Filling in the GAPs in the ADP-ribosylation factor story

Abstract

The GTP-binding proteins known as ADP-ribosylation factors (ARFs) function in cells to regulate membrane traffic and structure. Like all GTPases, ARFs cycle between a GDP-bound, inactive and a GTP-bound, active form. When GTP-bound, ARFs alter membrane lipid composition, assemble cytosolic coat proteins, and remodel actin associated with various membrane compartments. Although much of the research in the past has focused on the role of ARF1 in membrane trafficking and structure in the endoplasmic reticulum–Golgi system, there is increased interest in functions of ARF1 and the other five mammalian ARFs in the plasma and endosomal membrane systems. This interest has been fueled, in part, by the finding that ARF1 recruits coat proteins onto endosomal membranes and that ARF6 regulates membrane trafficking through endosomes and influences cortical actin at the plasma membrane (PM; refs. 1 and 2). Furthermore, over the years, there has been circumstantial evidence, although no direct proof, that the GTPase cycle of ARF could be coordinated by signaling from the PM. Several years ago, the growing list of guanine nucleotide exchange factors that catalyze exchange of GTP for GDP and convert ARFs to the active, GTP-bound state dominated the attention of those studying ARF proteins. Attention has now shifted to the function of the GTPase-activating proteins (GAPs), accessory molecules whose activities result in the hydrolysis of ARF-bound GTP and return ARFs to the inactive, GDP-bound state. These interesting multidomain GAPs, many of which have been identified over the past year and found to be peripherally localized, clearly do more than turn off ARF. They provide the link between the ARF GTPase cycle and various signal transduction events in the cell.