ArfGAPs: Not Only for the Termination - Ras Superfamily Small G Proteins: Biology and Mechanisms 2 - page 261

Fig. 11.2 A classical model of the activity of ArfGAPs, primarily based on the possible interac-
tion of ArfGAP1 with GTP-Arf1. GTP-Arf1 recruits the COP-I complexes to initiate membrane
budding, in which assembly and accumulation of the COP-I complexes generate curves in the
membranes. ArfGAP1 is then recruited to these curved membranes via its ALPS motif, to be
localized in proximity to GTP-Arf1, in order to hydrolyze GTP and hence release Arf1 from the
vesicle. On the other hand, the dissociation of COP-I from vesicles appears to be unnecessary for
the hydrolysis of GTP and the release of Arf1
(Donaldson and Jackson 2011 ). This property of Arf6 may be crucial for its role in
membrane “recycling,” in order to memorize which compartments of membranes
should be brought back to the recycling processes. On the other hand, we have
previously discussed a possible reason why AMAP1 and AMAP2 nevertheless
exhibit GAP activity toward other Arfs, like Arf1 and Arf5, in the presence of
Mg 2+ (Sabe 2003 ).
Dysregulation of Ca 2+ homeostasis has long been highly implicated in the
development of cancer malignancy, including invasiveness and metastatic poten-
tials (Prevarskaya et al. 2011 ). The AMAP1 protein is overexpressed in most
malignant breast cancers, and constitutes a core component of the Arf6-based
invasion machinery (Onodera et al. 2005 , 2012 ). Expression of the ASAP3/
DDEFL1 gene is also upregulated in hepatocellular carcinomas (Okabe
et al. 2004 ), and overexpression of the AMAP1 gene was shown to be associated
with malignant phenotypes of colorectal cancer (M¨ ller et al. 2010 ), uveal mela-
nomas (Ehlers et al. 2005 ), prostate cancer (Lin et al. 2008 ), and pancreatic
carcinoma and adenocarcinoma (Harada et al. 2009 ). These bodies of information
support the idea that the above hypothesis deserves further experimental scrutiny to
clarify the following: (1) what kinds of the stimuli that induce intracellular free
Ca 2+ to activate the GAP activity of AMAPs/ASAPs, and (2) whether a Mg 2+ ion, if
it preoccupies ArfGAPs, can be replaced by a Ca 2+ ion within the same ArfGAP
molecule.