Biology Reference
In-Depth Information
Figure 10.2 A model for ARF6 function in the control of membrane recycling at the
plasma membrane. Engagement of surface receptors such as FcRs on macrophages triggers
the activation of ARF6 at the plasma membrane. The signalling cascades leading to GTP-
loading on ARF6 are not precisely known. They probably involve Sec7 domain-containing
GEFs belonging to the ARNO and EFA6 families. Accumulation of GTP-bound ARF6
leads to the recruitment and activation of specific effector proteins, including PLDs and
PIP 5K. Production of PA and PIP
2
by these enzymes participates in the remodelling of the
plasma membrane and of the cortical actin cytoskeleton. Yet unknown ARF6-specific
effectors are probably also involved in controlling the delivery and fusion of recycling
vesicles from the endosomes. Membrane recycling is essential for the formation of
membrane protrusions such as pseudopods during phagocytosis, or lamellipodia at the
leading edge of migrating cells
surface (D'Souza-Schorey et al., 1995). Along similar lines, treatment of HeLa
cells over-expressing ARF6 with aluminium fluoride (AlF) was found to
trigger the formation of actin-based membrane protrusions that contained
ARF6 (Radhakrishna et al., 1996, 1999; Radhakrishna and Donaldson, 1997).
Although the mechanism of action of AlF on ARFs is mysterious and may
even be indirect through heterotrimeric G proteins, Donaldson and colleagues
have proposed that ARF6 activation (by AlF) induces transport of
membranes from recycling endosomes to the plasma membrane and influences
the actin cytoskeleton along the plasma membrane. Of special note, in
contrast to the situation in CHO cells, ARF6 was found to regulate tra
c of
membrane between the plasma membrane and a non-clathrin-derived early
endosomal compartment in HeLa cells (Radhakrishna and Donaldson, 1997).
Finally, it has been reported that the active ARF6Q67L mutant stimulates
clathrin-mediated endocytosis in epithelial Madin-Darby Canine Kidney cells
(Altschuler et al., 1999; Palacios et al., 2001). Interestingly, ARF6-induced
activation of the clathrin-dependent pathway was found to affect epithelial
