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very low GAP activity for ARL3 relative to RP2 (Veltel et al.
2008a
). Four residues
important for GAP activity of RP2, including its catalytic arginine, are also
conserved in cofactor C, suggesting a similar GAP domain and mechanism (Veltel
et al.
2008a
). That cofactor C exhibits such weak activity for ARL3 and no activity
for ARL2 may suggest that ARL3 is not the biological substrate of cofactor C in
cells or that those assays omitted important cofactors or co-regulators. These
findings are also intriguing because whereas ELMODs are GAPs with dual speci-
ficity for ARFs and ARLs, cofactor C and RP2 display dual specificity for ARLs
and tubulin. Better quantification of specific activities of each GAP against a broad
array of substrates would certainly help researchers assess the likely biological
significance of each GAP-GTPase pairing.
RP2 has been linked to the most severe form of retinitis pigmentosa and
contributes to the maintenance of photoreceptor function, most likely through its
role in regulating the traffic of proteins to the cilium. Several studies have reported
mutations in RP2 linked to retinitis pigmentosa in human families. Depletion of
RP2 in zebrafish or the targeted knockout of RP2 in mice resulted in retinal
degeneration (Schwahn et al.
1998
; Miano et al.
2001
; Shu et al.
2011
;Li
et al.
2013
). RP2 is ubiquitously expressed and localizes primarily to the plasma
membrane (Chapple et al.
2000
). RP2 also localizes to the basal body and
periciliary ridge of the cilium and to the Golgi complex (Evans et al.
2010
). RP2
and ARL3 facilitate vesicular traffic of proteins between the Golgi and the primary
cilium (Evans et al.
2010
). Co-expression of RFP-RP2 and ARL3[Q71L] resulted in
a redistribution of both proteins from the plasma membrane and cytosol, respec-
tively, to co-localize on intracellular vesicles. Using the well-studied cargo VSVG-
GFP as a marker for intracellular vesicles, knockdown of RP2 reduced both the
number of vesicles in cells and their average distance from the Golgi. Expression of
ARL3[Q71L] phenocopied this effect. Finally, RP2 and ARL3 are essential to the
maintenance of Golgi morphology as depletion of either by siRNA resulted in the
loss in Golgi morphology and dispersion throughout the cell (Zhou et al.
2006
;
Evans et al.
2010
). These data were taken as evidence that RP2 and ARL3 are
involved in regulating membrane traffic, though effectors or other details of mech-
anisms by which they do so are currently lacking.
RP2 is also involved in the transport of lipid-modified cargos to the cilium
through the HRG4 pathway discussed in the ARL2 and ARL3 sections of this
review. This transport is mediated by a ternary complex between RP2, ARL3, and
HRG4 (Veltel et al.
2008b
) and at least one cargo has been identified to use this
machinery (Wright et al.
2011
). RP2 and ARL3 are also necessary for the proper
localization of the G
ʲ
subunit of transducin to the plasma membrane which may
also use this transport mechanism (Schwarz et al.
2012b
). That a stable complex
forms including ARL3 and RP2 is consistent with its functioning as an effector of
ARL3 in this transport pathway.
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