A. Sicard and J.-P. Semblat contributed equally to this work.
Activation of a PAK-MEK signalling pathway in malaria parasite-infected erythrocytes
Article first published online: 4 MAR 2011
© 2011 Blackwell Publishing Ltd
Volume 13, Issue 6, pages 836–845, June 2011
How to Cite
Sicard, A., Semblat, J.-P., Doerig, C., Hamelin, R., Moniatte, M., Dorin-Semblat, D., Spicer, J. A., Srivastava, A., Retzlaff, S., Heussler, V., Waters, A. P. and Doerig, C. (2011), Activation of a PAK-MEK signalling pathway in malaria parasite-infected erythrocytes. Cellular Microbiology, 13: 836–845. doi: 10.1111/j.1462-5822.2011.01582.x
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- Issue published online: 16 MAY 2011
- Article first published online: 4 MAR 2011
- Accepted manuscript online: 8 FEB 2011 04:31AM EST
- Received 31 August, 2010; revised 18 January, 2011; accepted 20 January, 2011.
Merozoites of malaria parasites invade red blood cells (RBCs), where they multiply by schizogony, undergoing development through ring, trophozoite and schizont stages that are responsible for malaria pathogenesis. Here, we report that a protein kinase-mediated signalling pathway involving host RBC PAK1 and MEK1, which do not have orthologues in the Plasmodium kinome, is selectively stimulated in Plasmodium falciparum-infected (versus uninfected) RBCs, as determined by the use of phospho-specific antibodies directed against the activated forms of these enzymes. Pharmacological interference with host MEK and PAK function using highly specific allosteric inhibitors in their known cellular IC50 ranges results in parasite death. Furthermore, MEK inhibitors have parasiticidal effects in vitro on hepatocyte and erythrocyte stages of the rodent malaria parasite Plasmodium berghei, indicating conservation of this subversive strategy in malaria parasites. These findings have profound implications for the development of novel strategies for antimalarial chemotherapy.