Models for the functions of Arf GAPs

Abstract

Arf GAPs (ADP-ribosylation factor GTPase-activating proteins) are essential components of Arf (ADP-ribosylation factor) signaling pathways. Arf GAPs stimulate the hydrolysis of GTP to GDP to transition Arf from the active, GTP bound, state to the inactive, GDP bound, state. Based on this activity, Arf GAPs were initially proposed to function primarily or exclusively as terminators of Arf signaling. Further studies of Arf GAPs have revealed that they also function as effectors of Arf signaling in at least a few steps or processes in which Arfs are not directly involved. In this review we discuss the non-canonical functions of Arf GAPs and address several key questions in the field, including: whether (1) Arf GAPs are terminators or effectors of Arf signaling, (2) Arf GAPs positively or negatively regulate COPI assembly, (3) Arf GAPs are involved in vesicle fission, and (4) Arf GAPs regulate vesicle uncoating.

Figure 1

Model of Arf GAP functions in Arf-dependent signaling and termination. The GTP cycle of Arf depends upon Arf GEFs to facilitate the exchange of bound GDP for GTP and Arf GAPs to stimulate hydrolysis of GTP to GDP. GTP binding by Arf induces a conformational change that increases the affinity of Arf for effector proteins ultimately leading to a biological response, mediated by effectors. As discussed in the text, association with Arf GAPs or with Arf GAP/effector complexes also results in biological responses, suggesting that Arf GAPs can serve as Arf effectors. Thus, Arf GAPs have at least dual roles in regulating Arf signaling as terminators and effectors. This conclusion also points to the regulation of Arf GAP activity as a critical, yet understudied, aspect of Arf and Arf GAP signaling.