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.

RAB2A controls MT1-MMP endocytic and E-cadherin polarized Golgi trafficking to promote invasive breast cancer programs / Kajiho, H; Kajiho, Y; Frittoli, E; Confalonieri, S; Bertalot, G; Viale, G; Di Fiore, Pp; Oldani, A; Garre, M; Beznoussenko, Gv; Palamidessi, A; Vecchi, M; Chavrier, P; Perez, F; Scita, G. - In: EMBO REPORTS. - ISSN 1469-221X. - 17:7(2016), pp. 1061-1080. [10.15252/embr.201642032]

RAB2A controls MT1-MMP endocytic and E-cadherin polarized Golgi trafficking to promote invasive breast cancer programs

Bertalot G;
2016-01-01

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.
2016
7
Kajiho, H; Kajiho, Y; Frittoli, E; Confalonieri, S; Bertalot, G; Viale, G; Di Fiore, Pp; Oldani, A; Garre, M; Beznoussenko, Gv; Palamidessi, A; Vecchi, M; Chavrier, P; Perez, F; Scita, G
RAB2A controls MT1-MMP endocytic and E-cadherin polarized Golgi trafficking to promote invasive breast cancer programs / Kajiho, H; Kajiho, Y; Frittoli, E; Confalonieri, S; Bertalot, G; Viale, G; Di Fiore, Pp; Oldani, A; Garre, M; Beznoussenko, Gv; Palamidessi, A; Vecchi, M; Chavrier, P; Perez, F; Scita, G. - In: EMBO REPORTS. - ISSN 1469-221X. - 17:7(2016), pp. 1061-1080. [10.15252/embr.201642032]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11572/361802
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