Extracellular cyclophilin-A stimulates ERK1/2 phosphorylation in a cell-dependent manner but broadly stimulates nuclear factor kappa B

Cancer Cell International

Elan Eisenmesser⁴  James DeGregori²  Robert Sclafani²  Colin Weekes³  Fengli Zhang¹  Madalina Ciobanu³  Jasmina Redzic²  Michael Holliday²  Curtis Henry²  Karim Bahmed² 

[1] National High Magnetic Field Laboratory, Tallahassee, FL, 32310, USA;Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Denver, Aurora, CO, 80045, USA;Department of Medicine, Division of Oncology, School of Medicine, University of Colorado Denver, Aurora, CO, 80045, USA;12801 E 17th Ave, Aurora, CO, 80045, USA

关键词: Leukemia;    Pancreatic cancer;    Interleukins;    Cytokine;    MMP;    CD147;    EMMPRIN;    BSG;    PPIA;    Extracellular cyclophilin-A;   

Others  :  795029
DOI  :  10.1186/1475-2867-12-19

 received in 2012-02-21, accepted in 2012-05-25,  发布年份 2012

【 摘 要 】

Background

Although the peptidyl-prolyl isomerase, cyclophilin-A (peptidyl-prolyl isomerase, PPIA), has been studied for decades in the context of its intracellular functions, its extracellular roles as a major contributor to both inflammation and multiple cancers have more recently emerged. A wide range of activities have been ascribed to extracellular PPIA that include induction of cytokine and matrix metalloproteinase (MMP) secretion, which potentially underlie its roles in inflammation and tumorigenesis. However, there have been conflicting reports as to which particular signaling events are under extracellular PPIA regulation, which may be due to either cell-dependent responses and/or the use of commercial preparations recently shown to be highly impure.

Methods

We have produced and validated the purity of recombinant PPIA in order to subject it to a comparative analysis between different cell types. Specifically, we have used a combination of multiple methods such as luciferase reporter screens, translocation assays, phosphorylation assays, and nuclear magnetic resonance to compare extracellular PPIA activities in several different cell lines that included epithelial and monocytic cells.

Results

Our findings have revealed that extracellular PPIA activity is cell type-dependent and that PPIA signals via multiple cellular receptors beyond the single transmembrane receptor previously identified, Extracellular Matrix MetalloPRoteinase Inducer (EMMPRIN). Finally, while our studies provide important insight into the cell-specific responses, they also indicate that there are consistent responses such as nuclear factor kappa B (NFκB) signaling induced in all cell lines tested.

Conclusions

We conclude that although extracellular PPIA activates several common pathways, it also targets different receptors in different cell types, resulting in a complex, integrated signaling network that is cell type-specific.

【 授权许可】

   
2012 Bahmed et al.; licensee BioMed Central Ltd.

【 图 表 】

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