ADP-ribosylation factor 6 regulation of phosphatidylinositol-4,5-bisphosphate synthesis, endocytosis, and exocytosis

Unlike other members of the ADP-ribosylation factor (ARF) family, Arf6 is localized to the plasma membrane and endosomes, and regulates membrane traffic from and into the plasma membrane. Arf6 regulates a clathrin-independent endocytic membrane recycling pathway in nonpolarized cells and clathrin-dependent endocytosis in polarized cells. It also regulates recycling endosome traffic back to the plasma membrane as well as dense-core vesicle exocytosis in neuroendocrine cells. A key effector for Arf6 is phosphatidylinositol 4-monophosphate 5-kinase, which catalyzes plasma membrane synthesis of phosphatidylinositol-4,5-bisphosphate (PIP(2)), a common required cofactor for several endocytic and exocytic membrane trafficking pathways. Long-term expression of a constitutively active Arf6 mutant in cells can lead to the depletion of PIP(2) from the plasma membrane, its accumulation in intracellular vacuoles, and the inhibition of PIP(2)-dependent membrane trafficking at the plasma membrane.