Fig. 4

A model for the cyclic activation and inactivation of ARF1 during GPCR-stimulated neutrophil chemotaxis. (a) RAC2 is crucial for the generation of actin-based leading edges in neutrophils, whereas RAC1 is important for directional migration. Polarized activation of GPCR at cell surface areas facing a chemoattractant gradient, such as by fMLP, releases the Gβγ subunit, which leads to RAC2 activation via the production of PI(3, 4, 5)P₃ upon activation of PI3Kγ by Gβγ, to generate the actin-based leading edge [2, 31]. GBF1 is recruited to the leading edge from the Golgi, also by the Gβγ-PI3Kγ-mediated production of PI(3, 4, 5)P₃. Gβγ proteins may furthermore form a complex with PAK1-αPIX at the leading edges. (b) GBF1 then recruits and activates ARF1 at the leading edges, although the mechanism by which ARF1 is recruited by GBF1 remains unknown. (c) The activated ARF1 then recruits RAC1 and GIT2 to the leading edges. (d) RAC1 is activated by αPIX and functions with PAK1. Integration of GIT2 into the Gβγ-PAK1-αPIX complex provides a mechanism by which ARF1 can be inactivated when RAC1 becomes activated and functional. This system may enable the cyclic activation and inactivation of ARF1 for the repetitive recruitment of RAC1 molecules into the growing leading edges, culminating in the directional migration of GPCR-stimulated neutrophils. On the other hand, GTP-ARF1 and GTP-RAC1 need to function together to perform certain cellular functions (see Text). Thus, ARF1 might not always be inactivated when RAC1 is activated, and the timing of ARF1 inactivation by the Gβγ-PAK1-αPIX-GIT2 complex might be controlled by unknown mechanisms