Activation of tissue plasminogen activator by metastasis-inducing S100P protein

Clarke, Christopher J, Gross, Stephane R, Ismail, Thamir M ORCID: 0000-0001-5624-6593, Rudland, Philip S ORCID: 0000-0002-7491-0846, Al-Medhtiy, Morteta, Santangeli, Michael and Barraclough, Roger ORCID: 0000-0002-7203-1194
(2017) Activation of tissue plasminogen activator by metastasis-inducing S100P protein. BIOCHEMICAL JOURNAL, 474 (19). pp. 3227-3240.

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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 <i>in vitro</i> 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 <i>in vitro</i>, 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.

Item Type: Article
Uncontrolled Keywords: Cell Line, Tumor, Animals, Rats, Neoplasm Invasiveness, Neoplasm Metastasis, Cations, Divalent, Calcium, Plasminogen, Tissue Plasminogen Activator, Calcium-Binding Proteins, Neoplasm Proteins, Protease Inhibitors, Mutation
Depositing User: Symplectic Admin
Date Deposited: 18 Sep 2018 09:26
Last Modified: 19 Jan 2023 01:17
DOI: 10.1042/BCJ20170578
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