ARF: the most misunderstood GTPase I ever knew

Paul Randazzo^1,2*Rachel E Turn³Joel Bryan Dacks⁴Olivier Soubias²Eric M Rosenberg, Jr²John K Northup⁵

• ¹independent researcher, Bethesda, United States
• ²National Cancer Institute Center for Cancer Research, Bethesda, United States
• ³Stanford University, Stanford, United States
• ⁴University of Alberta, Edmonton, Canada
• ⁵National Institutes of Health, Bethesda, United States

ADP-ribosylaUon factors (ARFs) are GTP binding proteins that were discovered in the early 1980s, shortly a\er heterotrimeric GTP-binding proteins (G proteins) and nearly simultaneously with Ras. G proteins were the basis for the signaling paradigm that has been broadly applied to GTPases, including both RAS and ARF. In this paradigm, GTP-binding proteins act as switches. When converted from the GDP-bound form to the GTP-bound form, GTPases bind effector proteins to transduce a signal. This paradigm is consistent, at least in part, with RAS funcUon as RAS•GTP acUvates effectors to drive cellular responses such as proliferaUon. ARF, on the other hand, funcUons outside of this paradigm, at least in its first discovered physiological role: regulaUon of membrane traffic. Nevertheless, ARFs are o\en generalized as "on" and "off" switches controlling signaling pathways. Here, we (i) briefly describe the history of the discoveries of three families of GTPases to provide understanding of the genesis of the G protein signaling model, (ii) enumerate some key differences between ARFs vs RAS and G proteins (which beeer fit the paradigm of molecular switches) and (iii) describe an alternate model for ARFs in which their cycling between GTP binding and hydrolysis mediates cellular acUviUes, rather than ARFs acUng as mediators in a signaling cascade. Furthermore, we highlight the key role of GTPase-acUvaUng proteins (GAPs) as integral to ARF funcUon.