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

Hiroaki Kajiho, Yuko Kajiho, Emanuela Frittoli, Stefano Confalonieri, Giovanni Bertalot, Giuseppe Viale, Pier Paolo Di Fiore, Amanda Oldani, Massimiliano Garre, Galina V. Beznoussenko, Andrea Palamidessi, Manuela Vecchi, Philippe Chavrier, Frank Perez, Giorgio Scita

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1061-1080
Number of pages20
JournalEMBO Reports
Volume17
Issue number7
DOIs
Publication statusPublished - Jul 1 2016

Keywords

  • cancer migration and invasion
  • membrane trafficking
  • RAB GTPases
  • RAB2A

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Biochemistry

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