Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

ARF1

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101488

Synonyms

Historical Background

The ADP-ribosylation factor 1 (ARFA1) was first identified as a cellular activity required for cholera toxin to ADP-ribosylate the Gs heterotrimeric G protein and exert its toxic effect (Kahn and Gilman 1986; O’Neal et al. 2005). This ADP-ribosylation factor (ARF) activity is shared by several closely related proteins, which were later numbered ARF1–ARF6, although ARF2 (a close relative of ARF1) is present in mice and rats but not in humans (Boman and Kahn 1995). However, the endogenous roles of ARF1–6 do not involve ADP-ribosylation, but rather participation in membrane traffic and organization of the cytoskeleton.

Regulation of ARF1 Activity

ARF1 is a member of the Ras superfamily, which can be divided into five major families: ARF, Rab, Ran, Ras, and Rho (Wennerberg et al. 2005). The members of the ARF family are sometimes called GTPases, but they cannot hydrolyze GTP in the absence of a GTPase-activating protein (GAP) and this is their specific characters.

ARF1 is 20 kDa GTP-binding proteins. ARF1 contains an N-terminal amphipathic helix, which is N-terminally myristoylated. When ARF1 becomes GTP binding form, this myristoylation enables ARF1 to anchor itself to target membrane. ARF1 protein has switch regions that change conformation upon GTP binding, and its interswitch region is also mobile (Goldberg 1998; Pasqualato et al. 2002) (Fig. 1). Upon GTP binding, the interswitch moves away from the switch regions and displaces the N-terminal helix from a pocket it occupies in the GDP-bound state. This amphipathic helix (modeled for ARF1-GTP) is thus encouraged to interact with an adjacent lipid bilayer and ARF1 exert its roles in vesicle formation.
ARF1, Fig. 1

Domain structure of ARF1. Domains found in the human ARF1 protein (NCBI accession: NP_001694.1) are schematically shown. Myristoyl N-terminally myristoylated, Amph an N-terminal amphipathic helix, Swich1 Swich1 region, Switch2 Switch2 region, Interswitch Interswitch region

Role of ARF1 in Vesicule Formation

ARF1 regulates vesicle formation on intracellular membranes. The budding of vesicles from Golgi cisternae is fully reconstituted in the presence of ARF1 and coatomer (COPI) (Ostermann et al. 1993; Rothoman and Wieland 1996; Donaldson and Jackson 2011). ARF1 recruits coatomers to budding vesicles and is then released from these vesicles to stimulate their uncoating and fusion with target membranes (Ostermann et al. 1993; Tanigawa et al. 1993) and COPI on the endoplasmic reticulum (Bednarek et al. 1995; Nie et al. 2003). The coupling of ARF1 and Cdc42 activities regulates endocytosis at the plasma membrane. Thus, endocytosis and secretion share the common regulator ARF1, which provides a molecular basis for crosstalk between these two processes (Kumari and Mayor 2008). In addition, ARF1 may also function in the control of integrin-mediated cell adhesion (Norman et al. 1998).

ARF1 and Closely Related Family Member ARF2-5 Complement Each Other

The endogenous roles of ARF1–6 do not involve ADP-ribosylation or regulation of heterotrimeric G proteins, but rather participation in membrane traffic and organization of the cytoskeleton. ARF1–6 are related to a wider set of small G proteins that do not have ARF activity but share with ARF1–6 a set of structural features that defines a larger Arf family (Pasqualato et al. 2002).

Small interfering RNA can be used to specifically deplete each human Arf and thereby examine the roles of Arf1–5 in live cells (Volpicelli-Daley et al. 2005). Surprisingly, no single Arf, including ARF1, is required for Golgi function or any step of membrane trafficking examined in HeLa cells. Instead, pairs of Arfs cooperate at particular steps. For example, Arf1 and Arf4 act redundantly during transport in the early secretory pathway. These results suggest that the cooperation of two or more Arfs at the same site is a general feature of Arf signaling. This is supported by the fact that yeast has two Arfs and that the disruption of both genes is lethal; thus Arfs are essential for mitotic growth in yeast. Although many cell biological and biochemical analyses have proven the importance of ARF1, the physiological role of ARF1 in mice, as well as the cooperation of two or more Arfs at the same site, remains to be elucidated.

ARF1 in Embryogenesis

To investigate the activity of ARF1 in vivo, Hayakawa et al. established ARF1-deficient (Arf−/−) mice, which lacked the entire open reading frame of ARF1 (Hayakawa et al. 2014). Arf1(−/−) blastocysts were indistinguishable from wild-type and heterozygous (Arf+/−) blastocysts and grew normally in an in vitro culture system. Arf (−/−) embryos were degenerated at E5.5, and no viable Arf (−/−) pups were born, suggesting that Arf (−/−) embryos died soon after implantation. These results show that ARF1 is indispensable for mouse embryonic development after implantation.

ARF1 in Cancer

ARF1 plays important roles in many biological functions. For example, ARF1 regulates epidermal growth factor-dependent breast cancer cell invasion, growth, and migration (Boulay et al. 2008; Schlienger et al. 2014). Phosphatase of regenerating liver 3 exerts a promigratory role through the activation of ARF1, inducing faster trafficking of integrin molecules in colorectal cancer (Krndija et al. 2012). Therefore, the inhibitors of ARF1 were developed with the expectation that they would be valuable tools to study membrane trafficking and also be anticancer drug candidates (Ohashi et al. 2012).

Summary

ARF1 is 20 kDa GTP-binding proteins. ARF1 contains an N-terminal amphipathic helix, which is N-terminally myristoylated. When ARF1 become GTP binding form, this myristoylation enables ARF1 to anchor itself to target membrane. ARF1 regulates vesicle formation on intracellular membranes. The budding of vesicles from Golgi cisternae is fully reconstituted in the presence of ARF1 and coatomer (COPI). The coupling of ARF1 and Cdc42 activities regulates endocytosis at the plasma membrane. Thus, endocytosis and secretion share the common regulator ARF1, which provides a molecular basis for crosstalk between these two processes. In addition, ARF1 may also function in the control of integrin-mediated cell adhesion. ARF1 is indispensable for mouse embryonic development after implantation. ARF1 regulates epidermal growth factor-dependent breast cancer cell invasion, growth, and migration. Phosphatase of regenerating liver 3 exerts a promigratory role through the activation of ARF1, inducing faster trafficking of integrin molecules in colorectal cancer. Therefore, inhibitors of ARF1 were developed with the expectation that they would be valuable tools to study membrane trafficking and also be anticancer drug candidates.

References

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Biological ScienceGraduate School of Humanities and SciencesNaraJapan
  2. 2.Department of Cell SignalingInstitute of Biomedical Science, Kansai Medical UniversityHirakataJapan