ArfGAPs: Not Only for the Termination - Ras Superfamily Small G Proteins: Biology and Mechanisms 2 - page 257

through this binding, AMAP1 is involved in EGFR recycling (Kowanetz
et al. 2004 ).
We have originally identified ASAP1 as PAG2 (Kondo et al. 2000 ), and now call
it AMAP1 following the proposal by Kahn ( 2003 ). We have shown that AMAP1 is
overexpressed frequently in malignant and invasive breast cancers, and plays
essential roles in cancer invasion (Onodera et al. 2005 ). Overexpression of the
AMAP1 protein was also observed in colorectal cancers, and correlated with
metastasis and poor prognosis of the patients (M¨ ller et al. 2010 ). AMAP1 was
found to bind to PRKD2 (protein kinase D2) and to form a complex with β 1 integrin
in breast cancer cells; and hence promotes the recycling of β 1 integrins upon EGF
stimulation (Onodera et al. 2012 ). The AMAP1 and CIN85 complex was also found
to localize to the invadopodia of breast cancer cells, and CIN85-mediated
monoubiquitination of AMAP1 by Cbl was shown to be crucial for invasion activity
(Nam et al. 2007 ). GEP100 acts as a GEF for Arf6 in cancer invasion (Morishige
et al. 2008 ). Co-overexpression of AMAP1and GEP100 was found to correlate with
rapid local recurrence in breast cancer patients after breast conservative therapy
(Kinoshita et al. 2013 ).

11.9 ACAP Subfamily

ACAP1 and ACAP2 were identified using cDNA databases, by searching for
proteins with predicted structural similarity to ASAPs (Jackson et al. 2000 ). They
possess the BAR domain, the PH domain, the GAP domain, and three ANK repeats.
ACAP is an acronym for ArfGAP proteins with coiled-coil, ANK repeat and PH
domain. ACAPs were shown to exhibit GAP activity preferentially toward Arf6
in vitro and in vivo (Jackson et al. 2000 ). ACAP1/2 primarily function at the cell
periphery, and colocalize with Arf6 (Jackson et al. 2000 ).
ACAP1 is a key component of the clathrin coat complex, in which Arf6
regulates the recycling of the transferrin receptor (TfR) (Dai et al. 2004 ), integrin
(Li et al. 2005 ), and Glut4 (glucose transporter type 4), which is required for
glucose homeostasis (Li et al. 2007 ). ACAP1 was shown to promote the sorting
of TfR, its cargo, through recognition of the sorting signals present in the cytoplas-
mic domain of TfR (Dai et al. 2004 ), and ACAP1 may hence promote TfR recycling
from recycling endosomes.
Regulation of 1 integrin recycling by ACAP1 was shown to require the

phosphorylation of ACAP1 by Akt (Li et al. 2005 ). A linker region between the
GAP and ANK domains acts to prevent

β

1 integrin binding, and phosphorylation at
Ser554 by Akt within the linker region relieves this autoinhibition (Bai et al. 2012 ).
Signaling from different growth factors enhances the Ser554 phosphorylation by
Akt and promotes binding of ACAP1 to the sorting signal of

β

1 integrin, which
results in enhanced integrin recycling (Li et al. 2005 ; Bai et al. 2012 ).
Integrins are involved in axon growth and regeneration. Suppression of Arf6
activation by ACAP1 was shown to increase the recycling of

β

β 1 integrins to the cell