MT1-MMP targeting to endolysosomes is mediated by upregulation of flotillins

J Cell Sci. 2018 Sep 5;131(17):jcs218925. doi: 10.1242/jcs.218925.

Abstract

Tumor cell invasion and metastasis formation are the major cause of death in cancer patients. These processes rely on extracellular matrix (ECM) degradation mediated by organelles termed invadopodia, to which the transmembrane matrix metalloproteinase MT1-MMP (also known as MMP14) is delivered from its reservoir, the RAB7-containing endolysosomes. How MT1-MMP is targeted to endolysosomes remains to be elucidated. Flotillin-1 and -2 are upregulated in many invasive cancers. Here, we show that flotillin upregulation triggers a general mechanism, common to carcinoma and sarcoma, which promotes RAB5-dependent MT1-MMP endocytosis and its delivery to RAB7-positive endolysosomal reservoirs. Conversely, flotillin knockdown in invasive cancer cells greatly reduces MT1-MMP accumulation in endolysosomes, its subsequent exocytosis at invadopodia, ECM degradation and cell invasion. Our results demonstrate that flotillin upregulation is necessary and sufficient to promote epithelial and mesenchymal cancer cell invasion and ECM degradation by controlling MT1-MMP endocytosis and delivery to the endolysosomal recycling compartment.

Keywords: Cancer cell invasion; Endolysosomal vesicular trafficking; Extracellular matrix degradation; Flotillin; MT1-MMP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Endocytosis
  • Endosomes / genetics
  • Endosomes / metabolism*
  • Extracellular Matrix / genetics
  • Extracellular Matrix / metabolism
  • Humans
  • Lysosomes / genetics
  • Lysosomes / metabolism*
  • Matrix Metalloproteinase 14 / genetics
  • Matrix Metalloproteinase 14 / metabolism*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Neoplasm Invasiveness
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Podosomes / genetics
  • Podosomes / metabolism
  • Protein Transport
  • Up-Regulation
  • rab GTP-Binding Proteins / genetics
  • rab GTP-Binding Proteins / metabolism
  • rab5 GTP-Binding Proteins / genetics
  • rab5 GTP-Binding Proteins / metabolism

Substances

  • Membrane Proteins
  • flotillins
  • rab7 protein
  • MMP14 protein, human
  • Matrix Metalloproteinase 14
  • RAB5C protein, human
  • rab GTP-Binding Proteins
  • rab5 GTP-Binding Proteins