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Nature Cell Biology 6, 393–404 (1 May 2004) | doi:10.1038/ncb1119

FAPPs control Golgi-to-cell-surface membrane traffic by binding to ARF and PtdIns(4)P

Anna Godi , Antonella Di Campli , Athanasios Konstantakopoulos , Giuseppe Di Tullio , Dario R. Alessi , Gursant S. Kular , Tiziana Daniele , Pierfrancesco Marra , John M. Lucocq & M. Antonietta De Matteis

The molecular mechanisms underlying the formation of carriers trafficking from the Golgi complex to the cell surface are still ill-defined; nevertheless, the involvement of a lipid-based machinery is well established. This includes phosphatidylinositol 4-phosphate (PtdIns(4)P), the precursor for phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2). In yeast, PtdIns(4)P exerts a direct role, however, its mechanism of action and its targets in mammalian cells remain uncharacterized. We have identified two effectors of PtdIns(4)P, the four-phosphate-adaptor protein 1 and 2 (FAPP1 and FAPP2). Both proteins localize to the trans-Golgi network (TGN) on nascent carriers, and interact with PtdIns(4)P and the small GTPase ADP-ribosylation factor (ARF) through their plekstrin homology (PH) domain. Displacement or knockdown of FAPPs inhibits cargo transfer to the plasma membrane. Moreover, overexpression of FAPP-PH impairs carrier fission. Therefore, FAPPs are essential components of a PtdIns(4)P- and ARF-regulated machinery that controls generation of constitutive post-Golgi carriers.