Biology Reference
In-Depth Information
analog of G
s
and G
i
since it copurified with G
bg
subunits.
73
Upon cloning of
the gene from a human placental library, it was renamed as the human
homolog of the yeast cell division cycle protein Cdc42.
74
Similar to other
GTPase of the Rho family, Cdc42 participates in actin remodeling. Activa-
tion of this isoform has been associated with filopodia formation as well as
numerous other cellular processes including cell cycle progression. Stimula-
tion of the serotonin 5-HT
7
receptor leads to activation of Cdc42 via a
mechanism involving G
a
12
in NIH3T3 cells.
75
The role of
b
-arrestins in the activation of this monomeric G protein was
studied in MEFs. It was previously reported that stimulation of the PAR2
receptor with a synthetic ligand (2-furoyl-LIGRL-
O
-NH
2
) promoted
Cdc42 deactivation in this cell line. However, this dampening of Cdc42 activ-
ity was not observed in double
b
-arrestin1/2 knock-out MEFs treated with
this agonist. Instead, a twofold increase in Cdc42 activation was reported.
Transfection of either
b
-arrestin1or
b
-arrestin 2 inhibited Cdc42 activation,
suggesting that both
b
-arrestin isoforms contributed to PAR2-mediated
Cdc42 deactivation.
25
Stimulation of numerous 7TM receptors has been
shown to promote Cdc42 activation. These include the endothelin, the
Ang II, adenosine, and the bradykinin receptors.
76-79
Whether
b
-arrestin reg-
ulates Cdc42 activation in response to these stimuli remains to be addressed.
The involvement of
b
-arrestins in regulation of Cdc42 by non-7TM
receptors has also been investigated. In an ovarian cancer cell line
(Ovca429), simple expression of the type III TGF
b
receptor (T
b
RIII) mark-
edly enhanced basal activation levels of Cdc42. Inhibition of
b
-arrestin 2
expression by transfection of specific siRNA inhibited this T
b
RIII-
mediated Cdc42 activation. Furthermore, expression of a mutant receptor
impaired in its ability to bind
b
-arrestin 2 (T
b
RIII
T841A
) failed to constitu-
tively activate the GTPase. These data suggest that the T
b
RIII/
b
-arrestin 2
interaction is essential for the activation of Cdc42.
26
4. RAB FAMILY GTPases
The Rab family of GTPases is the largest of the Ras superfamily of small
G proteins with over 60 members identified. The first
rab
gene was discovered
in yeast (SEC4/YPT1), and numerous mammalian homologs were subse-
quently cloned and named
rab
(
ras
-like in rat brain).
80,81
These small GTPases
are ubiquitously expressed, and although their structure is highly homologous,
their intracellular localization is quite diverse. Rab GTPases have been asso-
ciated with many steps of membrane trafficking such as vesicle formation,
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