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proliferation while RalB is critical for cell viability.
38,39
In some signaling
pathways, Ral acts downstream of Ras. For example, Ras-mediated onco-
genic transformation and propagation of mitogenic signals have been shown
to require signaling via RalGEFs, considered direct effectors of Ras.
40
It is
generally accepted that binding of RalGEFs to activated Ras is responsible
for Ral activation.
41
Activation of Ral-dependent, but Ras-independent,
signaling pathways has also been identified. For example, this family of small
GTPases can be activated following calcium influx.
42
Furthermore, formyl-
Met-Leu-Phe (fMLP) stimulation promotes Ral activation by a mechanism
involving a GEF, RalGDS.
18
RalGDS was first identified as a binding partner for H-Ras and
R-Ras.
43,44
The CDC25 GEF domain and the Ras-binding domain are
responsible for the ability of RalGDS proteins to mediate cross talk between
Ras and Ral in the context of EGF receptor activation.
45
However, Ras-
independent mechanisms of RalGDS activation have also been reported.
In a yeast two-hybrid assay, this RalGEF was identified as a binding partner
for
b
-arrestin. The interaction of RalGDS with
b
-arrestin 1 was subse-
quently confirmed by coimmunoprecipitation experiments.
18
The two pro-
teins interact in the cytosol in the absence of stimulation, and it has been
proposed that
b
-arrestin 1 serves to maintain RalGDS in an inactive state.
Stimulation by fMLP destabilized the interaction leading to rapid dissocia-
tion of RalGDS and relocalization of the GEF to its GTPase at the plasma
membrane. Interestingly, translocation of
b
-arrestin to the plasma mem-
brane contributed, in part, to the redistribution of RalGDS to sites of mem-
brane ruffling. Attenuation of the ruffling response correlated with the
reassociation of
b
-arrestin 1 with RalGDS in the cytosol. The
b
-arrestin/
RalGDS/Ral signaling axis, therefore, plays a key role in fMLP-stimulated
plasma membrane ruffling in HEK293 cells as well as to chemoattractant
receptor signaling in hematopoietic cell lines.
18
A role for RalA was also
observed in the context of second messenger production following stimu-
lation of the AT
1
R. In HEK293 cells, Ang II stimulation is known to pro-
mote inositol phosphate (IP) synthesis following activation of G
a
q
and PLC.
A careful examination of this signaling pathway has revealed that for this
receptor, the
b
-arrestin-dependent translocation of RalGDS is required
for the activation of RalA, which controls PLC-
d
1 activity and generation
of IP.
9
Ral GTPases were also reported to stimulate breast cancer cell pro-
liferation and metastasis.
46-48
Rals, as well as
b
-arrestins, are aberrantly
expressed in human breast tumors, and knockdown of either
b
-arrestin or
Ral reduced the ability of invasive breast cancer cells to migrate and
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