期刊
EMBO REPORTS
卷 17, 期 7, 页码 1061-1080出版社
WILEY
DOI: 10.15252/embr.201642032
关键词
cancer migration and invasion; membrane trafficking; RAB2A; RAB GTPases
资金
- Associazione Italiana per la Ricerca sul Cancro (AIRC) [10168]
- MIUR (the Italian Ministry of University and Scientific Research)
- Italian Ministry of Health: Worldwide Cancer Research [AICR-14-0335]
- European Research Council (Advanced ERC) [268836]
- Associazione Italiana per la Ricerca sul Cancro [AIRC IG 14404, MCO 10.000]
- Italian Ministry of Health
- Monzino Foundation
- Ligue Nationale Contre le Cancer (Equipe Labellisee)
- Institut Curie
- CNRS
- Fondation pour la Recherche Medicale [DEQ20120323723]
- Agence Nationale pour la Recherche [ANR-12-BSV2-0003-01]
- Marie Curie/AIRC TRAIN fellowship
- Agence Nationale de la Recherche (ANR) [ANR-12-BSV2-0003] Funding Source: Agence Nationale de la Recherche (ANR)
- European Research Council (ERC) [268836] Funding Source: European Research Council (ERC)
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.
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