1. RAB2A controls MT1‐MMP endocytic and E‐cadherin polarized Golgi trafficking to promote invasive breast cancer programs
- Author
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Giovanni Bertalot, Manuela Vecchi, Emanuela Frittoli, Pier Paolo Di Fiore, Hiroaki Kajiho, Galina V. Beznoussenko, Frank Perez, Andrea Palamidessi, Giuseppe Viale, Giorgio Scita, Yuko Kajiho, Stefano Confalonieri, Massimiliano Garrè, Amanda Oldani, and Philippe Chavrier
- Subjects
0301 basic medicine ,Endosome ,Endocytic cycle ,Cell ,Gene Expression ,Golgi Apparatus ,Breast Neoplasms ,Endosomes ,GTPase ,Biology ,Biochemistry ,Exocytosis ,03 medical and health sciences ,symbols.namesake ,Recurrence ,Cell Line, Tumor ,Biomarkers, Tumor ,Matrix Metalloproteinase 14 ,Genetics ,medicine ,Humans ,Neoplasm Invasiveness ,Gene Silencing ,Molecular Biology ,Homeodomain Proteins ,Cadherin ,Gene Expression Profiling ,Tumor Suppressor Proteins ,Mesenchymal stem cell ,Articles ,Golgi apparatus ,Cadherins ,Prognosis ,Extracellular Matrix ,Cell biology ,Protein Transport ,030104 developmental biology ,medicine.anatomical_structure ,rab GTP-Binding Proteins ,Proteolysis ,symbols ,Female ,Rab - 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.
- Published
- 2016
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