b-Arrestins: Modulators of Small GTPase Activation and Function - Progress in Molecular Biology and Translational Science - page 145

of different and specific effector proteins. The GTP-bound state is there-
fore regarded as the active (ON) state. Typically, these proteins require gua-
nine nucleotide exchange factors (GEFs) to exchange GTP for GDP. Some
GTPases possess limited intrinsic GTPase activity, which depends on a few
conserved amino acids in critical positions. GTPase-activating proteins
(GAPs) activate the intrinsic GTPase activity, catalyzing the hydrolysis of
GTP into GDP. It is the interplay between the GTPases, the GEFs, and
the GAPs that coordinates signal transduction regulated by GTPases

( Fig. 6.1 ).
More than 150 small G proteins have been identified in humans. These
are traditionally classified into five families. 3 Ras proteins were the first
members of the entire superfamily and were initially discovered on the basis
of their homology to rat sarcoma virus genes. 4,5 The best-characterized
members are H-Ras, N-Ras, and K-Ras, which have been implicated in
many types of cancers and considered protooncogenes. However, the Ral
and Rap families of small GTPases also belong to this prototypical class of
more than 30 members. Members of the Ras homologous (Rho) family
comprise a second group of more than 20 proteins. The three major mem-
bers are Rho (A, B, C), Rac, 1-3 and Cdc42. This family of GTPase is well
known for its role in remodeling of the actin cytoskeleton and gene

Guanine nucleotide exchange factors
(GEF)

GDI

GDP

GTP

GTPase GTPase

Effectors

“OFF” “ON”

GTPase-activating proteins
(GAP)

Figure 6.1 Mode of activation of small GTPases. Small GTPases are inactive (OFF) when
bound to GDP and active when bound to GTP (ON). Cycling of these molecular switches
is controlled by the combined activities of guanine nucleotide exchange factors (GEFs),
which catalyze the exchange of GDP for GTP, and GTPase-activating proteins (GAPs),
which increase the rate of GTP hydrolysis. For some GTPases, another level of regulation
is provided by guanosine dissociation inhibitors (GDIs) that assure stability of the inac-
tive GDP-bound state. Upon their activation, GTPases control a broad variety of effectors
to regulate the timing, localization, and specificity of the cellular response.