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

被引：84

作者：

Kajiho, Hiroaki ^{[1
]}

Kajiho, Yuko ^{[1
,2
]}

Frittoli, Emanuela ^{[1
]}

Confalonieri, Stefano ^{[1
]}

Bertalot, Giovanni ^{[3
]}

Viale, Giuseppe ^{[4
,5
]}

Di Fiore, Pier Paolo ^{[1
,3
,4
]}

Oldani, Amanda ^{[1
]}

Garre, Massimiliano ^{[1
]}

Beznoussenko, Galina V. ^{[1
]}

Palamidessi, Andrea ^{[1
]}

Vecchi, Manuela ^{[1
,3
]}

Chavrier, Philippe ^{[6
,7
]}

Perez, Frank ^{[6
,7
]}

Scita, Giorgio ^{[1
,3
]}

机构：

[1] IFOM, Milan, Italy

[2] Univ Tokyo, Grad Sch Med, Dept Pediat, Tokyo, Japan

[3] European Inst Oncol, Program Mol Med, Milan, Italy

[4] Univ Milan, Dept Oncol & Hematooncol, Milan, Italy

[5] European Inst Oncol, Dept Pathol, Milan, Italy

[6] PSL Res Univ, Inst Curie, Paris 05, France

[7] CNRS, Unite Mixte Rech 144, Paris 05, France

来源：

EMBO REPORTS | 2016年 / 17卷 / 07期

基金：

欧洲研究理事会;

关键词：

cancer migration and invasion; membrane trafficking; RAB2A; RAB GTPases; CELL INVASION; TUMOR DISSEMINATION; MATRIX-METALLOPROTEINASE; CAENORHABDITIS-ELEGANS; EXTRACELLULAR-MATRIX; EPITHELIAL-CELLS; INVADOPODIA; PROTEIN; METASTASIS; EXPRESSION;

D O I：

10.15252/embr.201642032

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1061 / 1080

页数：20

共 69 条

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