Activation of tissue plasminogen activator by metastasis-inducing S100P protein

Christopher Clarke, Stephane R. Gross, Thamir Ismail, Philip Rudland, Morteta Al-Medhtiy, Michael Santangeli, Roger Barraclough*

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Article numberBCJ20170578
Pages (from-to)3227-3240
Number of pages14
JournalBiochemical Journal
Volume474
Issue number19
Early online date10 Aug 2017
DOIs
Publication statusPublished - 12 Sep 2017

Bibliographical note

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 http://dx.doi.org/10.1042/BCJ20170578.

Copyright: Portland Press

Funding: The Cancer and Polio Research Fund, Ministry of Higher Education and Scientific Research, Kufa University

Keywords

  • S100P
  • plasminogen activator
  • cell invasion

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    Clarke, C., Gross, S. R., Ismail, T., Rudland, P., Al-Medhtiy, M., Santangeli, M., & Barraclough, R. (2017). Activation of tissue plasminogen activator by metastasis-inducing S100P protein. Biochemical Journal, 474(19), 3227-3240. [BCJ20170578]. https://doi.org/10.1042/BCJ20170578