ArfGAPs: Not Only for the Termination - Ras Superfamily Small G Proteins: Biology and Mechanisms 2 - page 254

Cdc42 and the dynamics of actin fibers under integrins (Brown et al. 2002 ; Premont
et al. 2004 ). Under GPCRs, Git2 is integral for chemotaxis and the suppressive
control of superoxide production in neutrophils, by forming the G βʳ -Pak1-

Pix -Git2 signaling axis upon GPCR activation (Mazaki et al. 2006 ). Git1 functions

under ephrin receptor A2 (EphA2) in epithelial cells, in which Git1 suppresses Arf6
activity in order to block the endocytosis of E-cadherin during cell-cell contacting,
and hence contributes to the maturation of adherence junctions as well as the tight
junction (Miura et al. 2009 ). Likewise, Git1 also plays a role in the negative
regulation of clathrin-dependent endocytosis. Arf6 has been shown to play a key
role in the formation of clathrin-coated pits, in which Arf6 is activated by ARNO
(Claing et al. 2001 ).
Suppression of Arf6 activity by Git1 was shown to suppress the internalization
of GPCRs, such as

ʱ

2 adrenergic receptors and the M1 muscarinic receptor,
and ligand-activated EGFR, all of which are otherwise thought to be internalized
via clathrin-coated pits (Claing et al. 2000 , 2001 ).
Slit2-Roundabout4 (Robo4) signaling is known to inhibit the migration of cells
toward a chemoattractant gradient (Park et al. 2003 ; Seth et al. 2005 ). In endothelial
cells, Slit2-Robo4 signaling blocks Arf6 and Rac activation in response to VEGFR
and integrin activation. Concomitant initiation of Slit2-Robo4 signaling stimulates
the recruitment of the paxillin and Git1 complex to the cytoplasmic tail of Robo4,
which induces the inactivation of Arf6 and Rac. Blocking of this protrusive activity
is necessary for vascular stability (Jones et al. 2009 ).
Blocking of Arp2/3-dependent actin polymerization by PICK1 is one of the main
mechanisms for AMPA receptor (AMAPR) internalization and long-term depres-
sion (LTD) (Rocca et al. 2008 ; Nakamura et al. 2011 ). PICK1 was shown to be an
Arf1 effector. GTP-Arf1 inhibits the PICK1-mediated inhibition of Arp2/3-
dependent actin polymerization. NMDA receptor activation leads to the activation
of Git1, which inhibits Arf1 activity and then activates PICK1. The Git1-Arf1-
PICK1-Arp2/3 pathway appears to regulate LTD via AMPAR internalization
(Rocca et al. 2013 ).
In bone metabolism, Git2, but not Git1, was reported to be involved in the
suppression of Arf6 activity, for the proper maintenance of the polarity of osteo-
clasts (Heckel et al. 2009 ).
Pathologically, Gits are involved in Huntington's disease. Git1 interacts with the
N-terminal region of huntingtin (HTT), which contains a polyglutamine domain,
and this interaction results in the augmentation of HTT levels (Blagoveshchenskaya
et al. 2002 ; Goehler et al. 2004 ). Git1 was moreover implicated in attention deficit
hyperactivity disorder (ADHD) in humans (Won et al. 2011 ) and the infection of
HIV (Hoefen and Berk 2006 ).

β 1 and β