Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.7 (plasmin)
 9,023 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

S100A10 is a key plasminogen receptor of the extracellular cell surface that is overexpressed in many cancer cells. Typically, S100A10 is thought to be anchored to the plasma membrane via the phospholipid-binding sites of its binding partner, annexin A2. Here, using the potent and highly sequence-specific mechanism of RNA interference (RNAi), we have stably silenced the expression of the S100A10 gene in colorectal (CCL-222) cancer cells. We show that siRNA expression mediated by the pSUPER vector causes efficient, stable, and specific down-regulation of S100A10 gene expression. The siRNA-mediated down-regulation of S100A10 gene expression resulted in a major decrease in the appearance of extracellular S100A10 protein and correlated with a 45% loss of plasminogen binding, a 65% loss in cellular plasmin generation and a complete loss in plasminogen-dependent cellular invasiveness. We also observed that the CCL-222 cells do not express annexin A2 on their extracellular surface. Thus, the data show that annexin A2 is not required by S100A10 for its association with the plasma membrane, for its colocalization with uPAR, or for its binding and activation of plasminogen.
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PMID:RNA interference-mediated silencing of the S100A10 gene attenuates plasmin generation and invasiveness of Colo 222 colorectal cancer cells. 1457 Aug 93

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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PMID:Cell surface protease activation during RAS transformation: Critical role of the plasminogen receptor, S100A10. 2735 Dec 26