Activation of a PAK-MEK signalling pathway in malaria parasite-infected erythrocytes

Sicard, A.; Semblat, J. P.; Doerig, C.; Hamelin, R.; Moniatte, M.; Dorin-Semblat, D.; Spicer, J. A.; Srivastava, A.; Retzlaff, S.; Heussler, Volker; Waters, A. P.; Doerig, C. (2011). Activation of a PAK-MEK signalling pathway in malaria parasite-infected erythrocytes. Cellular microbiology, 13(6), pp. 836-845. Oxford: Blackwell 10.1111/j.1462-5822.2011.01582.x

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

08 Faculty of Science > Department of Biology > Institute of Cell Biology
08 Faculty of Science > Department of Biology > Institute of Cell Biology > Malaria

UniBE Contributor:

Heussler, Volker

Subjects:

500 Science > 570 Life sciences; biology

ISSN:

1462-5814

Publisher:

Blackwell

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:27

Last Modified:

11 May 2016 09:52

Publisher DOI:

10.1111/j.1462-5822.2011.01582.x

Web of Science ID:

000290626800006

URI:

https://boris.unibe.ch/id/eprint/10102 (FactScience: 215941)

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