ArfGAPs: Not Only for the Termination - Ras Superfamily Small G Proteins: Biology and Mechanisms 2 - page 259

Therefore, aberrantly high expression of AGAP2 appears to contribute to both the
initiation and progression of carcinogenesis (Cai et al. 2009 ).

11.11 ARAP Subfamily

ARAP1 and ARAP2 were identified by their homology with other ArfGAPs (Miura
et al. 2002 ). ARAP3 was identified using a phosphoinositide-affinity matrix, as a
phosphatidylinositol (3,4,5)-trisphosphate (PI(3,4,5)P 3 )-binding protein
(Krugmann et al. 2002 ). ARAPs are the most structurally complex members of
the ArfGAPs, and contain the SAM (sterile

motif) domain, 5 PH domains, the
Rho-GAP domain, the Ras-association domains, and ANK repeats, besides the
GAP domain. ARAPs show PI(3,4,5)P 3 -dependent GAP activity toward Arf6
(Miura et al. 2002 ; Krugmann et al. 2002 ; Yoon et al. 2006 ).
ARAP1 localizes to the plasma membrane, the Golgi complex, and endosomal
compartments, such as recycling endosomes, late endosomes/multivesicular bodies
(MVBs), and lysosomes. The subcellular localization of ARAP1 appears to be
controlled by its phosphorylation, and also by its interaction with 3- and
4-phosphorylated phosphoinositides through its 5 PH domains (Daniele
et al. 2008 ). It was shown that EGF stimulation causes the translocation of
ARAP1 to endocytic compartments to colocalize with ligand-bound EGFR at
endosomes in order to regulate the attenuation of EGFR signal transduction
(Daniele et al. 2008 ; Yoon et al. 2008 ). ARAP2, which is different from ARAP1
and ARAP3, lacks RhoGAP activity, and likely functions as a Rho effector. ARAP2
localizes to the cell periphery and on focal adhesions composed of paxillin and
vinculin, and contributes to the assembly of both stress fibers and focal adhesions
(Yoon et al. 2006 ). ARAP3 is mostly localized in the cytoplasm (Krugmann
et al. 2002 ). Addition of EGF to PC12 cells caused a rapid translocation of some
of the GFP-ARAP3 to the plasma membrane, and addition of PDGF to PAE cells
caused some translocation of GFP-ARAP3 to the ruffling edges of lamellipodia
(Krugmann et al. 2002 ).

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11.12 How Is the Timing of GTP Hydrolysis by ArfGAPs
Controlled?

As already mentioned above, one of the representative classical model of vesicle
formation, which was mostly based on the possible interaction of Arf1 and
ArfGAP1, is as follows (Rothman and Wieland 1996 ; Schekman and Orci 1996 ;
Roth 1999 ). Arf1, when activated, initiates membrane budding by recruiting the
COP-I complexes. Assembly and accumulation of the COP-I complexes then
generate curved membranes. ArfGAP1 possesses the ALPS motif, which binds to