Cell surface protease activation during RAS transformation: Critical role of the plasminogen receptor, S100A10
| Autor: | David M. Waisman, Moamen Bydoun, Katy A. Garant, Patrick W. K. Lee, Paul A. O'Connell, Alamelu G. Bharadwaj, Patricia A. Madureira |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Plasmin Biology Transfection Mice 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Cell Line Tumor S100 Proteins/genetics medicine Animals Humans Annexin A2/genetics Fibrinolysin Receptor plasmin Fibrinolysin/genetics Cell Transformation Neoplastic/genetics S100 Proteins HEK 293 cells S100A10 Peptide Hydrolases/genetics HCT116 Cells annexin A2 Molecular biology Enzyme Activation Cell Transformation Neoplastic Genes ras HEK293 Cells 030104 developmental biology Oncology A549 Cells 030220 oncology & carcinogenesis Cancer cell MCF-7 Cells NIH 3T3 Cells ras Proteins plasminogen Cancer research biology.protein ras Proteins/biosynthesis Plasminogen activator Annexin A2 Peptide Hydrolases Research Paper RAS medicine.drug |
| Zdroj: | Oncotarget Repositório Científico de Acesso Aberto de Portugal Repositório Científico de Acesso Aberto de Portugal (RCAAP) instacron:RCAAP Madureira, P A, Bharadwaj, A G, Bydoun, M, Garant, K, O'Connell, P, Lee, P & Waisman, D M 2016, ' Cell surface protease activation during RAS transformation : critical role of the plasminogen receptor, S100A10 ', Oncotarget, vol. 7, no. 30, pp. 47720-47737 . https://doi.org/10.18632/oncotarget.10279 |
| ISSN: | 1949-2553 |
| DOI: | 10.18632/oncotarget.10279 |
| Popis: | // Patricia A. Madureira 1 , Alamelu G. Bharadwaj 2 , Moamen Bydoun 3 , Katy Garant 3 , Paul O'Connell 2 , Patrick Lee 3 , David M. Waisman 2, 3 1 Centre for Biomedical Research (CBMR), University of Algarve, Campus of Gambelas, Faro, Portugal 2 Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, Nova Scotia, Canada 3 Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada Correspondence to: David Waisman, email: david.waisman@dal.ca Keywords: S100A10, RAS, plasminogen, plasmin, annexin A2 Received: February 22, 2016 Accepted: June 12, 2016 Published: June 24, 2016 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. |
| Databáze: | OpenAIRE |
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