The formation of metastasis is one of the most critical problems in oncology. The phosphatase of regenerating liver 3 (PRL-3) is a new target in colorectal cancer mediating metastatic behavior through a promigratory function. However, detailed explanations for this effect have remained elusive. Here we show that PRL-3 is a specific interaction partner of the ADP-ribosylation factor 1 (Arf1). PRL-3 co-localizes with Arf1 in an endosomal compartment and associates with transmembrane proteins such as the transferrin receptor and α5-integrins. PRL-3 interacts with Arf1 through a distinct motif and regulates activation of Arf1. PRL-3-mediated migration depends on expression and activation of Arf1 and is sensitive to treatment with Brefeldin A. We also demonstrate that PRL-3 modulates recycling of α5-integrins and that its phosphatase activity as well as Arf activation and compartmentalization with Arf1 are required for this effect. In summary our data provide a new function for PRL-3 and identify Arf1 as a new PRL-3-dependent mediator of enhanced migration of cancer cells via enhanced recycling of matrix receptors

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