related Nuclear protein), which regulates nucleoplasmic transport dur-
ing interphase. This small G protein controls cell cycle progression. GTPases
that have been linked directly or indirectly to
b
-arrestins are listed in
Table 6.1
.
1.2. Modes of regulation of GTPase activity
As mentioned previously, GEFs and GAPs tightly regulate the activity of
monomeric G proteins. At any given time, the fraction of activated GTPases
is dependent on the activity of their GEFs and GAPs. Cells express a large
number of GEFs, GAPs, and GDIs, outnumbering GTPases themselves.
GEFs possess specific domains responsible for their activity as well as
protein- and lipid-binding domains that provide targeting. These allow
GEFs to exert their effects in multimeric protein complexes linking signaling
proteins to specific GTPases. GEFs are, therefore, themselves considered
scaffolding proteins. Some GEFs are specific to a GTPase, while others
can modulate the activation of different families. Their counterparts, the
GAP proteins, are responsible for the hydrolysis of GTP into GDP. Their
function is therefore monomeric G protein inactivation and downregulation
of signaling events activated by GTPases. Certain GAPs are also considered
effector proteins because they can link activated GTPases to new down-
stream signaling events. In addition to the GAP domain, these regulatory
proteins also possess a large variety of domains that mediate their diverse
interactions with binding partners. GAPs generally act specifically on a fam-
ily of GTPase, but a few are known to exhibit dual specificity. Finally, as
discussed earlier, the function of some small GTP-binding proteins, namely,
Rho and Rab family members, is further regulated by GDIs. These prefer-
entially interact with the GDP-bound form to prevent nucleotide exchange.
By binding to inactive GTPases, it is believed that they serve to sequester and
release GTPases in a regulated fashion.
In most signaling pathways, activation of small GTPases is basally regu-
lated. However, in many cases, receptor stimulation promotes GTP loading
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