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RAB2A controls MT1‐MMP endocytic and E‐cadherin polarized Golgi trafficking to promote invasive breast cancer programs
Author(s) -
Kajiho Hiroaki,
Kajiho Yuko,
Frittoli Emanuela,
Confalonieri Stefano,
Bertalot Giovanni,
Viale Giuseppe,
Di Fiore Pier Paolo,
Oldani Amanda,
Garre Massimiliano,
Beznoussenko Galina V,
Palamidessi Andrea,
Vecchi Manuela,
Chavrier Philippe,
Perez Frank,
Scita Giorgio
Publication year - 2016
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201642032
Subject(s) - endocytic cycle , golgi apparatus , endosome , microbiology and biotechnology , rab , biology , gtpase , transport protein , endocytosis , cell , endoplasmic reticulum , intracellular , genetics
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.