Journal
TRAFFIC
Volume 9, Issue 12, Pages 2221-2235Publisher
WILEY-BLACKWELL
DOI: 10.1111/j.1600-0854.2008.00823.x
Keywords
ARAP1; EGF; EGF-R; endocytosis; MVB; RNAi; signalling; trafficking
Categories
Funding
- Foundation for Cancer Research [Fondazione Italiana per la Ricerca sul Cancro (FIRC)]
- Telethon and Italian Association for Cancer Research [Associazione Italiana per la Ricerca sul Cancro (AIRC)].
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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.
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