Cell surface protease activation during RAS transformation: critical role of the plasminogen receptor, S100A10

Patricia A. Madureira, Alamelu G. Bharadwaj, Moamen Bydoun, Katy Garant, Paul O'Connell, Patrick Lee, David M. Waisman

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Abstract

The link between oncogenic RAS expression and the acquisition of the invasive phenotype has been attributed to alterations in cellular activities that control degradation of the extracellular matrix. Oncogenic RAS-mediated upregulation of matrix metalloproteinase 2 (MMP-2), MMP-9 and urokinase-type plasminogen activator (uPA) is critical for invasion through the basement membrane and extracellular matrix. The uPA converts cell surface-bound plasminogen to plasmin, a process that is regulated by the binding of plasminogen to specific receptors on the cell surface, however, the identity of the plasminogen receptors that function in this capacity is unclear. We have observed that transformation of cancer cells with oncogenic forms of RAS increases plasmin proteolytic activity by 2- to 4-fold concomitant with a 3-fold increase in cell invasion. Plasminogen receptor profiling revealed RAS-dependent increases in both S100A10 and cytokeratin 8. Oncogenic RAS expression increased S100A10 gene expression which resulted in an increase in S100A10 protein levels. Analysis with the RAS effector-loop mutants that interact specifically with Raf, Ral GDS pathways highlighted the importance of the RalGDS pathways in the regulation of S100A10 gene expression. Depletion of S100A10 from RAS-transformed cells resulted in a loss of both cellular plasmin generation and invasiveness. These results strongly suggest that increases in cell surface levels of S100A10, by oncogenic RAS, plays a critical role in RAS-stimulated plasmin generation, and subsequently, in the invasiveness of oncogenic RAS expressing cancer cells.

Original languageEnglish
Pages (from-to)47720-47737
Number of pages18
JournalOncotarget
Volume7
Issue number30
DOIs
Publication statusPublished - 24 Jun 2016

Keywords

  • A549 Cells
  • Animals
  • Annexin A2/genetics
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic/genetics
  • Enzyme Activation
  • Fibrinolysin/genetics
  • Genes, ras
  • HCT116 Cells
  • HEK293 Cells
  • Humans
  • MCF-7 Cells
  • Mice
  • NIH 3T3 Cells
  • Peptide Hydrolases/genetics
  • S100 Proteins/genetics
  • Transfection
  • ras Proteins/biosynthesis

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