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

EMBO Rep. 2016 Jul;17(7):1061-80. doi: 10.15252/embr.201642032. Epub 2016 Jun 2.


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.

Keywords: RAB GTPases; RAB2A; cancer migration and invasion; membrane trafficking.

MeSH terms

  • Biomarkers, Tumor
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology*
  • Cadherins / metabolism*
  • Cell Line, Tumor
  • Endosomes / metabolism
  • Exocytosis
  • Extracellular Matrix / metabolism
  • Female
  • Gene Expression
  • Gene Expression Profiling
  • Gene Silencing
  • Golgi Apparatus / metabolism*
  • Homeodomain Proteins / metabolism
  • Humans
  • Matrix Metalloproteinase 14 / metabolism*
  • Neoplasm Invasiveness
  • Prognosis
  • Protein Transport
  • Proteolysis
  • Recurrence
  • Tumor Suppressor Proteins / metabolism
  • rab GTP-Binding Proteins / genetics
  • rab GTP-Binding Proteins / metabolism*


  • Biomarkers, Tumor
  • Cadherins
  • HOPX protein, human
  • Homeodomain Proteins
  • Tumor Suppressor Proteins
  • MMP14 protein, human
  • Matrix Metalloproteinase 14
  • rab GTP-Binding Proteins