TY - JOUR
T1 - RAB2A controls MT1-MMP endocytic and E-cadherin polarized Golgi trafficking to promote invasive breast cancer programs
AU - Kajiho, Hiroaki
AU - Kajiho, Yuko
AU - Frittoli, Emanuela
AU - Confalonieri, Stefano
AU - Bertalot, Giovanni
AU - Viale, Giuseppe
AU - Di Fiore, Pier Paolo
AU - Oldani, Amanda
AU - Garre, Massimiliano
AU - Beznoussenko, Galina V.
AU - Palamidessi, Andrea
AU - Vecchi, Manuela
AU - Chavrier, Philippe
AU - Perez, Frank
AU - Scita, Giorgio
PY - 2016/7/1
Y1 - 2016/7/1
N2 - 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.
AB - 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.
KW - cancer migration and invasion
KW - membrane trafficking
KW - RAB GTPases
KW - RAB2A
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U2 - 10.15252/embr.201642032
DO - 10.15252/embr.201642032
M3 - Article
C2 - 27255086
AN - SCOPUS:84977514825
VL - 17
SP - 1061
EP - 1080
JO - EMBO Reports
JF - EMBO Reports
SN - 1469-221X
IS - 7
ER -