Cell surface protease activation during RAS transformation: Critical role of the plasminogen receptor, S100A10
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Patricia A. Madureira1, Alamelu G. Bharadwaj2, Moamen Bydoun3, Katy Garant3, Paul O'Connell2, Patrick Lee3, David M. Waisman2,3
1Centre for Biomedical Research (CBMR), University of Algarve, Campus of Gambelas, Faro, Portugal
2Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, Nova Scotia, Canada
3Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada
David Waisman, email: [email protected]
Keywords: S100A10, RAS, plasminogen, plasmin, annexin A2
Received: February 22, 2016 Accepted: June 12, 2016 Published: June 24, 2016
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.
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