RAB2A controls MT1‐MMP endocytic and E‐cadherin polarized Golgi trafficking to promote invasive breast cancer programs |
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| Authors: | Hiroaki Kajiho Yuko Kajiho Emanuela Frittoli Stefano Confalonieri Giovanni Bertalot Giuseppe Viale Pier Paolo Di Fiore Amanda Oldani Massimiliano Garre Galina V Beznoussenko Andrea Palamidessi Manuela Vecchi Philippe Chavrier Frank Perez Giorgio Scita |
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| Affiliation: | 1. IFOM, the FIRC Institute of Molecular Oncology, Milan, Italy;2. Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan;3. Molecular Medicine Program, European Institute of Oncology, Milan, Italy;4. Department of Oncology and Hemato‐Oncology, Università degli Studi di Milano, Milan, Italy;5. Department of Pathology, European Institute of Oncology, Milan, Italy;6. Institut Curie, PSL Research University, Paris Cedex 05, France;7. Centre National de la Recherche Scientifique, Unité Mixte de Recherche 144 CNRS, UMR 144, Paris Cedex 05, France |
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| Abstract: | The mechanisms of tumor cell dissemination and the contribution of membrane trafficking in this process are poorly understood. Through a functional siRNA screening of human RAB GTPases, we found that RAB2A, a protein essential for ER‐to‐Golgi transport, is critical in promoting proteolytic activity and 3D invasiveness of breast cancer (BC) cell lines. Remarkably, RAB2A is amplified and elevated in human BC and is a powerful and independent predictor of disease recurrence in BC patients. Mechanistically, RAB2A acts at two independent trafficking steps. Firstly, by interacting with VPS39, a key component of the late endosomal HOPS complex, it controls post‐endocytic trafficking of membrane‐bound MT1‐MMP, an essential metalloprotease for matrix remodeling and invasion. Secondly, it further regulates Golgi transport of E‐cadherin, ultimately controlling junctional stability, cell compaction, and tumor invasiveness. Thus, RAB2A is a novel trafficking determinant essential for regulation of a mesenchymal invasive program of BC dissemination. |
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| Keywords: | cancer migration and invasion membrane trafficking RAB2A RAB GTPases |
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