Activation of tissue plasminogen activator by metastasis-inducing S100P protein

Clarke, Christopher; Gross, Stephane R.; Ismail, Thamir; Rudland, Philip; Al-Medhtiy, Morteta; Santangeli, Michael and Barraclough, Roger Activation of tissue plasminogen activator by metastasis-inducing S100P protein. Biochemical Journal, 474 (19), pp. 3227-3240.


S100P protein in human breast cancer cells is associated with reduced patient survival and, in a model system of metastasis, it confers a metastatic phenotype upon benign mammary tumour cells. S100P protein possesses a C-terminal lysine residue. Using a multiwell in vitro assay, S100P is now shown for the first time to exhibit a strong, C-terminal lysine-dependent activation of tissue plasminogen activator (tPA), but not of urokinase-catalysed plasminogen activation. The presence of 10 μM calcium ions stimulates tPA activation of plasminogen 2-fold in an S100P-dependent manner. S100P physically interacts with both plasminogen and tPA in vitro, but not with urokinase. Cells constitutively expressing S100P exhibit detectable S100P protein on the cell surface, and S100P-containing cells show enhanced activation of plasminogen compared with S100P-negative control cells. S100P shows C-terminal lysine-dependent enhancement of cell invasion. An S100P antibody, when added to the culture medium, reduced the rate of invasion of wild-type S100P-expressing cells, but not of cells expressing mutant S100P proteins lacking the C-terminal lysine, suggesting that S100P functions outside the cell. The protease inhibitors, aprotinin or α-2-antiplasmin, reduced the invasion of S100P-expressing cells, but not of S100P-negative control cells, nor cells expressing S100P protein lacking the C-terminal lysine. It is proposed that activation of tPA via the C-terminal lysine of S100P contributes to the enhancement of cell invasion by S100P and thus potentially to its metastasis-promoting activity.

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Divisions: Life & Health Sciences > Biosciences
Life & Health Sciences
Life & Health Sciences > Biomedical Sciences research group
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Additional Information: This is an Accepted Manuscript, not the final Version of Record of the artcile published in the Biochemical Journal. The link to the Version of Record is Copyright: Portland Press Funding: The Cancer and Polio Research Fund, Ministry of Higher Education and Scientific Research, Kufa University
Uncontrolled Keywords: S100P,plasminogen activator,cell invasion,Biochemistry,Molecular Biology,Cell Biology


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