title: ARAP1 regulates EGF receptor trafficking and signalling.
abstract: The activation state of the EGF receptor (EGF-R) is tightly controlled in the cell so as to prevent excessive signalling, with the dangerous consequences that this would have on cell growth and proliferation. This control occurs at different levels, with a key level being the trafficking and degradation of the EGF-R itself. Multiple guanosine triphosphatases belonging to the Arf, Rab and Rho families and their accessory proteins have key roles in these processes. In this study, we have identified ARAP1, a multidomain protein with both Arf GTPase-activating protein (GAP) and Rho GAP activities, as a novel component of the machinery that controls the trafficking and signalling of the EGF-R. We show that ARAP1 localizes to multiple cell compartments, including the Golgi complex, as previously reported, and endosomal compartments, where it is enriched in the internal membranes of multivesicular bodies. ARAP1 distribution is controlled by its phosphorylation and by its interactions with the 3- and 4-phosphorylated phosphoinositides through its five PH domains. We provide evidence that ARAP1 controls the late steps of the endocytic trafficking of the EGF-R, with ARAP1 knockdown leading to EGF-R accumulation in a sorting/late endosomal compartment and to the inhibition of EGF-R degradation that is accompanied by prolonged signalling.
authors.affiliation: Laboratory of Physiopathology of Secretion, Department of Cell Biology and Oncology, Consorzio Mario Negri Sud, 66030 Santa Maria Imbaro, Chieti, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Daniele
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Di Tullio
authors.forename: Michele
authors.initials: M
authors.lastname: Santoro
authors.forename: Gabriele
authors.initials: G
authors.lastname: Turacchio
authors.forename: Maria A
authors.initials: MA
authors.lastname: De Matteis