ARF-Like (ARL) Proteins - Ras Superfamily Small G Proteins: Biology and Mechanisms 2 - page 216

10.3 ARFRP1
ADP-ribosylation factor-related protein 1 (ARFRP1) was first discovered through
PCR-based screenings of cDNA libraries (Schurmann et al. 1995 ). ARFRP1 shares
only 33 % sequence identity with ARF1 and only slightly more with other ARLs, at
39 % identity with ARL3. ARFRP1 exhibits a low level of GAP-independent
hydrolysis of GTP, and thus may contrast to ARFs which have none. It also lacks
the N-terminal myristoylation site (glycine 2) found in ARFs and ARL1. Instead, it
was shown in yeast that N-acetylation of ARFRP1 is required for its localization to
the Golgi apparatus and that this is accomplished through interaction with the
integral membrane protein, Sys1p (Behnia et al. 2004 ; Setty et al. 2004 ). Note
that the S. cerevisiae ortholog of ARFRP1 continues to be named Arl3p, despite the
willingness of curators of other genomes to remedy this confusion. No GEFs or
GAPs have been identified for ARFRP1.
ARFRP1 localizes to the trans -Golgi, where its activity is required for ARL1
association with the same membranes (Setty et al. 2003 ; Behnia et al. 2004 ).
Knockdown of ARFRP1 in HeLa cells or knockout in mouse embryos abrogated
the Golgi association of ARL1 and its effectors, including Golgin-245 (Zahn
et al. 2006 ). Recruitment of these proteins to the Golgi was dependent upon the
GTP-bound, active state of ARFRP1. However, these conclusions may be in
contention as a later study found that ARFRP1 is not required for the Golgi
localization of ARL1 and its effectors (Nishimoto-Morita et al. 2009 ). This same
study showed distinct roles for ARFRP1 and ARL1 in Golgi-mediated anterograde
and retrograde transport, respectively. Export of vesicular stomatitis virus glyco-
protein G (VSV-G) from the trans -Golgi was inhibited by siRNA-mediated knock-
down of ARFRP1 in HeLa cells, but was unaffected by depletion of ARL1.
ARFRP1 is required for export of the planar cell polarity signaling protein,
Vangl2, through its interaction with AP-1, despite the fact that its traffic was
unaffected by ARL1 (Guo et al. 2013 ). The simplest explanation to reconcile the
different dependencies on ARL1 is simply that ARFRP1 uses multiple effectors and
only a subset depends upon ARL1 acting downstream.
ARFRP1 is an essential gene and is required for the proper sorting and traffic of
diverse signaling proteins. ARFRP1-null mice are embryonically lethal (Mueller
et al. 2002 ), likely resulting from defects in cell-cell adhesion, as the loss of
ARFRP1 leads to disruption of E-cadherin transport from the Golgi to the plasma
membrane (Zahn et al. 2008 ). Hepatocyte-specific knockout of ARFRP1 in mice
led to reduced expression and impaired transport of insulin-like growth factor
1 (IGF1) and the glucose transporter, GLUT2 (Hesse et al. 2012 ). These effects
led to reduced glycogen uptake and glucose storage in the liver, which ultimately
resulted in growth retardation at an early age. The absence of ARFRP1 in liver cells
also caused a reduction in lipidation and assembly of very low-density lipoproteins
(VLDLs), impairing the ability of the liver to recycle and redistribute lipids to other
organs in the body (Hesse et al. 2014 ).