The Role of ARF Family Proteins and Their Regulators and Effectors in Cancer Progression: A Therapeutic Perspective

Abstract

The Adenosine diphosphate-Ribosylation Factor (ARF) family belongs to the RAS superfamily of small GTPases and is involved in a wide variety of physiological processes, such as cell proliferation, motility and differentiation by regulating membrane traffic and associating with the cytoskeleton. Like other members of the RAS superfamily, ARF family proteins are activated by Guanine nucleotide Exchange Factors (GEFs) and inactivated by GTPase-Activating Proteins (GAPs). When active, they bind effectors, which mediate downstream functions. Several studies have reported that cancer cells are able to subvert membrane traffic regulators to enhance migration and invasion. Indeed, members of the ARF family, including ARF-Like (ARL) proteins have been implicated in tumorigenesis and progression of several types of cancer. Here, we review the role of ARF family members, their GEFs/GAPs and effectors in tumorigenesis and cancer progression, highlighting the ones that can have a pro-oncogenic behavior or function as tumor suppressors. Moreover, we propose possible mechanisms and approaches to target these proteins, toward the development of novel therapeutic strategies to impair tumor progression.

Roles for ELMOD2 and Rootletin in ciliogenesis

“…Members of the ARF (ADP-ribosylation factor) family of regulatory GTPases, as well as their downstream effectors and GTPase activating proteins (GAPs) that regulate their activities, drive an incredibly diverse array of cellular functions (Francis et al, 2016;Sztul et al, 2019;Casalou et al, 2020;Fisher et al, 2020). Consisting of 6 ARFs, 22 ARLs (ARF-like proteins), and 2 SARs in mammals, the ARF family is ancient, with multiple members traced back to the last eukaryotic common ancestor (Li et al, 2004).…”

“Roles for ELMOD2 and Rootletin in Ciliogenesis”

“…Members of the ARF (ADP-ribosylation factor) family of regulatory GTPases, as well as their downstream effectors and GTPase activating proteins (GAPs) that regulate their activities, drive an incredibly diverse array of cellular functions (Casalou et al, 2020; Fisher et al, 2020; Francis et al, 2016; Sztul et al, 2019). Consisting of 6 ARFs, 22 ARLs (ARF-like proteins), and 2 SARs in mammals, the ARF family is ancient, with multiple members traced back to the last eukaryotic common ancestor (Li et al, 2004).…”

Subversion of Ras Small GTPases in Cutaneous Melanoma Aggressiveness

“…However, Ras GTPases have been referred to as undruggable targets due to their structural features with limited small-molecule binding pockets ( O’Bryan, 2019 ). Additionally, one of the main barriers to the success of these approaches is the ubiquitous expression of most of these proteins among human tissues and their essential physiological functions for cell homeostasis and survival ( Casalou et al, 2020 ). Hence, the targeting of Ras GTPases could have harmful effects on tissues not affected by the disease.…”

“…Rat sarcoma (Ras) superfamily of small guanosine-5′-triphosphate (GTP)ases regulate many essential cellular activities such as cell signaling, membrane trafficking and cytoskeleton dynamics ( Vetter and Wittinghofer, 2001 ; Zhen and Stenmark, 2015 ; Casalou et al, 2016 , 2019 ; Toma-Fukai and Shimizu, 2019 ). Although Ras small GTPases control crucial physiological functions in cell homeostasis, several superfamily members are involved in the aberrant activation of signaling cascades that play a central role in a broad spectrum of human diseases, including cancer ( Aspenström, 2018 ; Casalou et al, 2020 ; Gopal Krishnan et al, 2020 ). In recent years, a growing interest in the functions of small GTPases in the context of cancer has emerged.…”