Sphingosine kinase 1 is essential for proteinase-activated receptor-1 signalling in epithelial and endothelial cells.
Tools
Tools
Billich, Andreas, Urtz, Nicole, Reuschel, Roland and Baumruker, Thomas (2009) Sphingosine kinase 1 is essential for proteinase-activated receptor-1 signalling in epithelial and endothelial cells. The International Journal of Biochemistry & Cell Biology, 41 (7). pp. 1547-1555. ISSN 1878-5875
Abstract
There is accumulating evidence that activation of sphingosine kinase 1 (SPHK1) is an important element in intracellular signalling cascades initiated by stimulation of multiple receptors, including certain growth factor, cytokine, and also G-protein coupled receptors. We here report that stimulation of the lung epithelial cell line A549 by thrombin leads to transient increase of SPHK1 activity and elevation of intracellular sphingosine-1-phosphate (S1P); abrogation of this stimulation by SPHK1-specific siRNA, pharmacological inhibition, or expression of a dominant-negative SPHK1 mutant blocks the response to thrombin, as measured by secretion of MCP-1, IL-6, IL-8, and PGE(2). Using selective stimulation of proteinase-activated receptors (PARs) a specific involvement of SPHK1 in the PAR-1 induced responses in A549 cell, including activation of NFkappaB, was evident, while PAR-2 and PAR-4 responses were independent of SPHK1. Moreover, PAR-1 or thrombin-induced cytokine production and adhesion factor expression of human umbilical vein endothelial cells was also seen to depend on SPHK1. Using dermal microvascular endothelial cells from SPHK1-deficient mice, we showed that absence of the enzyme abrogates MCP-1 production induced in these cells upon treatment with thrombin or PAR-1 activating peptide. We propose SPHK1 inhibition as a novel way to block PAR-1 mediated signalling, which could be useful in treatment of a number of diseases, in particular in atherosclerosis.
| Item Type: | Article |
|---|---|
| Related URLs: | |
| Additional Information: | author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used |
| Keywords: | Proteinase-activated receptor; Sphingosine kinase; Sphingosine-1-phosphate; Thrombin |
| Related URLs: | |
| Date Deposited: | 14 Dec 2009 13:48 |
| Last Modified: | 31 Jan 2013 00:54 |
| URI: | https://oak.novartis.com/id/eprint/1440 |