ARF-Like (ARL) Proteins - Ras Superfamily Small G Proteins: Biology and Mechanisms 2 - page 221

of STAT3 accumulated in the nucleus upon activation. Thus, the likely mechanism
of ARL2 in STAT3 signaling is as a nuclear retention signal for STAT3 as part of a
complex with BART and STAT3. It is unfortunate that more is not known about the
actions of ARL2 in the nucleus as indirect immunofluorescence staining of cells in
culture with ARL2-specific antisera shows a very strong signal there. The small size
of BART (19 kDa) and the permeability of the nuclear pore have made accurate
determination of the size of the nuclear pool of ARL2 by cell fractionation
impossible.
Finally, ARL2 has been linked to the transport of farnesylated GTPases outside
of the ARF family. The ARL2 binding partner PDE ʴ binds to farnesylated GTPases
and sequesters the hydrophobic moiety to increase solubility and promote transport
between membranes (Williams 2011 ). ARL2 binds PDE

directly and in a
GTP-dependent manner to stimulate the release of farnesylated Rheb or Ras from
PDE

ʴ

(Hanzal-Bayer et al. 2002 , 2005 ; Ismail et al. 2011 ). Several structural
studies of ARL2 and PDE

ʴ

ʴ suggest an allosteric mechanism of ARL2-stimulated

release of cargo from PDE (Renault et al. 2001 ; Hanzal-Bayer et al. 2002 ; Ismail

et al. 2011 ; Watzlich et al. 2013 ).
Interestingly, though less directly, ARL2 also has been linked to actin-based
cilia and functions in the inner ear. After the discovery of ELMOD2 as the first
ARL2 GAP (Bowzard et al. 2007 ; East et al. 2012 ) and description of its paralogs,
ELMOD1 and ELMOD3, as sharing GAP activity for members of the ARF family it
was recently discovered that mutations in each of these paralogs are linked to
deafness in mice (Johnson et al. 2012 ) and humans (Jaworek et al. 2013 ), respec-
tively. Though these GAPs were first discovered through actions as ARL2 GAPs
there is currently no evidence demonstrating a role for ARL2 in stereocilia or that
defects in ARL2 signaling contribute to deafness. Indeed, a recent study found that
ELMODs are very active as GAPs directed against a number of different members
of the ARF family (Ivanova et al. 2014 ). However, the fact that ELMODs are single
domain proteins, and that domain has been shown to be the GAP domain (East
et al. 2012 ), is strongly suggestive that one or more members of the ARF family will
be found to regulate key aspects of stereocilia development or biology.

ʴ

10.5 ARL GAPs

A wealth of information is currently available regarding ARF GEFs and ARF GAPs
and regulators of the two SARs (Casanova 2007 ; Gillingham and Munro 2007 ;
Kahn et al. 2008 ; Miller and Barlowe 2010 ; East and Kahn 2011 ; Schlacht
et al. 2013 ). Considerably less is known about the regulators of the ARL proteins
despite there being far more ARLs than ARFs. To date, only five GAPs for any of
the 22 mammalian ARLs have been identified and there are no known GEFs. The
five mammalian ARL GAPs include the three paralogous ELMO domain
containing proteins ELMOD1-3, cofactor C, and retinitis pigmentosa 2 (RP2)
(Bowzard et al. 2007 ; Veltel et al. 2008a ; Jaworek et al. 2013 ). In the yeast